Sample records for abolish elevated glucose

  1. Fever is not responsible for the elevated glucose kinetics in sepsis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lang, C.H.; Bagby, G.J.; Blakesley, H.L.

    Previous studies have suggested that alterations in the classical neuroendocrine system may not be responsible for the increased glucose metabolism observed during hypermetabolic sepsis. The purpose of the present study was to determine whether inhibition of the cyclooxygenase pathway with indomethacin, which prevents the production of arachidonic acid metabolites by this pathway and the sepsis-induced increase in body temperature, would abolish the increases in glucose appearance (Ra), recycling, and hyperlactacidemia. Sepsis was induced in chronically catheterized conscious rats by multiple injections of live Escherichia coli via a subcutaneous catheter. Septic animals received iv injections of indomethacin every 6-8 hr tomore » block the cyclooxygenase pathway. Glucose kinetics were assessed in 24-hr fasted rats using a constant iv infusion of (6-/sup 3/H)- and (U-/sup 14/C) glucose. Treatment with indomethacin prevented the 1-2/sup 0/C increase in body temperature observed in septic animals. Septic rats exhibited an elevated plasma lactate concentration and increased rates of glucose appearance and recycling. The sepsis-induced alterations in these variables were not attenuated by indomethacin. These results suggest that neither elevated body temperature nor the generation of arachidonic acid metabolites of the cyclooxygenase pathway is responsible for increasing glucose production in hypermetabolic septic rats.« less

  2. Red cell distribution width is associated with hemoglobin A1C elevation, but not glucose elevation.

    PubMed

    Bao, Xue; Wan, Min; Gu, Yeqing; Song, Yanqi; Zhang, Qing; Liu, Li; Meng, Ge; Wu, Hongmei; Xia, Yang; Shi, HongBin; Su, Qian; Fang, Liyun; Yang, Huijun; Yu, Fei; Sun, Shaomei; Wang, Xing; Zhou, Ming; Jia, Qiyu; Song, Kun; Wang, Guolin; Yu, Ming; Niu, Kaijun

    2017-10-01

    To investigate the association between red cell distribution width (RDW) and elevation of glucose/glycated hemoglobin (HbA1c). An analysis was conducted using data from a prospective cohort study of adults. People without prediabetes or diabetes (n=7,795) were followed for a mean of 2.90years (range: 1-7years, 95% confidence interval: 2.86-2.94years). Glucose elevation is defined as fasting glucose levels exceeding 5.6mmol/l, or 2-hour glucose values in the oral glucose tolerance test exceeding 7.8mmol/l. HbA1c elevation is defined as a HbA1c value exceeding a normal limit of 39mmol/mol (5.7%). Adjusted Cox proportional hazards regression models were used to assess the association between RDW quartiles and elevation of HbA1c/glucose. The multiple-adjusted hazard ratios (95% confidence interval) of HbA1c elevation for increased quartiles of RDW were 1.00 (reference), 1.08 (0.89, 1.30), 1.28 (1.07, 1.54), and 1.54 (1.29, 1.85) (P for trend<0.0001). However, no significant association was observed between RDW and blood glucose (fasting and postprandial). Elevated RDW is independently related to future HbA1c elevation, but not to glucose elevation. This suggests that RDW may associate with HbA1c through a non-glycemic way, which should be taken into consideration when using HbA1c as a diagnostic criterion of prediabetes or diabetes. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Renal hemodynamic response to galanin: importance of elevated plasma glucose.

    PubMed

    Premen, A J

    1989-12-01

    Although recent data point to a possible indirect role for galanin in modulating renal blood flow (RBF) and fluid homeostasis in experimental animals, there have been no systematic studies exploring the possible direct effects of the peptide on the mammalian kidney. We ascertained the RBF, glomerular filtration rate (GFR) and plasma glucose responses to direct intrarenal infusion of three progressively increasing doses of synthetic galanin in anesthetized dogs. A 50 ng/kg per min dose (n = 6) failed to affect RBF, GFR or arterial plasma glucose (APG). Yet, a 100 ng/kg per min dose elevated RBF and GFR by 13 and 14%, respectively, while concomitantly increasing APG by 38%. At 200 ng/kg per min, galanin elevated RBF and GFR by 32 and 33%, respectively, while elevating APG by 57%. Intrarenal infusion of glucose (12.5 mg/kg per min; n = 6), reproducing the percentage rise in glucose (62%) elicited by the highest dose of galanin, elevated RBF and GFR by 20 and 23%, respectively. These data indicate that the elevated plasma glucose level, stimulated by galanin infusion, may account for about 63 and 70% of the RBF and GFR responses, respectively, elicited by galanin infusion at the 200 ng dose. The factors mediating the remaining renal hyperemia and hyperfiltration await resolution.

  4. High serum selenium levels are associated with impaired fasting glucose and elevated fasting serum glucose in Linyi, China.

    PubMed

    Li, Zhe; Li, Xia; Ju, Wen; Wu, Guanrui; Yang, Xiaomei; Fu, Xiaofeng; Gao, Xibao

    2018-01-01

    The relationship between selenium level and impaired fasting glucose or elevated fasting serum glucose remains controversial. This study aimed to evaluate these associations in China. This observational population study adopted a cluster sampling approach to enroll participants. Baseline information on selenium categories was tested using one-way analysis of variance and Kruskal-Wallis equality-of-populations rank tests. Multivariable logistic regression was used to investigate the association between serum selenium level and impaired fasting glucose or elevated fasting serum glucose. The mean serum selenium concentration was 121.5μg/L which in a relatively high baseline Se status. Differences were observed among individuals with normal, impaired fasting glucose and elevated fasting serum glucose levels in their basic information, physical examination results and laboratory findings. After adjusting for their basic information, physical examination results and laboratory findings, compared with the low-selenium group, the high-selenium groups (124.9-143.9 and above 143.9μg/L) had ORs for elevated fasting serum glucose of 2.31 (1.37-3.90) and 2.67 (1.59-4.48), respectively (both P<0.05). A sex-difference was observed, and a significant association between selenium levels and impaired fasting glucose was observed for males but not for females. The findings of this observational study suggest that relatively high selenium levels might be positively associated with elevated fasting serum glucose and relatively high selenium levels might be positively associated with impaired fasting glucose in men. Copyright © 2017 Elsevier GmbH. All rights reserved.

  5. Antiproliferative effect of elevated glucose in human microvascular endothelial cells

    NASA Technical Reports Server (NTRS)

    Kamal, K.; Du, W.; Mills, I.; Sumpio, B. E.

    1998-01-01

    Diabetic microangiopathy has been implicated as a fundamental feature of the pathological complications of diabetes including retinopathy, neuropathy, and diabetic foot ulceration. However, previous studies devoted to examining the deleterious effects of elevated glucose on the endothelium have been performed largely in primary cultured cells of macrovessel origin. Difficulty in the harvesting and maintenance of microvascular endothelial cells in culture have hindered the study of this relevant population. Therefore, the objective of this study was to characterize the effect of elevated glucose on the proliferation and involved signaling pathways of an immortalized human dermal microvascular endothelial cell line (HMEC-1) that possess similar characteristics to their in vivo counterparts. Human dermal microvascular endothelial cells (HMEC-1) were grown in the presence of normal (5 mM) or high D-glucose (20 mM) for 14 days. The proliferative response of HMEC-1 was compared under these conditions as well as the cAMP and PKC pathways by in vitro assays. Elevated glucose significantly inhibited (P < 0.05) HMEC-1 proliferation after 7, 10, and 14 days. This effect was not mimicked by 20 mM mannitol. The antiproliferative effect was more pronounced with longer exposure (1-14 days) to elevated glucose and was irreversible 4 days after a 10-day exposure. The antiproliferative effect was partially reversed in the presence of a PKA inhibitor, Rp-cAMP (10-50 microM), and/or a PKC inhibitor, Calphostin C (10 nM). HMEC-1 exposed to elevated glucose (20 mM) for 14 days caused an increase in cyclic AMP accumulation, PKA, and PKC activity but was not associated with the activation of downstream events such as CRE and AP-1 binding activity. These data support the hypothesis that HMEC-1 is a suitable model to study the deleterious effects of elevated glucose on microvascular endothelial cells. Continued studies with HMEC-1 may prove advantageous in delineation of the molecular

  6. Rapid rehydration and moderate plasma glucose elevation by fluid containing enzymatically synthesized glycogen.

    PubMed

    Inagaki, Kei; Ishihara, Kengo; Ishida, Mariko; Watanabe, Ai; Fujiwara, Mika; Komatsu, Yuko; Shirai, Mika; Kato, Yoshiho; Takanezawa, Ami; Furuyashiki, Takashi; Takata, Hiroki; Seyama, Yousuke

    2011-01-01

    Enzymatically synthesized glycogen (ESG) has high solubility and its solution has low osmotic pressure. Therefore ESG solution could be rapidly absorbed and could be adequate for water rehydration and carbohydrate supplementation during exercise. The object of this study was to evaluate the gastric emptying time and plasma glucose elevation after an administration of ESG solution in comparison with another carbohydrate solution by using a laboratory animal. Male BALB/c mice were administered 10% w/v solution of glucose, maltodextrin, starch, naturally synthesized glycogen (NSG) and ESG at a dose of 20 µL/g body weight for the measurement of gastric emptying rate (Experiment 1) and 10 µL/g body weight for the measurement of plasma glucose elevation (Experiment 2). The osmolarity of gastric content was lower in the ESG and maltodextrin group than the other carbohydrate group. Weight of gastric fluid was significantly lower in the ESG and water group than the glucose group (p<0.01). Plasma glucose level was significantly lower in the ESG group than the glucose group from 0 to 60 min after administration (p<0.01), whereas plasma glucose level was same from 60 to 120 min for the ESG and glucose group (p=0.948). In Experiment 3, BALB/c mice ran on a treadmill for 2 h and were administered 8% of ESG or glucose solution (1.75, 3.5 or 7.0 µL/g body weight) every 20 min during running. There was no difference in post-exercise muscle glycogen level. These data suggest that 1) ESG beverage does not disturb water absorption because of its short gastric emptying time and 2) ESG slowly elevates plasma glucose level and maintains it for a prolonged time compared to the glucose solution.

  7. Jew's mellow leaves (Corchorus olitorius) suppress elevation of postprandial blood glucose levels in rats and humans.

    PubMed

    Innami, Satoshi; Ishida, Hiroshi; Nakamura, Kahoru; Kondo, Mika; Tabata, Kimiko; Koguchi, Takashi; Shimizu, Jun; Furusho, Tadasu

    2005-01-01

    The study was performed to explore the suppressive effect of Jew's mellow leaves (JML) on postprandial blood glucose levels in rats and humans. A soluble dietary fiber (SDF) was extracted from the freeze-dried JML powder. An elevation of the postprandial blood glucose level in rats given 1% or 2% JML-SDF solution orally together with 20% glucose solution was significantly suppressed as compared with that observed in the control rats given only glucose solution. When seven healthy young male adults ingested 225 mL of JML mixed juice containing 15 g of freeze-dried powder with 75 g of glucose in the fasting state in the morning, the elevation of the postprandial blood glucose level was significantly suppressed as compared with the control subjects. The diffusion rate of glucose and the permeation rate of glucose in the cultured Caco-2 cells were both significantly reduced by the addition of appropriate amounts of JML-SDF when compared to the controls. These results indicate that the effective substance in JML for suppressing blood glucose elevation is a kind of mucilaginous SDF. The mechanism by which this suppression occurs may be largely attributable to the delayed absorption of glucose from the intestinal membrane in the upper digestive tract by viscous SDF.

  8. Synthetic peptide, Ala-Arg-Glu-Gly-Glu-Met, abolishes pro-proliferative and anti-apoptotic effects of high glucose in vascular smooth muscle cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Cao, Xiaozhou; Lyu, Yi; Collaborative Innovation Centre for Modern Grain Circulation and Safety, Nanjing University of Finance and Economics, Nanjing 210023

    Apoptosis plays a critical role in normal vascular development and atherosclerosis. However, high glucose has been reported to generate a certain level of ROS that can inhibit vascular smooth muscle cell (VSMC) apoptosis, with the underlying mechanism remaining unclear. In this study, a synthetic peptide AREGEM (Ala-Arg-Glu-Gly-Glu-Met) exhibited antioxidative effects and was used to investigate its function in VSMCs during hyperglycaemia. MTT assay results demonstrated that AREGEM significantly attenuated high glucose-induced VSMCs proliferation. Flow cytometry displayed that high glucose levels inhibited cell apoptosis, whereas this effect was attenuated by pre-incubation with AREGEM. In addition, the 2′,7'-dichlorofluorescein diacetate (DCFH-DA) fluorescent probemore » assay further demonstrated that AREGEM reduced intracellular ROS accumulation in VSMCs. Furthermore, this peptide was able to prevent the decrease of caspase-3 activity and the increase of the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose. These findings demonstrated that AREGEM is able to abolish the effects of high glucose in VSMCs; therefore, this peptide can be a potential candidate to develop a novel strategy for curing diabetic related diseases. - Highlights: • A peptide, AREGEM, can reduce intracellular ROS accumulation in vascular smooth muscle cells (VSMCs). • AREGEM significantly inhibits high glucose-induced proliferation of VSMCs. • AREGEM attenuates the inhibitory effect of high glucose on VSMC Apoptosis and caspase-3 activity. • AREGEM decreases the ratio of Bcl-2/Bax protein in VSMCs exposed to high glucose.« less

  9. Radiation from wireless technology elevates blood glucose and body temperature in 40-year-old type 1 diabetic male.

    PubMed

    Kleiber, Catherine E

    2017-01-01

    A type 1 diabetic male reports multiple instances when his blood glucose was dramatically elevated by the presence of microwave radiation from wireless technology and plummeted when the radiation exposure ended. In one instance, his body temperature elevated in addition to his blood glucose. Both remained elevated for nearly 48 h after exposure with the effect gradually decreasing. Possible mechanisms for microwave radiation elevating blood glucose include effects on glucose transport proteins and ion channels, insulin conformational changes and oxidative stress. Temperature elevation may be caused by microwave radiation-triggered Ca 2+ efflux, a mechanism similar to malignant hyperthermia. The potential for radiation from wireless technology to cause serious biological effects has important implications and necessitates a reevaluation of its near-ubiquitous presence, especially in hospitals and medical facilities.

  10. Elevated glucose concentrations during an oral glucose tolerance test are associated with the presence of metabolic syndrome in childhood obesity.

    PubMed

    Sabin, M A; Hunt, L P; Ford, A L; Werther, G A; Crowne, E C; Shield, J P H

    2008-03-01

    To investigate whether changes in glucose concentrations during an OGTT in obese children reflect the presence of peripheral insulin resistance and/or cardiovascular risk factors more closely than single measurements of fasting plasma glucose (FPG). One hundred and twenty-two obese children attending our Paediatric Obesity Service underwent formal OGTTs, following the measurement of blood pressure and fasting levels of insulin, glucose and lipid profiles in the majority. Fasting insulin was used as a surrogate measure of insulin sensitivity. Three different child-specific definitions for metabolic syndrome were used to identify clustering of cardiovascular risk factors in 65 of these children. In the whole group, 10.7% had IGT but changes in glucose during the OGTT were not influenced by age, sex, pubertal status or raw (or age- and sex-adjusted) body mass index (BMI). During the OGTT, FPG, glucose at 60 min and area under the glucose curve correlated highly with fasting insulin. Children with metabolic syndrome (defined using any of three definitions) had comparable FPG levels to those without metabolic syndrome, but they demonstrated significantly elevated glucose levels at 60 min. On sub-group analysis, obese children with normal carbohydrate metabolism were significantly more likely to have a 1 h glucose level > or = 7.8 mmol/l if they had metabolic syndrome (P = 0.026). These data suggest that an elevated 1 h post-load glucose measurement is seen in obese children who have a coexistent clustering of cardiovascular risk factors.

  11. Proteins altered by elevated levels of palmitate or glucose implicated in impaired glucose-stimulated insulin secretion

    PubMed Central

    Sol, E-ri M; Hovsepyan, Meri; Bergsten, Peter

    2009-01-01

    Background Development of type 2 diabetes mellitus (T2DM) is characterized by aberrant insulin secretory patterns, where elevated insulin levels at non-stimulatory basal conditions and reduced hormonal levels at stimulatory conditions are major components. To delineate mechanisms responsible for these alterations we cultured INS-1E cells for 48 hours at 20 mM glucose in absence or presence of 0.5 mM palmitate, when stimulatory secretion of insulin was reduced or basal secretion was elevated, respectively. Results After culture, cells were protein profiled by SELDI-TOF-MS and 2D-PAGE. Differentially expressed proteins were discovered and identified by peptide mass fingerprinting. Complimentary protein profiles were obtained by the two approaches with SELDI-TOF-MS being more efficient in separating proteins in the low molecular range and 2D-PAGE in the high molecular range. Identified proteins included alpha glucosidase, calmodulin, gars, glucose-6-phosphate dehydrogenase, heterogenous nuclear ribonucleoprotein A3, lon peptidase, nicotineamide adenine dinucleotide hydrogen (NADH) dehydrogenase, phosphoglycerate kinase, proteasome p45, rab2, pyruvate kinase and t-complex protein. The observed glucose-induced differential protein expression pattern indicates enhanced glucose metabolism, defense against reactive oxygen species, enhanced protein translation, folding and degradation and decreased insulin granular formation and trafficking. Palmitate-induced changes could be related to altered exocytosis. Conclusion The identified altered proteins indicate mechanism important for altered β-cell function in T2DM. PMID:19607692

  12. Rice (Oryza sativa japonica) Albumin Suppresses the Elevation of Blood Glucose and Plasma Insulin Levels after Oral Glucose Loading.

    PubMed

    Ina, Shigenobu; Ninomiya, Kazumi; Mogi, Takashi; Hase, Ayumu; Ando, Toshiki; Matsukaze, Narumi; Ogihara, Jun; Akao, Makoto; Kumagai, Hitoshi; Kumagai, Hitomi

    2016-06-22

    The suppressive effect of rice albumin (RA) of 16 kDa on elevation of blood glucose level after oral loading of starch or glucose and its possible mechanism were examined. RA suppressed the increase in blood glucose levels in both the oral starch tolerance test and the oral glucose tolerance test. The blood glucose concentrations 15 min after the oral administration of starch were 144 ± 6 mg/dL for control group and 127 ± 4 mg/dL for RA 200 mg/kg BW group, while those after the oral administration of glucose were 157 ± 7 mg/dL for control group and 137 ± 4 mg/dL for RA 200 mg/kg BW group. However, in the intraperitoneal glucose tolerance test, no significant differences in blood glucose level were observed between RA and the control groups, indicating that RA suppresses the glucose absorption from the small intestine. However, RA did not inhibit the activity of mammalian α-amylase. RA was hydrolyzed to an indigestible high-molecular-weight peptide (HMP) of 14 kDa and low-molecular-weight peptides by pepsin and pancreatin. Furthermore, RA suppressed the glucose diffusion rate through a semipermeable membrane like dietary fibers in vitro. Therefore, the indigestible HMP may adsorb glucose and suppress its absorption from the small intestine.

  13. Redox Signal-mediated Enhancement of the Temperature Sensitivity of Transient Receptor Potential Melastatin 2 (TRPM2) Elevates Glucose-induced Insulin Secretion from Pancreatic Islets.

    PubMed

    Kashio, Makiko; Tominaga, Makoto

    2015-05-08

    Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive Ca(2+)-permeable cation channel expressed by pancreatic β cells where channel function is constantly affected by body temperature. We focused on the physiological functions of redox signal-mediated TRPM2 activity at body temperature. H2O2, an important molecule in redox signaling, reduced the temperature threshold for TRPM2 activation in pancreatic β cells of WT mice but not in TRPM2KO cells. TRPM2-mediated [Ca(2+)]i increases were likely caused by Ca(2+) influx through the plasma membrane because the responses were abolished in the absence of extracellular Ca(2+). In addition, TRPM2 activation downstream from the redox signal plus glucose stimulation enhanced glucose-induced insulin secretion. H2O2 application at 37 °C induced [Ca(2+)]i increases not only in WT but also in TRPM2KO β cells. This was likely due to the effect of H2O2 on KATP channel activity. However, the N-acetylcysteine-sensitive fraction of insulin secretion by WT islets was increased by temperature elevation, and this temperature-dependent enhancement was diminished significantly in TRPM2KO islets. These data suggest that endogenous redox signals in pancreatic β cells elevate insulin secretion via TRPM2 sensitization and activity at body temperature. The results in this study could provide new therapeutic approaches for the regulation of diabetic conditions by focusing on the physiological function of TRPM2 and redox signals. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Non-high-density lipoprotein cholesterol and other lipid indices vs elevated glucose risk in Arab adolescents.

    PubMed

    Al-Daghri, Nasser M; Aljohani, Naji J; Al-Attas, Omar S; Al-Saleh, Yousef; Wani, Kaiser; Alnaami, Abdullah M; Alfawaz, Hanan; Al-Ajlan, Abdulrahman S M; Kumar, Sudhesh; Chrousos, George P; Alokail, Majed S

    2015-01-01

    Non-high-density lipoprotein cholesterol (non-HDL-C) has been identified as a significant predictor of various cardiovascular events in adults. Limited studies have been conducted in the pediatric population with diverse results, depending on ethnic origin. None has been conducted in the Arabic adolescent population so far; this study aims to fill this gap. In this cross-sectional study, 1690 Saudi school adolescents (968 boys [mean age 14.8 ± 1.7] and 722 girls [mean age 14.6 ± 1.7]) were recruited. Anthropometrics were obtained. Fasting blood glucose and lipid profiles were quantified routinely. Non-HDL-C was calculated and screening was done for dyslipidemia using cutoffs obtained from the cohort and elevated fasting glucose. Using the 90th percentile cutoff obtained, the overall prevalence of high non-HDL-C (≥4.26 mmol/L) was 10.1%. Prevalence was slightly higher in girls (10.5%) than boys (9.9%). Non-HDL-C was similar to other lipids in terms of significant associations with anthropometric measures and glucose in both boys and girls. Elevated triglycerides was most predictive of elevated glucose in both girls (odds ratio 2.41; confidence interval 1.43-4.08; P = .001) and boys (odds ratio 2.61; confidence interval 1.70-4.0); P < .001). Non-HDL-C appears to be gender-specific and is cardiometabolically more associated with Saudi boys, despite higher levels in girls. It is inferior compared with triglycerides in assessing elevated glucose risk. Further investigations may provide a more definite value for non-HDL-C use as a biomarker in assessing cardiometabolic risk in the Arab adolescent population. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.

  15. Patient, Provider, and System Factors Associated With Failure to Follow-Up Elevated Glucose Results in Patients Without Diagnosed Diabetes.

    PubMed

    Bowen, Michael E; Merchant, Zahra; Abdullah, Kazeen; Bhat, Deepa; Fish, Jason; Halm, Ethan A

    2017-01-01

    Although elevated glucose values are strongly associated with undiagnosed diabetes, they are frequently overlooked. Patient, provider, and system factors associated with failure to follow-up elevated glucose values in electronic medical records (EMRs) are not well described. We conducted a chart review in a comprehensive EMR with a patient portal and results management features. Established primary care patients with no known diagnosis of diabetes and ≥ 1 glucose value >125 mg/dL were included. Follow-up failure was defined as (1) no documented comment on the glucose value or result communication to the patient within 30 days or (2) no hemoglobin A 1c (HbA 1c ) ordered within 30 days or resulted within 12 months. Associations were examined using Wilcoxon and χ 2 tests. Of 150 charts reviewed, 97 met inclusion criteria. The median glucose was 133 mg/dL, and 20% of patients had multiple values >125 mg/dL. Only 36% of elevated glucose values were followed up. No associations were observed between patient characteristics, diabetes risk factors, or provider characteristics and follow-up failures. Automated flagging of glucose values ≥140 mg/dL by highlighting them red in the EMR was not associated with improved follow-up (46% vs 32%; P = .19). Even when follow-up occurred (n = 35), only 31% completed gold standard diabetes testing (HbA 1c ) within 12 months. Of the resulted HbA 1c tests (n = 11), 55% were in the prediabetes range (5.7%-6.4%). Two-thirds of elevated glucose values were not followed up, despite EMR features facilitating results management. Greater understanding of the results management process and improved EMR functionalities to support results management are needed.

  16. Elevated glucose levels in early puerperium, and association with high cortisol levels during parturition.

    PubMed

    Risberg, Anitha; Sjöquist, Mats; Wedenberg, Kaj; Larsson, Anders

    2016-07-01

    Background Gestational diabetes is one of the commonest metabolic problems associated with pregnancy and an accurate diagnosis is critical for the care. Research has shown that pregnant women have high levels of cortisol during the last stage of parturition. As cortisol is a diabetogenic hormone causing increased glucose levels, we wanted to study the association between cortisol and glucose levels during parturition. Materials and methods Glucose and cortisol were analyzed during parturition in 50 females divided according to slow (n = 11) and normal labors (n = 39). Blood samples were analyzed three times during the parturition and four times in the first day after delivery. Glucose levels were also measured once in each trimester. Results In the normal group, the glucose concentration increased from 6.2 (IQR 5.6-8.0) mmol/L in the latency phase to 11.6 (10.0-13.3) mmol/L at aftercare (p < 0.05). After parturition the glucose concentrations decreased gradually. There were significant Spearman rank correlations between glucose and cortisol values. Conclusions The changes associated with birth cause significant elevations of cortisol and glucose around parturition.

  17. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

    NASA Astrophysics Data System (ADS)

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A.; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-06-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation.

  18. Restoring Mitochondrial Function: A Small Molecule-mediated Approach to Enhance Glucose Stimulated Insulin Secretion in Cholesterol Accumulated Pancreatic beta cells

    PubMed Central

    Asalla, Suman; Girada, Shravan Babu; Kuna, Ramya S.; Chowdhury, Debabrata; Kandagatla, Bhaskar; Oruganti, Srinivas; Bhadra, Utpal; Bhadra, Manika Pal; Kalivendi, Shasi Vardhan; Rao, Swetha Pavani; Row, Anupama; Ibrahim, A; Ghosh, Partha Pratim; Mitra, Prasenjit

    2016-01-01

    Dyslipidemia, particularly the elevated serum cholesterol levels, aggravate the pathophysiology of type 2 diabetes. In the present study we explored the relationship between fasting blood sugar and serum lipid parameters in human volunteers which revealed a significant linear effect of serum cholesterol on fasting blood glucose. Short term feeding of cholesterol enriched diet to rodent model resulted in elevated serum cholesterol levels, cholesterol accumulation in pancreatic islets and hyperinsulinemia with modest increase in plasma glucose level. To explore the mechanism, we treated cultured BRIN-BD11 pancreatic beta cells with soluble cholesterol. Our data shows that cholesterol treatment of cultured pancreatic beta cells enhances total cellular cholesterol. While one hour cholesterol exposure enhances insulin exocytosis, overnight cholesterol accumulation in cultured pancreatic beta cells affects cellular respiration, and inhibits Glucose stimulated insulin secretion. We further report that (E)-4-Chloro-2-(1-(2-(2,4,6-trichlorophenyl) hydrazono) ethyl) phenol (small molecule M1) prevents the cholesterol mediated blunting of cellular respiration and potentiates Glucose stimulated insulin secretion which was abolished in pancreatic beta cells on cholesterol accumulation. PMID:27282931

  19. Glycolysis Controls Plasma Membrane Glucose Sensors To Promote Glucose Signaling in Yeasts

    PubMed Central

    Cairey-Remonnay, Amélie; Deffaud, Julien; Wésolowski-Louvel, Micheline; Lemaire, Marc

    2014-01-01

    Sensing of extracellular glucose is necessary for cells to adapt to glucose variation in their environment. In the respiratory yeast Kluyveromyces lactis, extracellular glucose controls the expression of major glucose permease gene RAG1 through a cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 glucose signaling pathway. This regulation depends also on intracellular glucose metabolism since we previously showed that glucose induction of the RAG1 gene is abolished in glycolytic mutants. Here we show that glycolysis regulates RAG1 expression through the K. lactis Rgt1 (KlRgt1) glucose signaling pathway by targeting the localization and probably the stability of Rag4, the single Snf3/Rgt2-type glucose sensor of K. lactis. Additionally, the control exerted by glycolysis on glucose signaling seems to be conserved in S. cerevisiae. This retrocontrol might prevent yeasts from unnecessary glucose transport and intracellular glucose accumulation. PMID:25512610

  20. Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat.

    PubMed

    Pawlosky, Robert J; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L

    2010-02-01

    Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Rats were infused with solutions of sodium acetate, ethanol, or saline containing (13)C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs' cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of (13)C-glucose into the brain compared to controls and the concentration of brain (13)C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg(2+) in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, alpha-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD(+)]/[NADH] was lower, the free mitochondrial [NAD(+)]/[NADH] and [CoQ]/[CoQH(2)] were oxidized and the DeltaG' of ATP lowered by acetate infusion from -61.4 kJ to -59.9 kJ/mol. Animals with elevated levels of blood ethanol or acetate had decreased (13)C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in (13)C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in DeltaG' of ATP was similar to administration of uncoupling agents indicating that the

  1. Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

    PubMed Central

    Pawlosky, Robert J.; Kashiwaya, Yoshihiro; Srivastava, Shireesh; King, Michael T.; Crutchfield, Calvin; Volkow, Nora; Kunos, George; Li, Ting-Kai; Veech, Richard L.

    2010-01-01

    Background Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Methods Rats were infused with solutions of sodium acetate, ethanol, or saline containing 13C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl-coenzyme A (CoA) compounds, and amino acids. Results Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of 13C-glucose into the brain compared to controls and the concentration of brain 13C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg2+ in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, α-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD+]/[NADH] was lower, the free mitochondrial [NAD+]/[NADH] and [CoQ]/[CoQH2] were oxidized and the ΔG′ of ATP lowered by acetate infusion from −61.4 kJ to −59.9 kJ/mol. Conclusions Animals with elevated levels of blood ethanol or acetate had decreased 13C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in 13C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents

  2. Effect of diabetes and elevated glucose on nitric oxide-mediated neurotransmission in rat anococcygeus muscle.

    PubMed Central

    Way, K. J.; Reid, J. J.

    1995-01-01

    1. Nitric oxide (NO)-mediated neurotransmission is impaired in anococcygeus muscle from 8-week streptozotocin-induced diabetic rats. This study investigated the effects of insulin treatment, and the duration of diabetes on this impairment. In addition, the effect of in vitro exposure to elevated glucose has been investigated on NO-mediated relaxations, in muscles from untreated rats. 2. Relaxant responses to field stimulation (0.5-5 Hz, 10s train), sodium nitroprusside (SNP; 5 and 10 nM) and NO (1 and 3 microM) were significantly impaired in anococcygeus muscles from 8-week diabetic rats, compared to responses from control rats. Insulin treatment (5 u Lente day-1, s.c.) of diabetic rats prevented the development of this impairment. 3. Consistent with findings in 8-week diabetic rats, relaxation induced by field stimulation, SNP and NO were attenuated in tissues from 2-week and 4-week diabetic rats compared to corresponding control responses, whereas relaxations to papaverine (3 and 10 microM) were not reduced. In contrast, diabetes of 3-days duration did not affect relaxations to field stimulation, SNP or NO. 4. Incubation of anococcygeus muscles from untreated rats in medium containing elevated glucose (44.1 mM) for 6 h, significantly impaired relaxations to field stimulation compared to responses obtained after normal glucose (11.1 mM) incubation. Relaxations to SNP and to NO were not affected by 6 h exposure to elevated glucose. Similarly, incubation in hyperosmolar solutions containing mannose or sucrose for 6 h, impaired relaxations to field stimulation, but not to SNP or NO.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582450

  3. Protection of vascular endothelial cells from high glucose-induced cytotoxicity by emodin.

    PubMed

    Gao, Yun; Zhang, Jun; Li, Guilin; Xu, Hong; Yi, Yun; Wu, Qin; Song, Miaomiao; Bee, Yong Mong; Huang, Liping; Tan, Mengxia; Liang, Shangdong; Li, GuoDong

    2015-03-01

    Induction of endothelial cytotoxicity by hyperglycemia in diabetes has been widely accepted. Emodin is a natural anthraquinone in rhubarb used for treatment of diabetes, but its mechanism of action is not fully understood. This study aimed to examine the potential beneficial effects of emodin on endothelial cytotoxicity caused by high glucose milieu. Culture of human umbilical vein endothelial cells (HUVECs) with high concentrations of glucose resulted in damage to the cells, leading to decreased formazan products by 14-27%, reduced DNA contents by 12-19%, and increased hypodiploid apoptosis by 40-109%. These adverse effects of high glucose could be prevented to a large extent by co-culture with 3 μM of emodin which per se did not affect HUVECs viability. In addition, CCL5 expression of HUVECs cultured in high glucose medium was significantly elevated at both mRNA and protein levels, an effect abolished after treatment with emodin. Moreover, the enhanced adhesion of monocytes to HUVECs (2.1-2.2 fold over control) and elevated chemotaxis activities (2.3-2.4 fold over control) in HUVECs cultured in high glucose medium were completely reversed by emodin. Emodin also suppressed activation of p38 MAPK and ERK1/2 due to high glucose. Our data demonstrated that endothelial cytotoxicity occurred clearly when HUVECs were exposed to high glucose milieu and emodin was able to alleviate the impairments. The protective effects of emodin might be related to the inhibition of CCL5 expression and subsequent cell stress/inflammatory events possibly mediated by activation of MAPK signaling pathways. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

    PubMed

    Jacobson, Peer B; von Geldern, Thomas W; Ohman, Lars; Osterland, Marie; Wang, Jiahong; Zinker, Bradley; Wilcox, Denise; Nguyen, Phong T; Mika, Amanda; Fung, Steven; Fey, Thomas; Goos-Nilsson, Annika; Grynfarb, Marlena; Barkhem, Tomas; Marsh, Kennan; Beno, David W A; Nga-Nguyen, Bach; Kym, Philip R; Link, James T; Tu, Noah; Edgerton, Dale S; Cherrington, Alan; Efendic, Suad; Lane, Benjamin C; Opgenorth, Terry J

    2005-07-01

    Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.

  5. Single Cell "Glucose Nanosensor" Verifies Elevated Glucose Levels in Individual Cancer Cells.

    PubMed

    Nascimento, Raphael A S; Özel, Rıfat Emrah; Mak, Wai Han; Mulato, Marcelo; Singaram, Bakthan; Pourmand, Nader

    2016-02-10

    Because the transition from oxidative phosphorylation to anaerobic glycolytic metabolism is a hallmark of cancer progression, approaches to identify single living cancer cells by their unique glucose metabolic signature would be useful. Here, we present nanopipettes specifically developed to measure glucose levels in single cells with temporal and spatial resolution, and we use this technology to verify the hypothesis that individual cancer cells can indeed display higher intracellular glucose levels. The nanopipettes were functionalized as glucose nanosensors by immobilizing glucose oxidase (GOx) covalently to the tip so that the interaction of glucose with GOx resulted in a catalytic oxidation of β-d-glucose to d-gluconic acid, which was measured as a change in impedance due to drop in pH of the medium at the nanopipette tip. Calibration studies showed a direct relationship between impedance changes at the tip and glucose concentration in solution. The glucose nanosensor quantified single cell intracellular glucose levels in human fibroblasts and the metastatic breast cancer lines MDA-MB-231 and MCF7 and revealed that the cancer cells expressed reproducible and reliable increases in glucose levels compared to the nonmalignant cells. Nanopipettes allow repeated sampling of the same cell, as cells remain viable during and after measurements. Therefore, nanopipette-based glucose sensors provide an approach to compare changes in glucose levels with changes in proliferative or metastatic state. The platform has great promise for mechanistic investigations, as a diagnostic tool to distinguish cancer cells from nonmalignant cells in heterogeneous tissue biopsies, as well as a tool for monitoring cancer progression in situ.

  6. Thioredoxin-interacting protein (Txnip) is a critical regulator of hepatic glucose production.

    PubMed

    Chutkow, William A; Patwari, Parth; Yoshioka, Jun; Lee, Richard T

    2008-01-25

    Thioredoxin-interacting protein (Txnip) has been recently described as a possible link between cellular redox state and metabolism; Txnip binds thioredoxin and inhibits its disulfide reductase activity in vitro, while a naturally occurring strain of Txnip-deficient mice has hyperlipidemia, hypoglycemia, and ketosis exacerbated by fasting. We generated Txnip-null mice to investigate the role of Txnip in glucose homeostasis. Txnip-null mice were hypoglycemic, hypoinsulinemic, and had blunted glucose production following a glucagon challenge, consistent with a central liver glucose-handling defect. Glucose release from isolated Txnip-null hepatocytes was 2-fold lower than wild-type hepatocytes, whereas beta-hydroxybutyrate release was increased 2-fold, supporting an intrinsic defect in hepatocyte glucose metabolism. While hepatocyte-specific gene deletion of Txnip did not alter glucose clearance compared with littermate controls, Txnip expression in the liver was required for maintaining normal fasting glycemia and glucose production. In addition, hepatic overexpression of a Txnip transgene in wild-type mice resulted in elevated serum glucose levels and decreased ketone levels. Liver homogenates from Txnip-null mice had no significant differences in the glutathione oxidation state or in the amount of available thioredoxin. However, overexpression of wild-type Txnip in Txnip-null hepatocytes rescued cellular glucose production, whereas overexpression of a C247S mutant Txnip, which does not bind thioredoxin, had no effect. These data demonstrate that Txnip is required for normal glucose homeostasis in the liver. While available thioredoxin is not changed in Txnip-null mice, the effects of Txnip on glucose homeostasis are abolished by a single cysteine mutation that inhibits binding to thioredoxin.

  7. Differences in Body Fat Distribution Play a Role in the Lower Levels of Elevated Fasting Glucose amongst Ghanaian Migrant Women Compared to Men.

    PubMed

    Nicolaou, Mary; Kunst, Anton E; Busschers, Wim B; van Valkengoed, Irene G; Dijkshoorn, Henriette; Boateng, Linda; Brewster, Lizzy M; Snijder, Marieke B; Stronks, Karien; Agyemang, Charles

    2013-01-01

    Despite higher levels of obesity, West African migrant women appear to have lower rates of type 2 diabetes than their male counterparts. We investigated the role of body fat distribution in these differences. Cross-sectional study of Ghanaian migrants (97 men, 115 women) aged 18-60 years in Amsterdam, the Netherlands. Weight, height, waist and hip circumferences were measured. Logistic regression was used to explore the association of BMI, waist and hip measurements with elevated fasting glucose (glucose≥5.6 mmol/L). Linear regression was used to study the association of the same parameters with fasting glucose. Mean BMI, waist and hip circumferences were higher in women than men while the prevalence of elevated fasting glucose was higher in men than in women, 33% versus 19%. With adjustment for age only, men were non-significantly more likely than women to have an elevated fasting glucose, odds ratio (OR) 1.81, 95% CI: 0.95, 3.46. With correction for BMI, the higher odds among men increased and were statistically significant (OR 2.84, 95% CI: 1.32, 6.10), but with consideration of body fat distribution (by adding both hip and waist in the analysis) differences were no longer significant (OR 1.56 95% CI: 0.66, 3.68). Analysis with fasting glucose as continuous outcome measure showed somewhat similar results. Compared to men, the lower rates of elevated fasting glucose observed among Ghanaian women may be partly due to a more favorable body fat distribution, characterized by both hip and waist measurements.

  8. Exposure to low levels of hydrogen sulfide elevates circulating glucose in maternal rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hayden, L.J.; Goeden, H.; Roth, S.H.

    1990-09-01

    Although the lethal effect of hydrogen sulfide (H{sub 2}S) has long been known, the results of exposure to low levels of H{sub 2}S have not been well documented. Rat dams and pups were exposed to low levels of H{sub 2}S (less than or equal to 75 ppm) from d 1 of gestation until d 21 postpartum and analyzed for changes in circulating enzymatic activity and metabolites. Blood glucose was significantly elevated in maternal blood on d 21 postpartum at all exposure levels. This increase in glucose was accompanied by a possible decrease in serum triglyceride in the pups and inmore » the dams on d 21 postpartum. There was no evidence of alterations in serum alkaline phosphatase, lactate dehydrogenase, or serum glutamate oxaloacetate transaminase.« less

  9. Euglycemic Diabetic Ketoacidosis with Elevated Acetone in a Patient Taking a Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor.

    PubMed

    Andrews, Tory J; Cox, Robert D; Parker, Christina; Kolb, James

    2017-02-01

    Sodium-glucose cotransporter-2 (SGLT2) inhibitor medications are a class of antihyperglycemic agents that increase urinary glucose excretion by interfering with the reabsorption of glucose in the proximal renal tubules. In May of 2015, the U.S. Food and Drug Administration released a warning concerning a potential increased risk of ketoacidosis and ketosis in patients taking these medications. We present a case of a 57-year-old woman with type 2 diabetes mellitus taking a combination of canagliflozin and metformin who presented with progressive altered mental status over the previous 2 days. Her work-up demonstrated a metabolic acidosis with an anion gap of 38 and a venous serum pH of 7.08. The serum glucose was 168 mg/dL. The urinalysis showed glucose > 500 mg/dL and ketones of 80 mg/dL. Further evaluation demonstrated an elevated serum osmolality of 319 mOsm/kg and an acetone concentration of 93 mg/dL. She was treated with intravenous insulin and fluids, and the metabolic abnormalities and her altered mental status resolved within 36 h. This was the first episode of diabetic ketoacidosis (DKA) for this patient. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Diabetic patients on SGLT2 inhibitor medications are at risk for ketoacidosis. Due to the renal glucose-wasting properties of these drugs, they may present with ketoacidosis with only mild elevations in serum glucose, potentially complicating the diagnosis. Acetone is one of the three main ketone bodies formed during DKA and it may be present at considerable concentrations, contributing to the serum osmolality. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Impact of admission blood glucose levels on prognosis of elderly patients with ST elevation myocardial infarction treated by primary percutaneous coronary intervention

    PubMed Central

    Ekmekci, Ahmet; Uluganyan, Mahmut; Tufan, Fatif; Uyarel, Huseyin; Karaca, Gurkan; Kul, Seref; Gungor, Barış; Ertas, Gokhan; Erer, Betul; Sayar, Nurten; Gul, Mehmet; Eren, Mehmet

    2013-01-01

    Objective Admission hyperglycemia in acute myocardial infarction (MI) is related with increased in-hospital and long term mortality and major cardiac adverse events. We aimed to investigate how admission hyperglycemia affects the short and long term outcomes in elderly patients (> 65 years) after primary percutaneous coronary intervention for ST elevation myocardial infarction. Methods We retrospectively analyzed 677 consecutive elderly patients (mean age 72.2 ± 5.4). Patients were divided into two groups according to admission blood glucose levels. Group 1: low glucose group (LLG), glucose < 168 mg/dL; and Group 2: high glucose group (HGG), glucose > 168 mg/dL. Results In-hospital, long term mortality and in-hospital major adverse cardiac events were higher in the high admission blood glucose group (P < 0.001). Multivariate regression analysis showed: Killip > 1, post-thrombolysis in MI < 3 and admission blood glucose levels were independent predictors of in-hospital adverse cardiac events (P < 0.001). Conclusions Admission hyperglycemia in elderly patients presented with ST elevation myocardial infarction is an independent predictor of in-hospital major adverse cardiac events and is associated with in-hospital and long term mortality. PMID:24454322

  11. Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD.

    PubMed

    Hannukainen, J C; Lautamäki, R; Mari, A; Pärkkä, J P; Bucci, M; Guzzardi, M A; Kajander, S; Tuokkola, T; Knuuti, J; Iozzo, P

    2016-07-01

    Insulin resistance, β-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in β-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia.

  12. Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD

    PubMed Central

    Hannukainen, J. C.; Lautamäki, R.; Mari, A.; Pärkkä, J. P.; Bucci, M.; Guzzardi, M. A.; Kajander, S.; Tuokkola, T.; Knuuti, J.

    2016-01-01

    Background: Insulin resistance, β-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. Methods and Results: We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in β-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. Conclusions: In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia. PMID:27045985

  13. Genistein improves spatial learning and memory in male rats with elevated glucose level during memory consolidation.

    PubMed

    Kohara, Yumi; Kawaguchi, Shinichiro; Kuwahara, Rika; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

    2015-03-01

    Cognitive dysfunction due to higher blood glucose level has been reported previously. Genistein (GEN) is a phytoestrogen that we hypothesized might lead to improved memory, despite elevated blood glucose levels at the time of memory consolidation. To investigate this hypothesis, we compared the effects of orally administered GEN on the central nervous system in normal versus glucose-loaded adult male rats. A battery of behavioral assessments was carried out. In the MAZE test, which measured spatial learning and memory, the time of normal rats was shortened by GEN treatment compared to the vehicle group, but only in the early stages of testing. In the glucose-loaded group, GEN treatment improved performance as mazes were advanced. In the open-field test, GEN treatment delayed habituation to the new environment in normal rats, and increased the exploratory behaviors of glucose-loaded rats. There were no significant differences observed for emotionality or fear-motivated learning and memory. Together, these results indicate that GEN treatment improved spatial learning and memory only in the early stages of testing in the normal state, but improved spatial learning and memory when glucose levels increased during memory consolidation. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Elevated HbA1c and Fasting Plasma Glucose in Predicting Diabetes Incidence Among Older Adults

    PubMed Central

    Lipska, Kasia J.; Inzucchi, Silvio E.; Van Ness, Peter H.; Gill, Thomas M.; Kanaya, Alka; Strotmeyer, Elsa S.; Koster, Annemarie; Johnson, Karen C.; Goodpaster, Bret H.; Harris, Tamara; De Rekeneire, Nathalie

    2013-01-01

    OBJECTIVE To determine which measures—impaired fasting glucose (IFG), elevated HbA1c, or both—best predict incident diabetes in older adults. RESEARCH DESIGN AND METHODS From the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100–125 mg/dL) and elevated HbA1c (5.7–6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA1c ≥6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA1c. RESULTS Among 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4–8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8–16.4) in those with elevated HbA1c (versus those with HbA1c <5.7%). When FPG and HbA1c were considered together, odds ratios were 3.5 (1.9–6.3) in those with IFG only, 8.0 (4.8–13.2) in those with elevated HbA1c only, and 26.2 (16.3–42.1) in those with both IFG and elevated HbA1c (versus those with normal FPG and HbA1c). Addition of elevated HbA1c to the model with IFG resulted in improved discrimination and calibration. CONCLUSIONS Older adults with both IFG and elevated HbA1c have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA1c may identify older adults at very high risk for diabetes. PMID:24135387

  15. The Role of SGLT1 and GLUT2 in Intestinal Glucose Transport and Sensing

    PubMed Central

    Röder, Pia V.; Geillinger, Kerstin E.; Zietek, Tamara S.; Thorens, Bernard; Koepsell, Hermann; Daniel, Hannelore

    2014-01-01

    Intestinal glucose absorption is mediated by SGLT1 whereas GLUT2 is considered to provide basolateral exit. Recently, it was proposed that GLUT2 can be recruited into the apical membrane after a high luminal glucose bolus allowing bulk absorption of glucose by facilitated diffusion. Moreover, SGLT1 and GLUT2 are suggested to play an important role in intestinal glucose sensing and incretin secretion. In mice that lack either SGLT1 or GLUT2 we re-assessed the role of these transporters in intestinal glucose uptake after radiotracer glucose gavage and performed Western blot analysis for transporter abundance in apical membrane fractions in a comparative approach. Moreover, we examined the contribution of these transporters to glucose-induced changes in plasma GIP, GLP-1 and insulin levels. In mice lacking SGLT1, tissue retention of tracer glucose was drastically reduced throughout the entire small intestine whereas GLUT2-deficient animals exhibited higher tracer contents in tissue samples than wild type animals. Deletion of SGLT1 resulted also in reduced blood glucose elevations and abolished GIP and GLP-1 secretion in response to glucose. In mice lacking GLUT2, glucose-induced insulin but not incretin secretion was impaired. Western blot analysis revealed unchanged protein levels of SGLT1 after glucose gavage. GLUT2 detected in apical membrane fractions mainly resulted from contamination with basolateral membranes but did not change in density after glucose administration. SGLT1 is unequivocally the prime intestinal glucose transporter even at high luminal glucose concentrations. Moreover, SGLT1 mediates glucose-induced incretin secretion. Our studies do not provide evidence for GLUT2 playing any role in either apical glucose influx or incretin secretion. PMID:24587162

  16. Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3β inhibition

    PubMed Central

    Chen, Yu; Zhou, Jun; Xie, Na; Huang, Chao; Zhang, Jun-qi; Hu, Zhuang-li; Ni, Lan; Jin, You; Wang, Fang; Chen, Jian-guo; Long, Li-hong

    2012-01-01

    Aim: To identify the mechanisms underlying the elevation of intracellular Ca2+ level ([Ca2+]i) induced by lowering extracellular glucose in rat hypothalamic arcuate nucleus NPY neurons. Methods: Primary cultures of hypothalamic arcuate nucleus (ARC) neurons were prepared from Sprague-Dawley rats. NPY neurons were identified with immunocytochemical method. [Ca2+]i was measured using fura-2 AM. Ca2+ current was recorded using whole-cell patch clamp recording. AMPK and GSK3β levels were measured using Western blot assay. Results: Lowering glucose level in the medium (from 10 to 1 mmol/L) induced a transient elevation of [Ca2+]i in ARC neurons, but not in hippocampal and cortical neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons depended on extracellular Ca2+, and was blocked by P/Q-type Ca2+channel blocker ω-agatoxin TK (100 nmol/L), but not by L-type Ca2+ channel blocker nifedipine (10 μmol/L) or N-type Ca2+channel blocker ω-conotoxin GVIA (300 nmol/L). Lowering glucose level increased the peak amplitude of high voltage-activated Ca2+ current in ARC neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons was blocked by the AMPK inhibitor compound C (20 μmol/L), and enhanced by the GSK3β inhibitor LiCl (10 mmol/L). Moreover, lowering glucose level induced the phosphorylation of AMPK and GSK3β, which was inhibited by compound C (20 μmol/L). Conclusion: Lowering glucose level enhances the activity of P/Q type Ca2+channels and elevates [Ca2+]i level in hypothalamic arcuate nucleus neurons via inhibition of GSK3β. PMID:22504905

  17. Elevated extracellular glucose and uncontrolled type 1 diabetes enhance NFAT5 signaling and disrupt the transverse tubular network in mouse skeletal muscle

    PubMed Central

    Hernández-Ochoa, Erick O; Robison, Patrick; Contreras, Minerva; Shen, Tiansheng; Zhao, Zhiyong; Schneider, Martin F

    2012-01-01

    The transcription factor nuclear factor of activated T-cells 5 (NFAT5) is a key protector from hypertonic stress in the kidney, but its role in skeletal muscle is unexamined. Here, we evaluate the effects of glucose hypertonicity and hyperglycemia on endogenous NFAT5 activity, transverse tubular system morphology and Ca2+ signaling in adult murine skeletal muscle fibers. We found that exposure to elevated glucose (25–50 mmol/L) increased NFAT5 expression and nuclear translocation, and NFAT-driven transcriptional activity. These effects were insensitive to the inhibition of calcineurin A, but sensitive to both p38a mitogen-activated protein kinases and phosphoinositide 3-kinase-related kinase inhibition. Fibers exposed to elevated glucose exhibited disrupted transverse tubular morphology, characterized by swollen transverse tubules and an increase in longitudinal connections between adjacent transverse tubules. Ca2+ transients elicited by a single, brief electric field stimuli were increased in amplitude in fibers challenged by elevated glucose. Muscle fibers from type 1 diabetic mice exhibited increased NFAT5 expression and transverse tubule disruptions, but no differences in electrically evoked Ca2+ transients. Our results suggest the hypothesis that these changes in skeletal muscle could play a role in the pathophysiology of acute and severe hyperglycemic episodes commonly observed in uncontrolled diabetes. PMID:22966145

  18. Elevation of blood β-hydroxybutyrate concentration affects glucose metabolism in dairy cows before and after parturition.

    PubMed

    Zarrin, M; Grossen-Rösti, L; Bruckmaier, R M; Gross, J J

    2017-03-01

    Recent studies in mid- and late-lactation dairy cows showed that β-hydroxybutyrate (BHB) infusion had a considerable effect on glucose metabolism and immune response during intramammary lipopolysaccharide challenge. The objective of the present study was to infuse BHB during the dry period and after parturition to investigate the effects of elevated plasma BHB concentrations on metabolism and endocrine changes in transition dairy cows. The hypothesis tested was that regulation of glucose metabolism would change at different physiological stages and an additional elevation of BHB concentration would alter glucose concentration. Multiparous Holstein cows in wk -2 (antepartum, a.p.; n = 6) and wk +2 (postpartum, p.p.; n = 8) relative to calving were infused (4 h from 0800 to 1200 h) with a BHB solution to increase plasma BHB concentration to 1.5 to 2.0 mmol/L (HyperB). The same period the next day without any infusion was considered the control period (CON). Blood samples were taken 1 h before the start of infusion as reference samples and every 30 min during the following 6 h (4 h of infusion and 2 h after infusion) in the HyperB and CON periods, and analyzed for glucose, BHB, insulin, and glucagon concentrations. During the steady state period (the latter 2 h of the 4-h infusion), plasma BHB concentration reached 1.87 ± 0.05 mmol/L (a.p.) and 1.93 ± 0.05 mmol/L (p.p.) in HyperB compared with 0.55 ± 0.06 mmol/L (a.p.) and 0.64 ± 0.04 mmol/L (p.p.) in CON, respectively. The 4-h average BHB infusion rate was 12.4 ± 1.0 and 13.3 ± 0.9 μmol/kg of BW per minute in wk -2 and +2, respectively. Infusion of BHB caused a decrease of plasma glucose concentrations relative to preinfusion levels both before and after parturition, although basal glucose concentrations were different before and after calving. Infusion of BHB increased plasma insulin concentrations a.p. but not p.p., despite a higher basal insulin concentration before than after parturition. These findings

  19. Effect of high altitude on blood glucose meter performance.

    PubMed

    Fink, Kenneth S; Christensen, Dale B; Ellsworth, Allan

    2002-01-01

    Participation in high-altitude wilderness activities may expose persons to extreme environmental conditions, and for those with diabetes mellitus, euglycemia is important to ensure safe travel. We conducted a field assessment of the precision and accuracy of seven commonly used blood glucose meters while mountaineering on Mount Rainier, located in Washington State (elevation 14,410 ft). At various elevations each climber-subject used the randomly assigned device to measure the glucose level of capillary blood and three different concentrations of standardized control solutions, and a venous sample was also collected for later glucose analysis. Ordinary least squares regression was used to assess the effect of elevation and of other environmental potential covariates on the precision and accuracy of blood glucose meters. Elevation affects glucometer precision (p = 0.08), but becomes less significant (p = 0.21) when adjusted for temperature and relative humidity. The overall effect of elevation was to underestimate glucose levels by approximately 1-2% (unadjusted) for each 1,000 ft gain in elevation. Blood glucose meter accuracy was affected by elevation (p = 0.03), temperature (p < 0.01), and relative humidity (p = 0.04) after adjustment for the other variables. The interaction between elevation and relative humidity had a meaningful but not statistically significant effect on accuracy (p = 0.07). Thus, elevation, temperature, and relative humidity affect blood glucose meter performance, and elevated glucose levels are more greatly underestimated at higher elevations. Further research will help to identify which blood glucose meters are best suited for specific environments.

  20. Effect of pertussis toxin pretreated centrally on blood glucose level induced by stress.

    PubMed

    Suh, Hong-Won; Sim, Yun-Beom; Park, Soo-Hyun; Sharma, Naveen; Im, Hyun-Ju; Hong, Jae-Seung

    2016-09-01

    In the present study, we examined the effect of pertussis toxin (PTX) administered centrally in a variety of stress-induced blood glucose level. Mice were exposed to stress after the pretreatment of PTX (0.05 or 0.1 µg) i.c.v. or i.t. once for 6 days. Blood glucose level was measured at 0, 30, 60 and 120 min after stress stimulation. The blood glucose level was increased in all stress groups. The blood glucose level reached at maximum level after 30 min of stress stimulation and returned to a normal level after 2 h of stress stimulation in restraint stress, physical, and emotional stress groups. The blood glucose level induced by cold-water swimming stress was gradually increased up to 1 h and returned to the normal level. The intracerebroventricular (i.c.v.) or intrathecal (i.t.) pretreatment with PTX, a Gi inhibitor, alone produced a hypoglycemia and almost abolished the elevation of the blood level induced by stress stimulation. The central pretreatment with PTX caused a reduction of plasma insulin level, whereas plasma corticosterone level was further up-regulated in all stress models. Our results suggest that the hyperglycemia produced by physical stress, emotional stress, restraint stress, and the cold-water swimming stress appear to be mediated by activation of centrally located PTX-sensitive G proteins. The reduction of blood glucose level by PTX appears to due to the reduction of plasma insulin level. The reduction of blood glucose level by PTX was accompanied by the reduction of plasma insulin level. Plasma corticosterone level up-regulation by PTX in stress models may be due to a blood glucose homeostatic mechanism.

  1. Resveratrol prevents insulin resistance caused by short-term elevation of free fatty acids in vivo.

    PubMed

    Pereira, Sandra; Park, Edward; Moore, Jessy; Faubert, Brandon; Breen, Danna M; Oprescu, Andrei I; Nahle, Ashraf; Kwan, Denise; Giacca, Adria; Tsiani, Evangelia

    2015-11-01

    Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL(-1) heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min(-1)) with or without resveratrol (3 mg·kg(-1)·h(-1)), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

  2. Cell-to-cell diffusion of glucose in the mammalian heart is disrupted by high glucose. Implications for the diabetic heart.

    PubMed

    De Mello, Walmor C

    2015-06-10

    The cell-to-cell diffusion of glucose in heart cell pairs isolated from the left ventricle of adult Wistar Kyoto rats was investigated. For this, fluorescent glucose was dialyzed into one cell of the pair using the whole cell clamp technique, and its diffusion from cell-to-cell was investigated by measuring the fluorescence in the dialyzed as well as in non-dialyzed cell as a function of time. The results indicated that: 1) glucose flows easily from cell-to-cell through gap junctions; 2) high glucose solution (25 mM) disrupted chemical communication between cardiac cells and abolished the intercellular diffusion of glucose; 3) the effect of high glucose solution on the cell-to-cell diffusion of glucose was drastically reduced by Bis-1 (10(-9)M) which is a PKC inhibitor; 4) intracellular dialysis of Ang II (100 nM) or increment of intracellular calcium concentration (10(-8)M) also inhibited the intercellular diffusion of glucose; 5) high glucose enhances oxidative stress in heart cells; 6) calculation of gap junction permeability (Pj) (cm/s) indicated a value of 0.74±0.08×10(-4) cm/s (5 animals) for the controls and 0.4±0.001×10(-5) cm/s; n=35 (5 animals) (P<0.05) for cells incubated with high glucose solution for 24h; 7) measurements of Pj for cell pairs treated with high glucose plus Bis-1 (10(-9)M) revealed no significant change of Pj (P>0.05); 8) increase of intracellular Ca(2+) concentration (10(-8)M) drastically decreased Pj (Pj=0.3±0.003×10(-5) cm/s). Conclusions indicate that: 1) glucose flows from cell-to-cell in the heart through gap junctions; 2) high glucose (25 mM) inhibited the intercellular diffusion of glucose-an effect significantly reduced by PKC inhibition; 3) high intracellular Ca(2+) concentration abolished the cell-to-cell diffusion of glucose; 4) intracellular Ang II (100 nM) inhibited the intercellular diffusion of glucose indicating that intracrine Ang II, in part activated by high glucose, severely impairs the exchange of glucose

  3. Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion.

    PubMed

    Howlett, Kirsten F; Andrikopoulos, Sofianos; Proietto, Joseph; Hargreaves, Mark

    2013-08-01

    To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30-60% of normal (CON) and approximately 5-10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake.

  4. Carboxypeptidase-D is elevated in prostate cancer and its anti-apoptotic activity is abolished by combined androgen and prolactin receptor targeting.

    PubMed

    Thomas, Lynn N; Merrimen, Jennifer; Bell, David G; Rendon, Ricardo; Goffin, Vincent; Too, Catherine K L

    2014-05-01

    Carboxypeptidase-D (CPD) cleaves C-terminal arginine for nitric oxide (NO) production. CPD and NO levels are upregulated by testosterone (T) and prolactin (PRL) to promote survival of prostate cancer (pCa) cells. This study evaluated CPD immunostaining and T/PRL regulation of CPD and NO levels in benign and malignant prostate tissues/cells to determine the role of CPD in pCa. Immunohistochemistry (IHC) and tissue microarrays (TMA) were used to determine CPD immunostaining in prostate specimens. QPCR and immunoblotting were used to quantify CPD mRNA/protein expression in prostate cells. NO production was measured using 4,5-diaminofluorescein diacetate assay. CPD staining increased from 8.9 ± 3.8% (Mean ± SEM, n = 15) of benign epithelial cell area to 30.9 ± 2.9% (n = 30) of tumor cell area in one set of TMAs (P = 0.0008) and from 5.9 ± 0.9% (n = 45) of benign epithelial cell area to 18.8 ± 1.9% (n = 55) of tumor area in another (P < 0.0001). IHC of prostate tissues (≥50 mm(2)) confirmed increased CPD staining, from 13.1 ± 2.9% in benign (n = 16) to 29.5 ± 4.4% in pCa (n = 31, P = 0.0095). T and/or PRL increased CPD expression in several pCa but not benign cell lines. T and PRL acted synergistically to increase NO production, which was abolished only when receptor antagonists flutamide and Δ1-9-G129R-hPRL were used together. CPD immunostaining and T/PRL-stimulated CPD expression were higher in pCa than benign tissues/cells. Elevated CPD increased NO production, which was abolished when both AR and PRLR were inhibited. Our study implicates a critical role for the T/PRL-stimulated CPD-Arg-NO pathway in pCa progression, and suggests that AR+PRLR inhibition is a more effective treatment for pCa. © 2014 Wiley Periodicals, Inc.

  5. Nervous glucose sensing regulates postnatal β cell proliferation and glucose homeostasis

    PubMed Central

    Tarussio, David; Metref, Salima; Seyer, Pascal; Mounien, Lourdes; Vallois, David; Magnan, Christophe; Foretz, Marc; Thorens, Bernard

    2013-01-01

    How glucose sensing by the nervous system impacts the regulation of β cell mass and function during postnatal development and throughout adulthood is incompletely understood. Here, we studied mice with inactivation of glucose transporter 2 (Glut2) in the nervous system (NG2KO mice). These mice displayed normal energy homeostasis but developed late-onset glucose intolerance due to reduced insulin secretion, which was precipitated by high-fat diet feeding. The β cell mass of adult NG2KO mice was reduced compared with that of WT mice due to lower β cell proliferation rates in NG2KO mice during the early postnatal period. The difference in proliferation between NG2KO and control islets was abolished by ganglionic blockade or by weaning the mice on a carbohydrate-free diet. In adult NG2KO mice, first-phase insulin secretion was lost, and these glucose-intolerant mice developed impaired glucagon secretion when fed a high-fat diet. Electrophysiological recordings showed reduced parasympathetic nerve activity in the basal state and no stimulation by glucose. Furthermore, sympathetic activity was also insensitive to glucose. Collectively, our data show that GLUT2-dependent control of parasympathetic activity defines a nervous system/endocrine pancreas axis that is critical for β cell mass establishment in the postnatal period and for long-term maintenance of β cell function. PMID:24334455

  6. Sucralose, an activator of the glucose-sensing receptor, increases ATP by calcium-dependent and -independent mechanisms.

    PubMed

    Li, Longfei; Ohtsu, Yoshiaki; Nakagawa, Yuko; Masuda, Katsuyoshi; Kojima, Itaru

    2016-08-31

    Sucralose is an artificial sweetener and activates the glucose-sensing receptor expressed in pancreatic β-cells. Although sucralose does not enter β-cells nor acts as a substrate for glucokinase, it induces a marked elevation of intracellular ATP ([ATP]c). The present study was conducted to identify the signaling pathway responsible for the elevation of [ATP]c induced by sucralose. Previous studies have shown that sucralose elevates cyclic AMP (cAMP), activates phospholipase C (PLC) and stimulates Ca(2+) entry by a Na(+)-dependent mechanism in MIN6 cells. The addition of forskolin induced a marked elevation of cAMP, whereas it did not affect [ATP]c. Carbachol, an activator of PLC, did not increase [ATP]c. In addition, activation of protein kinase C by dioctanoylglycerol did not affect [ATP]c. In contrast, nifedipine, an inhibitor of the voltage-dependent Ca(2+) channel, significantly reduced [ATP]c response to sucralose. Removal of extracellular Na(+) nearly completely blocked sucralose-induced elevation of [ATP]c. Stimulation of Na(+) entry by adding a Na(+) ionophore monensin elevated [ATP]c. The monensin-induced elevation of [ATP]c was only partially inhibited by nifedipine and loading of BAPTA, both of which completely abolished elevation of [Ca(2+)]c. These results suggest that Na(+) entry is critical for the sucralose-induced elevation of [ATP]c. Both calcium-dependent and -independent mechanisms are involved in the action of sucralose.

  7. Exercise-induced muscle glucose uptake in mice with graded, muscle-specific GLUT-4 deletion

    PubMed Central

    Howlett, Kirsten F; Andrikopoulos, Sofianos; Proietto, Joseph; Hargreaves, Mark

    2013-01-01

    To investigate the importance of the glucose transporter GLUT-4 for muscle glucose uptake during exercise, transgenic mice with skeletal muscle GLUT-4 expression approximately 30–60% of normal (CON) and approximately 5–10% of normal (KO) were generated using the Cre/Lox system and compared with wild-type (WT) mice during approximately 40 min of treadmill running (KO: 37.7 ± 1.3 min; WT: 40 min; CON: 40 min, P = 0.18). In WT and CON animals, exercise resulted in an overall increase in muscle glucose uptake. More specifically, glucose uptake was increased in red gastrocnemius of WT mice and in the soleus and red gastrocnemius of CON mice. In contrast, the exercise-induced increase in muscle glucose uptake in all muscles was completely abolished in KO mice. Muscle glucose uptake increased during exercise in both red and white quadriceps of WT mice, while the small increases in CON mice were not statistically significant. In KO mice, there was no change at all in quadriceps muscle glucose uptake. No differences in muscle glycogen use during exercise were observed between any of the groups. However, there was a significant increase in plasma glucose levels after exercise in KO mice. The results of this study demonstrated that a reduction in skeletal muscle GLUT-4 expression to approximately 10% of normal levels completely abolished the exercise-induced increase in muscle glucose uptake. PMID:24303141

  8. Association of serum orosomucoid with 30-min plasma glucose and glucose excursion during oral glucose tolerance tests in non-obese young Japanese women.

    PubMed

    Tsuboi, Ayaka; Minato, Satomi; Yano, Megumu; Takeuchi, Mika; Kitaoka, Kaori; Kurata, Miki; Yoshino, Gen; Wu, Bin; Kazumi, Tsutomu; Fukuo, Keisuke

    2018-01-01

    Inflammatory markers are elevated in insulin resistance (IR) and diabetes. We tested whether serum orosomucoid (ORM) is associated with postload glucose, β-cell dysfunction and IR inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period in 168 non-obese Japanese women (aged 18-24 years). OGTT responses, serum adiponectin and high-sensitivity C reactive protein (hsCRP) were cross-sectionally analyzed by analysis of variance and then Bonferroni's multiple comparison procedure. Stepwise multivariate linear regression analyses were used to identify most important determinants of ORM. Of 168 women, 161 had normal glucose tolerance. Postload glucose levels and the area under the glucose curve (AUCg) increased in a stepwise fashion from the first through the third ORM tertile. In contrast, there was no or modest, if any, association with fat mass index, trunk/leg fat ratio, adiponectin, hsCRP, postload insulinemia, the Matsuda index and homeostasis model assessment IR. In multivariable models, which incorporated the insulinogenic index, the Matsuda index and HOMA-IR, 30 min glucose (standardized β: 0.517) and AUCg (standardized β: 0.495) explained 92.8% of ORM variations. Elevated circulating orosomucoid was associated with elevated 30 min glucose and glucose excursion in non-obese young Japanese women independently of adiposity, IR, insulin secretion, adiponectin and other investigated markers of inflammation. Although further research is needed, these results may suggest a clue to identify novel pathways that may have utility in monitoring dysglycemia within normal glucose tolerance.

  9. Targeted Modification of Mitochondrial ROS Production Converts High Glucose-Induced Cytotoxicity to Cytoprotection: Effects on Anesthetic Preconditioning.

    PubMed

    Sedlic, Filip; Muravyeva, Maria Y; Sepac, Ana; Sedlic, Marija; Williams, Anna Marie; Yang, Meiying; Bai, Xiaowen; Bosnjak, Zeljko J

    2017-01-01

    Contradictory reports on the effects of diabetes and hyperglycemia on myocardial infarction range from cytotoxicity to cytoprotection. The study was designed to investigate acute effects of high glucose-driven changes in mitochondrial metabolism and osmolarity on adaptive mechanisms and resistance to oxidative stress of isolated rat cardiomyocytes. We examined the effects of high glucose on several parameters of mitochondrial bioenergetics, including changes in oxygen consumption, mitochondrial membrane potential, and NAD(P)H fluorometry. Effects of high glucose on the endogenous cytoprotective mechanisms elicited by anesthetic preconditioning (APC) and the mediators of cell injury were also tested. These experiments included real-time measurements of reactive oxygen species (ROS) production and mitochondrial permeability transition pore (mPTP) opening in single cells by laser scanning fluorescence confocal microscopy, and cell survival assay. High glucose rapidly enhanced mitochondrial energy metabolism, observed by increase in NAD(P)H fluorescence intensity, oxygen consumption, and mitochondrial membrane potential. This substantially elevated production of ROS, accelerated opening of the mPTP, and decreased survival of cells exposed to oxidative stress. Abrogation of high glucose-induced mitochondrial hyperpolarization with 2,4 dinitrophenol (DNP) significantly, but not completely, attenuated ROS production to a level similar to hyperosmotic mannitol control. DNP treatment reversed high glucose-induced cytotoxicity to cytoprotection. Hyperosmotic mannitol treatment also induced cytoprotection. High glucose abrogated APC-induced mitochondrial depolarization, delay in mPTP opening and cytoprotection. In conclusion, high glucose-induced mitochondrial hyperpolarization abolishes APC and augments cell injury. Attenuation of high glucose-induced ROS production by eliminating mitochondrial hyperpolarization protects cardiomyocytes. J. Cell. Physiol. 232: 216-224, 2017

  10. Lower extremity weakness is associated with elevated blood and cerebrospinal fluid glucose levels following multibranched endovascular aortic aneurysm repair.

    PubMed

    Hiramoto, Jade S; Fernandez, Charlene; Gasper, Warren; Vartanian, Shant; Reilly, Linda; Chuter, Timothy

    2017-02-01

    Hyperglycemia is associated with worsened clinical outcomes after central nervous system injury. The purpose of this study was to examine the association between lower extremity weakness (LEW) and the glucose levels of blood and cerebrospinal fluid (CSF) in patients undergoing multibranched endovascular aneurysm repair (MBEVAR) of thoracoabdominal and pararenal aortic aneurysms. Blood and CSF samples were collected preoperatively, immediately after aneurysm repair, and on postoperative day 1 in 21 patients undergoing MBEVAR. Data on demographics, operative repair, complications, and outcomes were collected prospectively. There were 21 patients who underwent successful MBEVAR. Two patients had pre-existing paraplegia from prior open aortic surgery and were excluded from the current analysis. The mean age was 73 ± 8 years, and 15 of 19 (79%) were men. In the postoperative period, 7 of 19 (37%) patients developed LEW. This was temporary in 5 of 19 (26%) patients and permanent in 2 of 19 (11%) patients. The LEW group was older than the non-LEW group (77 ± 6 vs 70 ± 9 years, respectively; P = .10), had a lower preoperative glomerular filtration rate (58.6 ± 18.5 vs 71.4 ± 23.5 mL/min per 1.73 m 2 ; P = .24), and was more likely to be taking a statin (100% vs 67%, respectively; P = .13), but these did not reach statistical significance. There was no significant difference in the prevalence of diabetes mellitus, hypertension, coronary artery disease, lung disease, or peripheral artery disease between the LEW and non-LEW groups. There was also no difference in operative time, blood loss, contrast material volume, or fluoroscopy times between the two groups. Preoperative blood and CSF glucose levels were similar in those with and without LEW. During the postoperative period, glucose values in the blood and CSF were significantly higher in those patients who developed LEW compared with those who did not develop LEW. In all patients with LEW, the elevation

  11. Coupling glucose fermentation and homoacetogenesis for elevated acetate production: Experimental and mathematical approaches.

    PubMed

    Ni, Bing-Jie; Liu, He; Nie, Yan-Qiu; Zeng, Raymond J; Du, Guo-Cheng; Chen, Jian; Yu, Han-Qing

    2011-02-01

    Homoacetogenesis is an important potential hydrogen sink in acetogenesis, in which hydrogen is used to reduce carbon dioxide to acetate. So far the acetate production from homoacetogenesis, especially its kinetics, has not been given sufficient attention. In this work, enhanced production of acetate from anaerobic conversion of glucose through coupling glucose fermentation and homoacetogenesis is investigated with both experimental and mathematical approaches. Experiments are conducted to explore elevated acetate production in a coupled anaerobic system. Acetate production could be achieved by homoacetogenesis with a relative high acetate yield under mixed fermentation conditions. With the experimental observations, a kinetic model is formulated to describe such a homoacetogenic process. The maximum homoacetogenic rate (k(m,homo)) is estimated to be 28.5 ± 1.7 kg COD kg⁻¹ COD day⁻¹ with an uptake affinity constant of 3.7 × 10⁻⁵± 3.1 × 10⁻⁶kg COD m⁻³. The improved calculation of homoacetogenic kinetics by our approach could correct the underestimation of homoacetogenesis in anaerobic fermentation processes, as it often occurs in these systems supported by literature analysis. The model predictions match the experimental results in different cases well and provide insights into the dynamics of anaerobic glucose conversion and acetate production. Furthermore, acetate production via homoacetogenesis increases by about 40% through utilizing the fed-batch coupling system, attributed to a balance between the hydrogen production in the acetogenesis phase and the hydrogen consumption in the homoacetogenesis phase. This work provides an effective way for increased anaerobic acetate production, and gives us a better understanding about the homoacetogenic kinetics in the anaerobic fermentation process. © 2010 Wiley Periodicals, Inc.

  12. Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis.

    PubMed

    Gray, Lawrence R; Sultana, Mst Rasheda; Rauckhorst, Adam J; Oonthonpan, Lalita; Tompkins, Sean C; Sharma, Arpit; Fu, Xiaorong; Miao, Ren; Pewa, Alvin D; Brown, Kathryn S; Lane, Erin E; Dohlman, Ashley; Zepeda-Orozco, Diana; Xie, Jianxin; Rutter, Jared; Norris, Andrew W; Cox, James E; Burgess, Shawn C; Potthoff, Matthew J; Taylor, Eric B

    2015-10-06

    Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Influence of abdominal surgical trauma and intra-operative infusion of glucose on splanchnic glucose metabolism in man.

    PubMed

    Stjernström, H; Jorfeldt, L; Wiklund, L

    1981-10-01

    Abdominal surgery increases blood glucose concentration and peripheral release and splanchnic uptake of gluconeogenic substrates, including alanine. During trauma or sepsis, infusion of glucose fails to depress alanine conversion to glucose. The effect of intra-operative glucose infusion on splanchnic metabolism was examined in the present study. In eight patients undergoing elective cholecystectomy, splanchnic glucose metabolism was investigated before, during and immediately after surgery. Glucose was infused at a constant rate of 1 mmol/min. Splanchnic blood flow and arterio-hepatic venous differences of oxygen, glucose, lactate, glycerol, 3-hydroxybutyrate and alanine were measured. Eight other patients, who received saline instead of glucose, served as a control group. Infusion of glucose resulted in total inhibition of splanchnic glucose release before as well as during and immediately after surgery. This was observed, even before surgery, at an arterial glucose level which was lower than that in the control group at the end of and immediately after surgery, at which no decrease of the splanchnic glucose release was recorded. changes in neuronal and hormonal factors due to the surgical trauma are considered responsible for this difference in glucose homeostasis. Splanchnic alanine uptake increased during surgery in both groups, but tended to be somewhat lower in the glucose group. The arterial glycerol concentration and splanchnic uptake, as well as the arterial concentration and splanchnic release of 3-hydroxybutyrate, were reduced. It is concluded that an intravenous infusion of glucose at the rate of 1 mmol/min during abdominal surgery (a) increases the arterial blood glucose level and abolishes splanchnic glucose release, (b) reduces, but does not totally prevent the increase in splanchnic uptake of gluconeogenic substrates, and (c) diminishes lipolysis and the formation of 3-hydroxybutyrate.

  14. Astrocytes in the nucleus of the solitary tract are activated by low glucose or glucoprivation: evidence for glial involvement in glucose homeostasis.

    PubMed

    McDougal, David H; Hermann, Gerlinda E; Rogers, Richard C

    2013-01-01

    Glucose homeostasis is maintained through interplay between central and peripheral control mechanisms which are aimed at storing excess glucose following meals and mobilizing these same stores during periods of fasting. The nucleus of the solitary tract (NST) in the dorsal medulla has long been associated with the central detection of glucose availability and the control of glucose homeostasis. Recent evidence has emerged which supports the involvement of astrocytes in glucose homeostasis. The aim of the present study was to investigate whether NST-astrocytes respond to physiologically relevant decreases in glucose availability, in vitro, as well as to the presence of the glucoprivic compound 2-deoxy-D-Glucose. This report demonstrates that some NST-astrocytes are capable of responding to low glucose or glucoprivation by increasing cytoplasmic calcium; a change that reverses with restoration of normal glucose availability. While some NST-neurons also demonstrate an increase in calcium signaling during low glucose availability, this effect is smaller and somewhat delayed compared to those observed in adjacent astrocytes. TTX did not abolish these hypoglycemia mediated responses of astrocytes, suggesting that NST-astrocytes may be directly sensing low glucose levels as opposed to responding to neuronal detection of hypoglycemia. Thus, chemodetection of low glucose by NST-astrocytes may play an important role in the autonomic regulation of glucose homeostasis.

  15. Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model

    PubMed Central

    Kim, Chea-Ha

    2015-01-01

    We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level. PMID:25792867

  16. Intracerebroventricular Kainic Acid-Induced Damage Affects Blood Glucose Level in d-glucose-fed Mouse Model.

    PubMed

    Kim, Chea-Ha; Hong, Jae-Seung

    2015-03-01

    We have previously reported that the intracerebroventricular (i.c.v.) administration of kainic acid (KA) results in significant neuronal damage on the hippocampal CA3 region. In this study, we examined possible changes in the blood glucose level after i.c.v. pretreatment with KA. The blood glucose level was elevated at 30 min, began to decrease at 60 min and returned to normal at 120 min after D-glucose-feeding. We found that the blood glucose level in the KA-pretreated group was higher than in the saline-pretreated group. The up-regulation of the blood glucose level in the KA-pretreated group was still present even after 1~4 weeks. The plasma corticosterone and insulin levels were slightly higher in the KA-treated group. Corticosterone levels decreased whereas insulin levels were elevated when mice were fed with D-glucose. The i.c.v. pretreatment with KA for 24 hr caused a significant reversal of D-glucose-induced down-regulation of corticosterone level. However, the insulin level was enhanced in the KA-pretreated group compared to the vehicle-treated group when mice were fed with D-glucose. These results suggest that KA-induced alterations of the blood glucose level are related to cell death in the CA3 region whereas the up-regulation of blood glucose level in the KA-pretreated group appears to be due to a reversal of D-glucose feeding-induced down-regulation of corticosterone level.

  17. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. © 2016 American Heart Association, Inc.

  18. PLACENTAL GROWTH FACTOR ADMINISTRATION ABOLISHES PLACENTAL ISCHEMIA-INDUCED HYPERTENSION

    PubMed Central

    Spradley, Frank T.; Tan, Adelene Y.; Joo, Woo S.; Daniels, Garrett; Kussie, Paul; Karumanchi, S. Ananth; Granger, Joey P.

    2016-01-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  19. 76 FR 81909 - Abolishment of Privacy Act System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... AGENCY: Office of the Secretary, USDA. ACTION: Notice of abolishment of records systems. SUMMARY: In accordance with the Privacy Act of 1974, the Department of Agriculture (USDA) is abolishing an existing Forest Service Privacy Act system of records. A review of USDA/FS-35 Congressional Correspondence has...

  20. 76 FR 81910 - Abolishment of Privacy Act System of Records

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... AGENCY: Office of the Secretary, USDA. ACTION: Notice of abolishment of records systems. SUMMARY: In accordance with the Privacy Act of 1974, the Department of Agriculture (USDA) is abolishing an existing Forest Service Privacy Act system of records. A review of USDA/FS-9 Employee Assistance Program CONCERN...

  1. Effect of exercise timing on elevated postprandial glucose levels.

    PubMed

    Hatamoto, Yoichi; Goya, Ryoma; Yamada, Yosuke; Yoshimura, Eichi; Nishimura, Sena; Higaki, Yasuki; Tanaka, Hiroaki

    2017-08-01

    There is no consensus regarding optimal exercise timing for reducing postprandial glucose (PPG). The purpose of the present study was to determine the most effective exercise timing. Eleven participants completed four different exercise patterns 1 ) no exercise; 2 ) preprandial exercise (jogging); 3 ) postprandial exercise; and 4 ) brief periodic exercise intervention (three sets of 1-min jogging + 30 s of rest, every 30 min, 20 times total) in a random order separated by a minimum of 5 days. Preprandial and postprandial exercise consisted of 20 sets of intermittent exercise (1 min of jogging + 30 s rest per set) repeated 3 times per day. Total daily exercise volume was identical for all three exercise patterns. Exercise intensities were 62.4 ± 12.9% V̇o 2peak Blood glucose concentrations were measured continuously throughout each trial for 24 h. After breakfast, peak blood glucose concentrations were lower with brief periodic exercise (99 ± 6 mg/dl) than those with preprandial and postprandial exercise (109 ± 10 and 115 ± 14 mg/dl, respectively, P < 0.05, effect size = 0.517). After lunch, peak glucose concentrations were lower with brief periodic exercise than those with postprandial exercise (97 ± 5 and 108 ± 8 mg/dl, P < 0.05, effect size = 0.484). After dinner, peak glucose concentrations did not significantly differ among exercise patterns. Areas under the curve over 24 h and 2 h postprandially did not differ among exercise patterns. These findings suggest that brief periodic exercise may be more effective than preprandial and postprandial exercise at attenuating PPG in young active individuals. NEW & NOTEWORTHY This was the first study to investigate the effect of different exercise timing (brief periodic vs. preprandial vs. postprandial exercise) on postprandial glucose (PPG) attenuation in active healthy men. We demonstrated that brief periodic exercise attenuated peak PPG levels more than preprandial and postprandial

  2. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

    PubMed

    Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

    2015-01-01

    Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Abolishing the Word-Length Effect

    ERIC Educational Resources Information Center

    Hulme, Charles; Suprenant, Aime M.; Bireta, Tamra J.; Stuart, George; Neath, Ian

    2004-01-01

    The authors report 2 experiments that compare the recall of long and short words in pure and mixed lists. In pure lists, long words were much more poorly remembered than short words. In mixed lists, this word-length effect was abolished and both the long and short words were recalled as well as short words in pure lists. These findings contradict…

  4. Incidental findings of elevated random plasma glucose in the ED as a prompt for outpatient diabetes screening: a retrospective study.

    PubMed

    Friedman, Steven Marc; Vallipuram, Janaki; Baswick, Brenda

    2013-12-18

    To determine whether random plasma glucose (RPG) collected from patients without known impaired glucose metabolism (IGM) in the emergency department (ED) is a useful screen for diabetes or prediabetes. Retrospective cohort study. ED of a Canadian teaching hospital over 1 month. Adult patients in ED with RPG over 7 mmol/L were recruited for participation. Exclusion criteria included known diabetes, hospital admission and inability to consent. Participants were contacted by mail, encouraged to follow-up with their family physician (FP) for further testing and subsequently interviewed. The primary outcome measure was the proportion of patients in the ED with RPG over 7 mmol/L and no previous diagnosis of IGM who were diagnosed with diabetes or prediabetes after secondary testing by FP with oral glucose tolerance test or fasting plasma glucose (FPG). Secondary outcomes included patient characteristics (age, gender, body mass index and language) and (2) compliance with advice to seek an appropriate follow-up care. RPG was drawn on approximately one-third (33%, n=1149) of the 3470 patients in the ED in March 2010. RPG over 7 mmol/L was detected in 24% (n=278) of patients, and after first telephone follow-up, 32% (n=88/278) met the inclusion criteria and were advised to seek confirmatory testing. 41% (n=114/278) of patients were excluded for known diabetes. 73% of patients contacted (n=64/88) followed up with their FP. 12.5% (n=11/88) of patients had abnormal FPG, and of these 11% (n=10/88) were encouraged to initiate lifestyle modifications and 1% (n=1/88) was started on an oral hypoglycaemic agent. For 7% (n=6/88) of patients, FP's declined to do follow-up fasting blood work. Elevated RPG in the ED is useful for identification of patients at risk for IGM and in need of further diabetic screening. Emergency physicians should advise patients with elevated RPG to consider screening for diabetes. For ED screening to be successful, patient education and collaboration with

  5. Evaluation of Correlation of Blood Glucose and Salivary Glucose Level in Known Diabetic Patients.

    PubMed

    Gupta, Anjali; Singh, Siddharth Kumar; Padmavathi, B N; Rajan, S Y; Mamatha, G P; Kumar, Sandeep; Roy, Sayak; Sareen, Mohit

    2015-05-01

    Diabetes mellitus is a chronic heterogenous disease in which there is dysregulation of carbohydrates, protein and lipid metabolism; leading to elevated blood glucose levels. The present study was conducted to evaluate the correlation between blood glucose and salivary glucose levels in known diabetic patients and control group and also to evaluate salivary glucose level as a diagnostic tool in diabetic patients. A total number of 250 patients were studied, out of which 212 formed the study group and 38 formed the control group. Among 250 patients, correlation was evaluated between blood glucose and salivary glucose values which on analysis revealed Pearson correlation of 0.073. The p-value was 0.247, which was statistically non significant. Salivary glucose values cannot be considered as a diagnostic tool for diabetic individuals.

  6. Corticosterone and exogenous glucose alter blood glucose levels, neurotoxicity, and vascular toxicity produced by methamphetamine.

    PubMed

    Bowyer, John F; Tranter, Karen M; Sarkar, Sumit; George, Nysia I; Hanig, Joseph P; Kelly, Kimberly A; Michalovicz, Lindsay T; Miller, Diane B; O'Callaghan, James P

    2017-10-01

    Our previous studies have raised the possibility that altered blood glucose levels may influence and/or be predictive of methamphetamine (METH) neurotoxicity. This study evaluated the effects of exogenous glucose and corticosterone (CORT) pretreatment alone or in combination with METH on blood glucose levels and the neural and vascular toxicity produced. METH exposure consisted of four sequential injections of 5, 7.5, 10, and 10 mg/kg (2 h between injections) D-METH. The three groups given METH in combination with saline, glucose (METH+Glucose), or CORT (METH+CORT) had significantly higher glucose levels compared to the corresponding treatment groups without METH except at 3 h after the last injection. At this last time point, the METH and METH+Glucose groups had lower levels than the non-METH groups, while the METH+CORT group did not. CORT alone or glucose alone did not significantly increase blood glucose. Mortality rates for the METH+CORT (40%) and METH+Glucose (44%) groups were substantially higher than the METH (< 10%) group. Additionally, METH+CORT significantly increased neurodegeneration above the other three METH treatment groups (≈ 2.5-fold in the parietal cortex). Thus, maintaining elevated levels of glucose during METH exposure increases lethality and may exacerbate neurodegeneration. Neuroinflammation, specifically microglial activation, was associated with degenerating neurons in the parietal cortex and thalamus after METH exposure. The activated microglia in the parietal cortex were surrounding vasculature in most cases and the extent of microglial activation was exacerbated by CORT pretreatment. Our findings show that acute CORT exposure and elevated blood glucose levels can exacerbate METH-induced vascular damage, neuroinflammation, neurodegeneration and lethality. Cover Image for this issue: doi. 10.1111/jnc.13819. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  7. Hepatic glucose sensing is required to preserve β cell glucose competence

    PubMed Central

    Seyer, Pascal; Vallois, David; Poitry-Yamate, Carole; Schütz, Frédéric; Metref, Salima; Tarussio, David; Maechler, Pierre; Staels, Bart; Lanz, Bernard; Grueter, Rolf; Decaris, Julie; Turner, Scott; da Costa, Anabela; Preitner, Frédéric; Minehira, Kaori; Foretz, Marc; Thorens, Bernard

    2013-01-01

    Liver glucose metabolism plays a central role in glucose homeostasis and may also regulate feeding and energy expenditure. Here we assessed the impact of glucose transporter 2 (Glut2) gene inactivation in adult mouse liver (LG2KO mice). Loss of Glut2 suppressed hepatic glucose uptake but not glucose output. In the fasted state, expression of carbohydrate-responsive element-binding protein (ChREBP) and its glycolytic and lipogenic target genes was abnormally elevated. Feeding, energy expenditure, and insulin sensitivity were identical in LG2KO and control mice. Glucose tolerance was initially normal after Glut2 inactivation, but LG2KO mice exhibited progressive impairment of glucose-stimulated insulin secretion even though β cell mass and insulin content remained normal. Liver transcript profiling revealed a coordinated downregulation of cholesterol biosynthesis genes in LG2KO mice that was associated with reduced hepatic cholesterol in fasted mice and reduced bile acids (BAs) in feces, with a similar trend in plasma. We showed that chronic BAs or farnesoid X receptor (FXR) agonist treatment of primary islets increases glucose-stimulated insulin secretion, an effect not seen in islets from Fxr–/– mice. Collectively, our data show that glucose sensing by the liver controls β cell glucose competence and suggest BAs as a potential mechanistic link. PMID:23549084

  8. High frequency stimulation abolishes thalamic network oscillations: an electrophysiological and computational analysis

    NASA Astrophysics Data System (ADS)

    Lee, Kendall H.; Hitti, Frederick L.; Chang, Su-Youne; Lee, Dongchul C.; Roberts, David W.; McIntyre, Cameron C.; Leiter, James C.

    2011-08-01

    Deep brain stimulation (DBS) of the thalamus has been demonstrated to be effective for the treatment of epilepsy. To investigate the mechanism of action of thalamic DBS, we examined the effects of high frequency stimulation (HFS) on spindle oscillations in thalamic brain slices from ferrets. We recorded intracellular and extracellular electrophysiological activity in the nucleus reticularis thalami (nRt) and in thalamocortical relay (TC) neurons in the lateral geniculate nucleus, stimulated the slice using a concentric bipolar electrode, and recorded the level of glutamate within the slice. HFS (100 Hz) of TC neurons generated excitatory post-synaptic potentials, increased the number of action potentials in both TC and nRt neurons, reduced the input resistance, increased the extracellular glutamate concentration, and abolished spindle wave oscillations. HFS of the nRt also suppressed spindle oscillations. In both locations, HFS was associated with significant and persistent elevation in extracellular glutamate levels and suppressed spindle oscillations for many seconds after the cessation of stimulation. We simulated HFS within a computational model of the thalamic network, and HFS also disrupted spindle wave activity, but the suppression of spindle activity was short-lived. Simulated HFS disrupted spindle activity for prolonged periods of time only after glutamate release and glutamate-mediated activation of a hyperpolarization-activated current (Ih) was incorporated into the model. Our results suggest that the mechanism of action of thalamic DBS as used in epilepsy may involve the prolonged release of glutamate, which in turn modulates specific ion channels such as Ih, decreases neuronal input resistance, and abolishes thalamic network oscillatory activity.

  9. Hepatocyte growth factor is elevated in amniotic fluid from obese women and regulates placental glucose and fatty acid metabolism.

    PubMed

    Visiedo, F; Bugatto, F; Carrasco-Fernández, C; Sáez-Benito, A; Mateos, R M; Cózar-Castellano, I; Bartha, J L; Perdomo, G

    2015-04-01

    To evaluate the impact of the pro-inflammatory cytokine hepatocyte growth factor (HGF) on the regulation of glucose and lipid placental metabolism. HGF levels were quantified in amniotic fluid and placenta from control and obese women. 2-deoxy-glucose (2-DOG) uptake, glycolysis, fatty acid oxidation (FAO), fatty acid esterification, de novo fatty acid synthesis, triglyceride levels and carnitine palmitoyltransferase activities (CPT) were measured in placental explants upon addition of pathophysiological HGF levels. In obese women, total- and -activated-HGF levels in amniotic fluid were elevated ∼24%, and placental HGF levels were ∼3-fold higher than in control women. At a similar dose to that present in amniotic fluid of obese women, HGF (30 ng/mL) increased Glut-1 levels and 2-DOG uptake by ∼25-30% in placental explants. HGF-mediated effect on 2-DOG uptake was dependent on the activation of phosphatidylinositol 3-kinase signaling pathway. In addition, HGF decreased ∼20% FAO, whereas esterification and de novo fatty acid synthesis increased ∼15% and ∼25% respectively, leading to 2-fold triglyceride accumulation in placental explants. In parallel, HGF reduced CPT-I activity ∼70%. HGF is a cytokine elevated in amniotic fluid and placental tissue of obese women, which through its ability to stimulate 2-DOG uptake and metabolism impairs FAO and enhances esterification and de novo fatty acid synthesis, leading to accumulation of placental triglycerides. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Increased expression of tissue plasminogen activator and its inhibitor and reduced fibrinolytic potential of human endothelial cells cultured in elevated glucose.

    PubMed

    Maiello, M; Boeri, D; Podesta, F; Cagliero, E; Vichi, M; Odetti, P; Adezati, L; Lorenzi, M

    1992-08-01

    In diabetic patients, elevated plasma levels of t-PA and PAI-1 accompany impaired fibrinolysis. To identify mechanisms for these abnormalities, we examined whether vascular endothelial cells exposed to high glucose upregulate t-PA and PAI-1 production and whether ambient PA activity is decreased concomitantly. In 17 cultures of human umbilical vein endothelial cells grown to confluency in 30 mM glucose, the t-PA antigen released to the medium in 24 h was (median) 52 ng/10(6) cells (range 10-384) and the PAI-1 antigen was 872 ng/10(6) cells (range 217-2074)--both greater (P less than 0.02) than the amounts released by paired control cultures grown in 5 mM glucose--29 ng/10(6) cells (range 7.5-216) and 461 ng/10(6) cells (range 230-3215), respectively. In the presence of high glucose, the steady-state levels of t-PA and PAI-1 mRNAs were increased correspondingly (median 142 and 183% of control, respectively, P less than 0.05); high glucose per se and hypertonicity contributed to the upregulation in additive fashion. The PA activity of conditioned medium from cultures exposed to high glucose was 0.4 IU/ml (range 0.2-0.6), which was significantly lower (P less than 0.02) than the PA activity of control medium (0.5 IU/ml, range 0.2-0.9). No difference was observed when comparing the PA activities of acidified conditioned media, expected to be depleted of inhibitors. Thus, high glucose coordinately upregulates endothelial t-PA and PAI-1 expression through effects exerted at the pretranslational level and enhanced by even mild degrees of hypertonicity.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells.

    PubMed

    Kojima, Itaru; Nakagawa, Yuko; Hamano, Kunihisa; Medina, Johan; Li, Longfei; Nagasawa, Masahiro

    2015-01-01

    Subunits of the sweet taste receptors T1R2 and T1R3 are expressed in pancreatic β-cells. Compared with T1R3, mRNA expression of T1R2 is considerably lower. At the protein level, expression of T1R2 is undetectable in β-cells. Accordingly, a major component of the sweet taste-sensing receptor in β-cells may be a homodimer of T1R3 rather than a heterodimer of T1R2/T1R3. Inhibition of this receptor by gurmarin or deletion of the T1R3 gene attenuates glucose-induced insulin secretion from β-cells. Hence the T1R3 homodimer functions as a glucose-sensing receptor (GSR) in pancreatic β-cells. When GSR is activated by the T1R3 agonist sucralose, elevation of intracellular ATP concentration ([ATP]i) is observed. Sucralose increases [ATP]i even in the absence of ambient glucose, indicating that sucralose increases [ATP]i not simply by activating glucokinase, a rate-limiting enzyme in the glycolytic pathway. In addition, sucralose augments elevation of [ATP]i induced by methylsuccinate, suggesting that sucralose activates mitochondrial metabolism. Nonmetabolizable 3-O-methylglucose also increases [ATP]i and knockdown of T1R3 attenuates elevation of [ATP]i induced by high concentration of glucose. Collectively, these results indicate that the T1R3 homodimer functions as a GSR; this receptor is involved in glucose-induced insulin secretion by activating glucose metabolism probably in mitochondria.

  12. Elevated 1-h post-challenge plasma glucose levels in subjects with normal glucose tolerance or impaired glucose tolerance are associated with whole blood viscosity.

    PubMed

    Marini, Maria Adelaide; Fiorentino, Teresa Vanessa; Andreozzi, Francesco; Mannino, Gaia Chiara; Perticone, Maria; Sciacqua, Angela; Perticone, Francesco; Sesti, Giorgio

    2017-08-01

    It has been suggested that glucose levels ≥155 mg/dl at 1-h during an oral glucose tolerance test (OGTT) may predict development of type 2 diabetes and cardiovascular events among adults with normal glucose tolerance (NGT 1 h-high). Studies showed a link between increased blood viscosity and type 2 diabetes. However, whether blood viscosity is associated with dysglycemic conditions such as NGT 1 h-high, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) is unsettled. 1723 non-diabetic adults underwent biochemical evaluation and OGTT. A validated formula based on hematocrit and total plasma proteins was employed to estimate whole blood viscosity. Subjects were categorized into NGT with 1 h glucose <155 mg/dL (NGT-1 h-low), NGT-1 h-high, IFG and/or IGT. Hematocrit and blood viscosity values appeared significantly higher in individuals with NGT 1 h-high, IFG and/or IGT as compared to NGT 1 h-low subjects. Blood viscosity was significantly correlated with age, waist circumference, blood pressure, HbA1c, fasting, 1- and 2-h post-challenge insulin levels, total cholesterol and low-density lipoprotein, triglycerides, fibrinogen, white blood cell, and inversely correlated with high-density lipoprotein and insulin sensitivity. Of the four glycemic parameters, 1-h post-challenge glucose showed the strongest correlation with blood viscosity (β = 0.158, P < 0.0001) in a multivariate regression analysis model including several atherosclerosis risk factors. Our results demonstrate a positive relationship between blood viscosity and 1-h post-challenge plasma glucose. They also suggest that a subgroup of NGT individuals with 1-h post-challenge plasma >155 mg/dl have increased blood viscosity comparable to that observed in subjects with IFG and/or IGT.

  13. Elevated alanine aminotransferase is associated with metabolic syndrome but not consistently associated with impaired fasting glucose or type 2 diabetes mellitus.

    PubMed

    Yueh, Chen-Yu; Chen, Jung-Hsiang; Lee, Li-Wen; Lu, Cheng-Wei; Parekh, Bhavin; Chi, Ching-Chi

    2011-10-01

    Abnormally elevated alanine aminotransferase (ALT) of nonspecific causes is a common outpatient problem. Without considering ethnicity, several studies had suggested that it was associated with insulin resistance (IR). To investigate whether nonspecific elevated ALT in Taiwanese population could reflect a likely underlying IR and was associated with impaired fasting glucose or type 2 diabetes mellitus (IFG/T2DM). The health examination profiles of 1313 Taiwanese were investigated cross-sectionally. The prevalence and odds ratios (ORs) for IFG/T2DM and metabolic abnormalities in relation to elevated ALT were analyzed. Subjects with metabolic syndrome (MS) all had IFG/T2DM. The elevated ALT significantly correlated with MS and IFG/T2DM (i.e., 19.9-29.2% vs. 7.8% for MS, and 27.0-31.5% vs. 16.1% for IFG/T2DM). However, after excluding MS and adjustment for age and sex, the elevated ALT alone was not consistently associated with IFG/T2DM (36 < ALT ≤ 80 IU/L with OR 0.97, 95% CI 0.58-1.61; 80 < ALT ≤ 120 IU/L with OR 0.55, 95% CI 0.13-2.37; none with ALT > 120 had IFG). In a cross-sectional analysis of Taiwanese industrial employees, elevated ALT associated with MS, but in subjects who did not meet MS criteria, elevated ALT by itself did not associate with IFG/T2DM. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Incidental findings of elevated random plasma glucose in the ED as a prompt for outpatient diabetes screening: a retrospective study

    PubMed Central

    Friedman, Steven Marc; Vallipuram, Janaki; Baswick, Brenda

    2013-01-01

    Objective To determine whether random plasma glucose (RPG) collected from patients without known impaired glucose metabolism (IGM) in the emergency department (ED) is a useful screen for diabetes or prediabetes. Design Retrospective cohort study. Setting ED of a Canadian teaching hospital over 1 month. Participants Adult patients in ED with RPG over 7 mmol/L were recruited for participation. Exclusion criteria included known diabetes, hospital admission and inability to consent. Participants were contacted by mail, encouraged to follow-up with their family physician (FP) for further testing and subsequently interviewed. Outcome measures The primary outcome measure was the proportion of patients in the ED with RPG over 7 mmol/L and no previous diagnosis of IGM who were diagnosed with diabetes or prediabetes after secondary testing by FP with oral glucose tolerance test or fasting plasma glucose (FPG). Secondary outcomes included patient characteristics (age, gender, body mass index and language) and (2) compliance with advice to seek an appropriate follow-up care. Results RPG was drawn on approximately one-third (33%, n=1149) of the 3470 patients in the ED in March 2010. RPG over 7 mmol/L was detected in 24% (n=278) of patients, and after first telephone follow-up, 32% (n=88/278) met the inclusion criteria and were advised to seek confirmatory testing. 41% (n=114/278) of patients were excluded for known diabetes. 73% of patients contacted (n=64/88) followed up with their FP. 12.5% (n=11/88) of patients had abnormal FPG, and of these 11% (n=10/88) were encouraged to initiate lifestyle modifications and 1% (n=1/88) was started on an oral hypoglycaemic agent. For 7% (n=6/88) of patients, FP's declined to do follow-up fasting blood work. Conclusions Elevated RPG in the ED is useful for identification of patients at risk for IGM and in need of further diabetic screening. Emergency physicians should advise patients with elevated RPG to consider screening for

  15. Ghrelin administered spinally increases the blood glucose level in mice.

    PubMed

    Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

    2014-04-01

    Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 μg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 μg) markedly attenuated ghrelin-induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 μg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Effectiveness of Panax ginseng on Acute Myocardial Ischemia Reperfusion Injury Was Abolished by Flutamide via Endogenous Testosterone-Mediated Akt Pathway

    PubMed Central

    Pei, Luo; Shaozhen, Hou; Gengting, Dong; Tingbo, Chen; Liang, Liu; Hua, Zhou

    2013-01-01

    Mechanisms for Panax ginseng's cardioprotective effect against ischemia reperfusion injury involve the estrogen-mediated pathway, but little is known about the role of androgen. A standardized Panax ginseng extract (RSE) was orally given with or without flutamide in a left anterior descending coronary artery ligation rat model. Infarct size, CK and LDH activities were measured. Time-related changes of NO, PI3K/Akt/eNOS signaling, and testosterone concentration were also investigated. RSE (80 mg/kg) significantly inhibited myocardial infarction and CK and LDH activities, while coadministration of flutamide abolished this effect of RSE. NO was increased by RSE and reached a peak after 15 min of ischemia; however, flutamide cotreatment suppressed this elevation. Western blot analysis showed that RSE significantly reversed the decreases of expression and activation of PI3K, Akt, and eNOS evoked by ischemia, whereas flutamide attenuated the effects of these protective mechanisms induced by RSE. RSE completely reversed the dropping of endogenous testosterone level induced by I/R injury. Flutamide plus RSE treatment not only abolished RSE's effect but also produced a dramatic change on endogenous testosterone level after pretreatment and ischemia. Our results for the first time indicate that blocking androgen receptor abolishes the ability of Panax ginseng to protect the heart from myocardial I/R injury. PMID:24282438

  17. Why Grants.gov Should Be Abolished

    ERIC Educational Resources Information Center

    Kolmertern, Carol

    2007-01-01

    In this article, the author explains why Grants.gov, a web site for US Federal Government grants, should be abolished. Her recent attempt to submit a grant proposal to the National Institutes of Health is a case in point. She recounts how frustrating her experience was to the grant-submission process of Grants.gov. She points out that Grants.gov…

  18. Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii

    PubMed Central

    Boychuk, Carie R.; Gyarmati, Peter; Xu, Hong

    2015-01-01

    Changes in blood glucose concentration alter autonomic function in a manner consistent with altered neural activity in brain regions controlling digestive processes, including neurons in the brain stem nucleus tractus solitarii (NTS), which process viscerosensory information. With whole cell or on-cell patch-clamp recordings, responses to elevating glucose concentration from 2.5 to 15 mM were assessed in identified GABAergic NTS neurons in slices from transgenic mice that express EGFP in a subset of GABA neurons. Single-cell real-time RT-PCR was also performed to detect glutamic acid decarboxylase (GAD67) in recorded neurons. In most identified GABA neurons (73%), elevating glucose concentration from 2.5 to 15 mM resulted in either increased (40%) or decreased (33%) neuronal excitability, reflected by altered membrane potential and/or action potential firing. Effects on membrane potential were maintained when action potentials or fast synaptic inputs were blocked, suggesting direct glucose sensing by GABA neurons. Glucose-inhibited GABA neurons were found predominantly in the lateral NTS, whereas glucose-excited cells were mainly in the medial NTS, suggesting regional segregation of responses. Responses were prevented in the presence of glucosamine, a glucokinase (GCK) inhibitor. Depolarizing responses were prevented when KATP channel activity was blocked with tolbutamide. Whereas effects on synaptic input to identified GABAergic neurons were variable in GABA neurons, elevating glucose increased glutamate release subsequent to stimulation of tractus solitarius in unlabeled, unidentified neurons. These results indicate that GABAergic NTS neurons act as GCK-dependent glucose sensors in the vagal complex, providing a means of modulating central autonomic signals when glucose is elevated. PMID:26084907

  19. Positive Allosteric Modulation of the Calcium-sensing Receptor by Physiological Concentrations of Glucose*

    PubMed Central

    Medina, Johan; Nakagawa, Yuko; Nagasawa, Masahiro; Fernandez, Anny; Sakaguchi, Kazushige; Kitaguchi, Tetsuya; Kojima, Itaru

    2016-01-01

    The calcium-sensing receptor (CaSR) is activated by various cations, cationic compounds, and amino acids. In the present study we investigated the effect of glucose on CaSR in HEK293 cells stably expressing human CaSR (HEK-CaSR cells). When glucose concentration in the buffer was raised from 3 to 25 mm, a rapid elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) was observed. This elevation was immediate and transient and was followed by a sustained decrease in [Ca2+]c. The effect of glucose was detected at a concentration of 4 mm and reached its maximum at 5 mm. 3-O-Methylglucose, a non-metabolizable analogue of glucose, reproduced the effect of glucose. Sucrose also induced an elevation of [Ca2+]c in HEK-CaSR cells. Similarly, sucralose was nearly as effective as glucose in inducing elevation of [Ca2+]c. Glucose was not able to increase [Ca2+]c in the absence of extracellular Ca2+. The effect of glucose on [Ca2+]c was inhibited by NPS-2143, an allosteric inhibitor of CaSR. In addition, NPS-2143 also inhibited the [Ca2+]c responses to sucralose and sucrose. Glucose as well as sucralose decreased cytoplasmic cAMP concentration in HEK-CaSR cells. The reduction of cAMP induced by glucose was blocked by pertussis toxin. Likewise, sucralose reduced [cAMP]c. Finally, glucose increased [Ca2+]c in PT-r parathyroid cells and in Madin-Darby canine kidney cells, both of which express endogenous CaSR. These results indicate that glucose acts as a positive allosteric modulator of CaSR. PMID:27613866

  20. Fasting glucose, NT-proBNP, treatment with eptifibatide, and outcomes in non-ST-segment elevation acute coronary syndromes: An analysis from EARLY ACS.

    PubMed

    Farhan, Serdar; Clare, Robert M; Jarai, Rudolf; Giugliano, Robert P; Lokhnygina, Yuliya; Harrington, Robert A; Kristin Newby, L; Huber, Kurt

    2017-04-01

    Higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been linked to a more favorable glucometabolic profile. Little is known about the interaction of NT-proBNP and fasting glucose in non-ST-segment elevation acute coronary syndrome (NSTE ACS). Fasting glucose and NT-proBNP were measured in 2240 patients enrolled in the EARLY ACS trial. Multivariable Cox models were used to assess associations between fasting glucose and NT-proBNP and a 96-hour composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout; 30-day death or MI; and 1-year mortality. In adjusted Cox models, neither NT-proBNP nor fasting glucose was associated with the 96-hour endpoint (p=0.95 and p=0.87). NT-proBNP was associated with 30-day death or MI (hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.02-1.22, p=0.02) and 1-year mortality (HR 1.63, 95% CI 1.42-1.89, p<0.0001), but fasting glucose was associated only with 1-year death (HR 1.53, 95% CI 1.08-2.16, p=0.02). NT-proBNP×glucose interaction terms were non-significant in all models. As fasting glucose levels increased, the risk of 96-hour and 30-day endpoints increased among patients who received early eptifibatide but not delayed, provisional use (p int =0.035 and p int =0.029). Higher NT-proBNP levels were associated with greater 30-day death or MI among patients who received early eptifibatide but not delayed, provisional use (p int =0.045). NT-proBNP and fasting glucose concentrations were associated with intermediate-term ischemic outcomes and may identify differential response to treatment with eptifibatide. CLINICALTRIALS. NCT00089895. Copyright © 2017. Published by Elsevier B.V.

  1. Vitreous Fluid and/or Urine Glucose Concentrations in 1,335 Civil Aviation Accident Pilot Fatalities

    DTIC Science & Technology

    2008-05-01

    glucose, and in those cases wherein glucose levels are elevated, blood hemoglobin A1c ( HbA1c ) is measured. These analyses are conducted to monitor...diabetes. In this study, the prevalence of elevated glucose concentrations in fatally injured civilian pilots is evaluated. Glucose and HbA1c are measured...whom samples were received during 1998–2005 and whose vitreous fluid and/or urine glucose concentrations were measured. HbA1c levels and information

  2. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis.

    PubMed

    Lansey, Melissa N; Walker, Natalie N; Hargett, Stefan R; Stevens, Joseph R; Keller, Susanna R

    2012-11-15

    Tight control of glucose uptake in skeletal muscles and adipocytes is crucial to glucose homeostasis and is mediated by regulating glucose transporter GLUT4 subcellular distribution. In cultured cells, Rab GAP AS160 controls GLUT4 intracellular retention and release to the cell surface and consequently regulates glucose uptake into cells. To determine AS160 function in GLUT4 trafficking in primary skeletal muscles and adipocytes and investigate its role in glucose homeostasis, we characterized AS160 knockout (AS160(-/-)) mice. We observed increased and normal basal glucose uptake in isolated AS160(-/-) adipocytes and soleus, respectively, while insulin-stimulated glucose uptake was impaired and GLUT4 expression decreased in both. No such abnormalities were found in isolated AS160(-/-) extensor digitorum longus muscles. In plasma membranes isolated from AS160(-/-) adipose tissue and gastrocnemius/quadriceps, relative GLUT4 levels were increased under basal conditions and remained the same after insulin treatment. Concomitantly, relative levels of cell surface-exposed GLUT4, determined with a glucose transporter photoaffinity label, were increased in AS160(-/-) adipocytes and normal in AS160(-/-) soleus under basal conditions. Insulin augmented cell surface-exposed GLUT4 in both. These observations suggest that AS160 is essential for GLUT4 intracellular retention and regulation of glucose uptake in adipocytes and skeletal muscles in which it is normally expressed. In vivo studies revealed impaired insulin tolerance in the presence of normal (male) and impaired (female) glucose tolerance. Concurrently, insulin-elicited increases in glucose disposal were abolished in all AS160(-/-) skeletal muscles and liver but not in AS160(-/-) adipose tissues. This suggests AS160 as a target for differential manipulation of glucose homeostasis.

  3. Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hsu, Ya-Yun; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Tseng, Yu-Ting

    Reactive oxygen intermediates production and apoptotic damage induced by high glucose are major causes of neuronal damage in diabetic neuropathy. Berberine (BBR), a natural antidiabetes drug with PI3K-activating activity, holds promise for diabetes because of its dual antioxidant and anti-apoptotic activities. We have previously reported that BBR attenuated H{sub 2}O{sub 2} neurotoxicity via activating the PI3K/Akt/Nrf2-dependent pathway. In this study, we further explored the novel protective mechanism of BBR on high glucose-induced apoptotic death and neurite damage of SH-SY5Y cells. Results indicated BBR (0.1–10 nM) significantly attenuated reactive oxygen species (ROS) production, nucleus condensation, and apoptotic death in high glucose-treatedmore » cells. However, AG1024, an inhibitor of insulin growth factor-1 (IGF-1) receptor, significantly abolished BBR protection against high glucose-induced neuronal death. BBR also increased Bcl-2 expression and decreased cytochrome c release. High glucose down-regulated IGF-1 receptor and phosphorylation of Akt and GSK-3β, the effects of which were attenuated by BBR treatment. BBR also activated nuclear erythroid 2-related factor 2 (Nrf2), the key antioxidative transcription factor, which is accompanied with up-regulation of hemeoxygenase-1 (HO-1). Furthermore, BBR markedly enhanced nerve growth factor (NGF) expression and promoted neurite outgrowth in high glucose-treated cells. To further determine the role of the Nrf2 in BBR neuroprotection, RNA interference directed against Nrf2 was used. Results indicated Nrf2 siRNA abolished BBR-induced HO-1, NGF, neurite outgrowth and ROS decrease. In conclusion, BBR attenuated high glucose-induced neurotoxicity, and we are the first to reveal this novel mechanism of BBR as an Nrf2 activator against glucose neurotoxicity, providing another potential therapeutic use of BBR on the treatment of diabetic complications. - Highlights: • BBR attenuates high glucose-induced ROS

  4. Evaluation of a novel supplement to reduce blood glucose through the use of a modified oral glucose tolerance test

    PubMed Central

    Smith, Adam J; Giunta, Brian; Shytle, R Douglas; Blum, James M

    2011-01-01

    Elevated blood glucose is a major component in metabolic syndrome and pre-diabetes, sometimes leading to type 2 diabetes mellitus (DM II). Additionally, it may lead to adipose deposits when left elevated for long periods. The epidemiology of DM II clearly shows that uncontrolled blood glucose levels leads to many adverse conditions including heart disease, retinal damage, renal failure, erectile dysfunction, and other significant medical conditions. Here we conducted a single-center, prospective, randomized, double-blinded, placebo-controlled, parallel-group- clinical trial of a nutraceutical supplement vs. placebo to measure its glucose lowering effect in generally healthy adults before and after a simple sugars meal. Subjects reported to the test clinic on multiple days to receive placebo or treatment, a simple sugars meal, as well as pre-and postprandial blood glucose measurement (modified oral glucose tolerance test). Each subject served as his or her own control and thirty-one subjects completed the trial with at least one oral glucose tolerance test (OGTT) with the nutraceutical supplement and placebo. Statistical analysis revealed the nutraceutical supplement significantly lowered postprandial glucose levels by 36% and 59% at 45 and 60 minutes, respectively (***P<.001). The study was limited by its composition of primarily overweight females. Future studies will be required over longer periods in more heterogeneous and larger groups to determine the long-term effect of this supplement on blood glucose levels in terms of prophylaxis or treatment for DM II. PMID:21416063

  5. Stimulus-dependent changes of extracellular glucose in the rat hippocampus determined by in vivo microdialysis.

    PubMed

    Rex, A; Bert, B; Fink, H; Voigt, J-P

    2009-10-19

    Neuronal activity is tightly coupled with brain energy metabolism; and glucose is an important energy substrate for neurons. The present in vivo microdialysis study was aimed at investigating changes in extracellular glucose concentrations in the rat ventral hippocampus due to exposure to the elevated plus maze. Determination of basal hippocampal glucose and lactate/pyruvate ratio in male Wistar rats was conducted in the home cage using in vivo microdialysis. Rats were exposed to the elevated plus maze, a rodent model of anxiety-related behaviour, or to unspecific stress induced by white noise (95dB) as a control condition. Basal hippocampal levels of glucose, as determined by zero-net-flux, and the basal lactate/pyruvate ratio were 1.49+/-0.05mmol/l and 13.8+/-1.1, respectively. In rats without manipulation, glucose levels remained constant throughout the experiment (120min). By contrast, exposure to the elevated plus maze led to a temporary decline in hippocampal glucose (-33.2+/-4.4%) which returned to baseline level in the home cage. White noise caused only a non-significant decrease in extracellular glucose level (-9.3+/-3.5%). In all groups, the lactate/pyruvate ratio remained unchanged by the experimental procedures. Our microdialysis study demonstrates that exposure to the elevated plus maze induces a transient decrease in extracellular hippocampal glucose concentration. In contrast, an unspecific stimulus did not change hippocampal glucose. The latter suggests that only specific behavioural stimuli increase hippocampal glucose utilization in the ventral hippocampus.

  6. Testosterone is protective against impaired glucose metabolism in male intrauterine growth-restricted offspring

    PubMed Central

    Dasinger, John Henry; Fahling, Joel M.; Backstrom, Miles A.; Alexander, Barbara T.

    2017-01-01

    Placental insufficiency alters the intrauterine environment leading to increased risk for chronic disease including impaired glucose metabolism in low birth weight infants. Using a rat model of low birth weight, we previously reported that placental insufficiency induces a significant increase in circulating testosterone in male intrauterine growth-restricted offspring (mIUGR) in early adulthood that is lost by 12 months of age. Numerous studies indicate testosterone has a positive effect on glucose metabolism in men. Female growth-restricted littermates exhibit glucose intolerance at 6 months of age. Thus, the aim of this paper was to determine whether mIUGR develop impaired glucose metabolism, and whether a decrease in elevated testosterone levels plays a role in its onset. Male growth-restricted offspring were studied at 6 and 12 months of age. No impairment in glucose tolerance was observed at 6 months of age when mIUGR exhibited a 2-fold higher testosterone level compared to age-matched control. Fasting blood glucose was significantly higher and glucose tolerance was impaired with a significant decrease in circulating testosterone in mIUGR at 12 compared with 6 months of age. Castration did not additionally impair fasting blood glucose or glucose tolerance in mIUGR at 12 months of age, but fasting blood glucose was significantly elevated in castrated controls. Restoration of elevated testosterone levels significantly reduced fasting blood glucose and improved glucose tolerance in mIUGR. Thus, our findings suggest that the endogenous increase in circulating testosterone in mIUGR is protective against impaired glucose homeostasis. PMID:29145418

  7. Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells.

    PubMed

    Hamano, Kunihisa; Nakagawa, Yuko; Ohtsu, Yoshiaki; Li, Longfei; Medina, Johan; Tanaka, Yuji; Masuda, Katsuyoshi; Komatsu, Mitsuhisa; Kojima, Itaru

    2015-07-01

    Glucose activates the glucose-sensing receptor T1R3 and facilitates its own metabolism in pancreatic β-cells. An inhibitor of this receptor would be helpful in elucidating the physiological function of the glucose-sensing receptor. The present study was conducted to examine whether or not lactisole can be used as an inhibitor of the glucose-sensing receptor. In MIN6 cells, in a dose-dependent manner, lactisole inhibited insulin secretion induced by sweeteners, acesulfame-K, sucralose and glycyrrhizin. The IC50 was ∼4 mmol/l. Lactisole attenuated the elevation of cytoplasmic Ca2+ concentration ([Ca2+]c) evoked by sucralose and acesulfame-K but did not affect the elevation of intracellular cAMP concentration ([cAMP]c) induced by these sweeteners. Lactisole also inhibited the action of glucose in MIN6 cells. Thus, lactisole significantly reduced elevations of intracellular [NADH] and intracellular [ATP] induced by glucose, and also inhibited glucose-induced insulin secretion. To further examine the effect of lactisole on T1R3, we prepared HEK293 cells stably expressing mouse T1R3. In these cells, sucralose elevated both [Ca2+]c and [cAMP]c. Lactisole attenuated the sucralose-induced increase in [Ca2+]c but did not affect the elevation of [cAMP]c. Finally, lactisole inhibited insulin secretion induced by a high concentration of glucose in mouse islets. These results indicate that the mouse glucose-sensing receptor was inhibited by lactisole. Lactisole may be useful in assessing the role of the glucose-sensing receptor in mouse pancreatic β-cells. © 2015 Society for Endocrinology.

  8. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion.

    PubMed

    Gustavsson, Natalia; Wang, Xiaorui; Wang, Yue; Seah, Tingting; Xu, Jun; Radda, George K; Südhof, Thomas C; Han, Weiping

    2010-11-09

    Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7. In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.

  9. Generation of a glucose de-repressed mutant of Trichoderma reesei using disparity mutagenesis.

    PubMed

    Iwakuma, Hidekazu; Koyama, Yoshiyuki; Miyachi, Ayako; Nasukawa, Masashi; Matsumoto, Hitoshi; Yano, Shuntaro; Ogihara, Jun; Kasumi, Takafumi

    2016-01-01

    We obtained a novel glucose de-repressed mutant of Trichoderma reesei using disparity mutagenesis. A plasmid containing DNA polymerase δ lacking proofreading activity, and AMAI, an autonomously replicating sequence was introduced into T. reesei ATCC66589. The rate of mutation evaluated with 5-fluoroorotic acid resistance was approximately 30-fold higher than that obtained by UV irradiation. The transformants harboring incompetent DNA polymerase δ were then selected on 2-deoxyglucose agar plates with hygromycin B. The pNP-lactoside hydrolyzing activities of mutants were 2 to 5-fold higher than the parent in liquid medium containing glucose. Notably, the amino acid sequence of cre1, a key gene involved in glucose repression, was identical in the mutant and parent strains, and further, the cre1 expression levels was not abolished in the mutant. Taken together, these results demonstrate that the strains of T. reesei generated by disparity mutagenesis are glucose de-repressed variants that contain mutations in yet-unidentified factors other than cre1.

  10. The Effect of Environmental Temperature on Glucose and Insulin After an Oral Glucose Tolerance Test in Healthy Young Men.

    PubMed

    Dumke, Charles L; Slivka, Dustin R; Cuddy, John S; Hailes, Walter S; Rose, Shawn M; Ruby, Brent C

    2015-09-01

    The purpose of this study was to compare glucose and insulin responses during an oral glucose tolerance test (OGTT) in cold (C), neutral (N), and hot (H) environments. Eleven males completed three 4-hour climate-controlled OGTT trials (C, 7.2°C; N, 22°C; and H, 43°C). Participants remained semireclined for 60 minutes before ingesting a 1.8 g/kg glucose beverage. Skin and rectal core temperatures were continuously monitored. Blood was collected just before glucose ingestion (time 0) and at 15, 30, 60, 90, 120, and 180 minutes, and analyzed for serum glucose, insulin, hematocrit, and hemoglobin. Expired gases were collected upon entering the chamber (-60 minutes), before glucose ingestion (0 minutes), and at 60, 120, and 180 minutes to determine V(O2) and respiratory exchange ratio. Rectal core temperature was greater in the H condition compared with both C and N (P < .001). Rectal core temperature was not different between C and N, whereas skin temperature was different across all trials (H greater than N greater than C). The V(O2) was greater in C than in both H and N during all time points. Carbohydrate oxidation was greater in C compared with H and N (P < 0.001). Glucose was higher during H compared with C and N (P ≤ 0.002). Glucose was elevated in C compared with N. Insulin was higher in H compared with C (P = 0.009). Area under the curve for serum glucose was greater in H compared with C and N (P ≤ 0.001); however, there was no significant difference in area under the curve for insulin. These data indicate that after an OGTT, glucose and insulin are elevated in a hot environment. Copyright © 2015 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.

  11. Glucose Regulates the Expression of the Apolipoprotein A5 Gene

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Fruchart, Jamila; Nowak, Maxime; Helleboid-Chapman, Audrey

    2008-04-07

    The apolipoprotein A5 gene (APOA5) is a key player in determining triglyceride concentrations in humans and mice. Since diabetes is often associated with hypertriglyceridemia, this study explores whether APOA5 gene expression is regulated by alteration in glucose homeostasis and the related pathways. D-glucose activates APOA5 gene expression in a time- and dose-dependent manner in hepatocytes, and the glycolytic pathway involved was determined using D-glucose analogs and metabolites. Together, transient transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that this regulation occurs at the transcriptional level through an increase of USF1/2 binding to an E-box in the APOA5 promoter.more » We show that this phenomenon is not due to an increase of mRNA or protein expression levels of USF. Using protein phosphatases 1 and 2A inhibitor, we demonstrate that D-glucose regulates APOA5 gene via a dephosphorylation mechanism, thereby resulting in an enhanced USF1/2-promoter binding. Last, subsequent suppressions of USF1/2 and phosphatases mRNA through siRNA gene silencing abolished the regulation. We demonstrate that APOA5 gene is up regulated by D-glucose and USF through phosphatase activation. These findings may provide a new cross talk between glucose and lipid metabolism.« less

  12. Astroglial pentose phosphate pathway rates in response to high-glucose environments

    PubMed Central

    Takahashi, Shinichi; Izawa, Yoshikane; Suzuki, Norihiro

    2012-01-01

    ROS (reactive oxygen species) play an essential role in the pathophysiology of diabetes, stroke and neurodegenerative disorders. Hyperglycaemia associated with diabetes enhances ROS production and causes oxidative stress in vascular endothelial cells, but adverse effects of either acute or chronic high-glucose environments on brain parenchymal cells remain unclear. The PPP (pentose phosphate pathway) and GSH participate in a major defence mechanism against ROS in brain, and we explored the role and regulation of the astroglial PPP in response to acute and chronic high-glucose environments. PPP activity was measured in cultured neurons and astroglia by determining the difference in rate of 14CO2 production from [1-14C]glucose and [6-14C]glucose. ROS production, mainly H2O2, and GSH were also assessed. Acutely elevated glucose concentrations in the culture media increased PPP activity and GSH level in astroglia, decreasing ROS production. Chronically elevated glucose environments also induced PPP activation. Immunohistochemical analyses revealed that chronic high-glucose environments induced ER (endoplasmic reticulum) stress (presumably through increased hexosamine biosynthetic pathway flux). Nuclear translocation of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), which regulates G6PDH (glyceraldehyde-6-phosphate dehydrogenase) by enhancing transcription, was also observed in association with BiP (immunoglobulin heavy-chain-binding protein) expression. Acute and chronic high-glucose environments activated the PPP in astroglia, preventing ROS elevation. Therefore a rapid decrease in glucose level seems to enhance ROS toxicity, perhaps contributing to neural damage when insulin levels given to diabetic patients are not properly calibrated and plasma glucose levels are not adequately maintained. These findings may also explain the lack of evidence for clinical benefits from strict glycaemic control during the acute phase of stroke. PMID:22300409

  13. MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase-Mediated Gluconeogenesis.

    PubMed

    Zhuo, Shu; Yang, Mengmei; Zhao, Yanan; Chen, Xiaofang; Zhang, Feifei; Li, Na; Yao, Pengle; Zhu, Tengfei; Mei, Hong; Wang, Shanshan; Li, Yu; Chen, Shiting; Le, Yingying

    2016-11-01

    MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes. © 2016 by the American Diabetes Association.

  14. Lifestyle, glucose regulation and the cognitive effects of glucose load in middle-aged adults.

    PubMed

    Riby, Leigh M; McLaughlin, Jennifer; Riby, Deborah M; Graham, Cheryl

    2008-11-01

    Interventions aimed at improving glucose regulatory mechanisms have been suggested as a possible source of cognitive enhancement in the elderly. In particular, previous research has identified episodic memory as a target for facilitation after either moderate increases in glycaemia (after a glucose drink) or after improvements in glucose regulation. The present study aimed to extend this research by examining the joint effects of glucose ingestion and glucose regulation on cognition. In addition, risk factors associated with the development of poor glucose regulation in middle-aged adults were considered. In a repeated measures design, thirty-three middle-aged adults (aged 35-55 years) performed a battery of memory and non-memory tasks after either 25 g or 50 g glucose or a sweetness matched placebo drink. To assess the impact of individual differences in glucose regulation, blood glucose measurements were taken on four occasions during testing. A lifestyle and diet questionnaire was also administered. Consistent with previous research, episodic memory ability benefited from glucose ingestion when task demands were high. Blood glucose concentration was also found to predict performance across a number of cognitive domains. Interestingly, the risk factors associated with poor glucose regulation were linked to dietary impacts traditionally associated with poor health, e.g. the consumption of high-sugar sweets and drinks. The research replicates earlier work suggesting that task demands are critical to the glucose facilitation effect. Importantly, the data demonstrate clear associations between elevated glycaemia and relatively poor cognitive performance, which may be partly due to the effect of dietary and lifestyle factors.

  15. Glucose and pyruvate metabolism in preimplantation blastocysts from normal and diabetic rats.

    PubMed

    Dufrasnes, E; Vanderheyden, I; Robin, D; Delcourt, J; Pampfer, S; De Hertogh, R

    1993-05-01

    Glucose metabolism was analysed in day-5 rat blastocysts incubated in the presence of [5-3H]-, [6-14C]- or [U-14C]glucose. Glycolysis, quantified by 3H2O recovery rate, was the main pathway of glucose utilization by fresh (11.5 +/- 0.36 pmol per embryo h-1) or cultured (24 h) blastocysts (20.4 +/- 0.6 pmol per embryo h-1). Glucose consumption rate was almost saturated at a medium glucose concentration of 0.28 mmol l-1 (Km: 0.17 mmol l-1; Vmax: 23 pmol per embryo h-1). A further 10% increase in glucose utilization was obtained with a tenfold higher glucose concentration (3 mmol l-1). Phloretin completely abolished the rapid component of glucose utilization kinetics, suggesting the existence of a Na(+)-independent glucose transport system. Less than 1% of [6-14C]glucose consumed by cultured blastocysts was oxidized through the Krebs cycle. [1-14C]pyruvate, however, was oxidized at a rate of 2 pmol per embryo h-1 by fresh blastocysts. The pentose-phosphate pathway accounted for about 2% of glucose utilization. One to two per cent of the total glucose metabolized in 24 h was retained in macromolecules. Insulin had no effect on glucose uptake, utilization, incorporation and turnover, or on pyruvate oxidation. Blastocysts from diabetic mothers utilized glucose at a rate similar to that of normal blastocysts. These results show that glucose is actively taken up by rat blastocysts and utilized mainly through the Embden-Meyerhof pathway, which is rapidly saturated at low glucose concentrations. Retention of glucose-derived products in macromolecules, although relatively small, may modulate the effect of high glucose concentrations on embryo growth.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Higher fasting glucose is associated with poorer cognition among healthy young adults.

    PubMed

    Hawkins, Misty A W; Gunstad, John; Calvo, Dayana; Spitznagel, Mary Beth

    2016-02-01

    Obesity is associated with cognitive deficits; however, the mechanisms are unclear, especially among otherwise healthy adults. Our objectives were to examine (a) whether obesity is linked to elevations in fasting glucose and (b) whether these elevations are associated with cognitive impairment among otherwise healthy young adults. Participants were 35 normal weight adults and 35 young adults with obesity who completed a task from the Automated Neuropsychological Assessment Metrics-4 (ANAM-4). Measured body mass index (BMI) and fasting blood glucose levels (mg/dL) were examined. Persons with obesity had higher fasting glucose levels than normal weight persons (p = .03). After applying Bonferroni correction for multiple tests, higher fasting glucose predicted less accurate performance on tests of inhibitory control: Go/No-Go Commission Errors (β = .33, p = .004). No effects were observed for sustained attention or working memory (ps ≥. 049). Persons with glucose levels in the prediabetes range had nearly twice as many errors as those with normal glucose, a large effect that was independent of BMI. Young adults who were obese but otherwise healthy had higher fasting glucose levels compared with normal weight peers. Higher glucose levels were associated with poorer cognitive performance on tests of inhibitory control, especially among individuals with prediabetes levels. Thus, subclinical elevations in blood glucose may contribute to cognitive impairment and, ultimately, greater impulsivity-well in advance of the development of chronic disease states (e.g., insulin resistance or Type 2 diabetes) and independently of excess adiposity--though prospective studies are needed to determine directionality of this relationship. (c) 2016 APA, all rights reserved).

  17. High Glucose Inhibits Neural Stem Cell Differentiation Through Oxidative Stress and Endoplasmic Reticulum Stress.

    PubMed

    Chen, Xi; Shen, Wei-Bin; Yang, Penghua; Dong, Daoyin; Sun, Winny; Yang, Peixin

    2018-06-01

    Maternal diabetes induces neural tube defects by suppressing neurogenesis in the developing neuroepithelium. Our recent study further revealed that high glucose inhibited embryonic stem cell differentiation into neural lineage cells. However, the mechanism whereby high glucose suppresses neural differentiation is unclear. To investigate whether high glucose-induced oxidative stress and endoplasmic reticulum (ER) stress lead to the inhibition of neural differentiation, the effect of high glucose on neural stem cell (the C17.2 cell line) differentiation was examined. Neural stem cells were cultured in normal glucose (5 mM) or high glucose (25 mM) differentiation medium for 3, 5, and 7 days. High glucose suppressed neural stem cell differentiation by significantly decreasing the expression of the neuron marker Tuj1 and the glial cell marker GFAP and the numbers of Tuj1 + and GFAP + cells. The antioxidant enzyme superoxide dismutase mimetic Tempol reversed high glucose-decreased Tuj1 and GFAP expression and restored the numbers of neurons and glial cells differentiated from neural stem cells. Hydrogen peroxide treatment imitated the inhibitory effect of high glucose on neural stem cell differentiation. Both high glucose and hydrogen peroxide triggered ER stress, whereas Tempol blocked high glucose-induced ER stress. The ER stress inhibitor, 4-phenylbutyrate, abolished the inhibition of high glucose or hydrogen peroxide on neural stem cell differentiation. Thus, oxidative stress and its resultant ER stress mediate the inhibitory effect of high glucose on neural stem cell differentiation.

  18. [Puerariae Lobatae Radix elevated expression levels of OB-R, IRS2, GLUT1 and GLUT2 to regulate glucose metabolism in insulin-resistance HepG2 cells].

    PubMed

    Li, Yu; Luo, Xin-Xin; Yan, Feng-Dong; Wei, Zhang-Bin; Tu, Jun

    2017-05-01

    To observe the anti-hyperglycemic effect of Puerariae Lobatae Radix in hepatocyte insulin resistance(IR) models, and investigate its preliminary molecular mechanism. IR-HepG2 cell model was stably established with 1×10-9 mol•L⁻¹ insulin plus 3.75×10-6 mol•L-1 dexamethasone treatment for 48 h according to optimized protocol in our research group. After IR-HepG2 cells were treated with different concentrations(5%,10% and 15%) of Puerariae Lobatae Radix-containing serum, cell viability was detected by CCK-8 assay; the glucose consumptions in IR-HepG2 cells were separately detected at different time points (12, 15, 18, 21, 24, 30, 36 h) by using glucose oxidase method; intracellular glycogen content was detected by anthrone method; and the protein expression levels of leptin receptor (Ob-R), insulin receptor substrate-2 (IRS2), glucose transporter 1(GLUT1) and GLUT2 were detected by Western blot assay. The results showed that Puerariae Lobatae Radix-containing serum (5%, 10% and 15%) had no significant effect on IR-HepG2 cell viability; 5% and 10% Puerariae Lobatae Radix-containing serum significantly increased glucose consumption of IR-HepG2 cells (P<0.01) at 18, 21 and 24 h; 15% Puerariae Lobatae Radix-containing serum elevated the glucose consumption of IR-HepG2 cells at 15 h (P<0.05), and significantly elevated the glucose consumption at 18, 21, 24 and 30 h (P<0.01) in a dose-dependent manner. The optimized time of anti-hyperglycemic effect was defined as 24 h, and further study showed that Puerariae Lobatae Radix-containing serum could increase intracellular glycogen content after 24 h treatment (P<0.01), and up-regulate IRS2, Ob-R, GLUT1 and GLUT2 protein expression levels. Our results indicated that Puerariae Lobatae Radix-containing serum could achieve the anti-hyperglycemic effect through important PI3K/PDK signaling pathway partially by up-regulating the expression levels of Ob-R and IRS2, GLUT1 and GLUT2 in IR-HepG2 cells, accelerating the glucose

  19. The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment.

    PubMed

    Riby, L M; Marriott, A; Bullock, R; Hancock, J; Smallwood, J; McLaughlin, J

    2009-04-01

    Previous research investigating the impact of glucose ingestion and/or improvements in glucose regulation has found selective cognitive facilitation on episodic memory tasks in successful ageing and dementia. The present study aimed to extend this research to mild cognitive impairment (MCI). In a repeated-measures design, 24 older adults with and 24 older adults without MCI performed a battery of memory and attention tasks after 25 g of glucose or a sweetness matched placebo. In addition, to assess the impact of individual differences in glucose regulation, blood glucose measurements were taken throughout the testing session. Consistent with previous research, cognitive facilitation was observed for episodic memory tasks only in both successful ageing and MCI. Older adults with MCI had a similar glucose regulatory response as controls but their fasting levels were elevated. Notably, higher levels of blood glucose were associated with impaired memory performance in both the glucose and placebo conditions. Importantly, both blood glucose and memory performance indices were significant predictors of MCI status. The utility of glucose supplementation and the use of glucose regulation as a biological marker are discussed in relation to these data.

  20. CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

    PubMed

    Zheng, Hongzhi; Fu, Jingqi; Xue, Peng; Zhao, Rui; Dong, Jian; Liu, Dianxin; Yamamoto, Masayuki; Tong, Qingchun; Teng, Weiping; Qu, Weidong; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo

    2015-04-01

    The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.

  1. Interstitial fluid glucose dynamics during insulin-induced hypoglycaemia.

    PubMed

    Steil, G M; Rebrin, K; Hariri, F; Jinagonda, S; Tadros, S; Darwin, C; Saad, M F

    2005-09-01

    Glucose sensors often measure s.c. interstitial fluid (ISF) glucose rather than blood or plasma glucose. Putative differences between plasma and ISF glucose include a protracted delay during the recovery from hypoglycaemia and an increased gradient during hyperinsulinaemia. These have often been investigated using sensor systems that have delays due to signal smoothing, or require long equilibration times. The aim of the present study was to define these relationships during hypoglycaemia in a well-equilibrated system with no smoothing. Hypoglycaemia was induced by i.v. insulin infusion (360 pmol.m(-2).min(-1)) in ten non-diabetic subjects. Glucose was sequentially clamped at approximately 5, 4.2 and 3.1 mmol/l and allowed to return to normoglycaemia. Subjects wore two s.c. glucose sensors (Medtronic MiniMed, Northridge, CA, USA) that had been inserted for more than 12 h. A two-compartment model was used to quantify the delay and gradient. The delay during the fall in plasma glucose was not different from the delay during recovery (8.3+/-0.67 vs 6.3+/-1.1 min; p=0.27) and no differences were observed in the ratio of sensor current to plasma glucose at basal insulin (2.7+/-0.25 nA.mmol(-1).l) compared with any of the hyperinsulinaemic clamp phases (2.8+/-0.18, 2.7+/-0.021, 2.9+/-0.21; p=NS). The ratio was significantly elevated following recovery to normoglycaemia (3.1+/-0.2 nA.mmol(-1).l; p<0.001). The elevated ratio suggests that the plasma to ISF glucose gradient was decreased following hypoglycaemia, possibly due to increased skin blood flow. Recovery from hypoglycaemia is not accompanied by a protracted delay and insulin does not increase the plasma to s.c. ISF glucose gradient.

  2. Glucose Deprivation Triggers Protein Kinase C-dependent β-Catenin Proteasomal Degradation*

    PubMed Central

    Choi, Seung-Won; Song, Jun-Kyu; Yim, Ye-Seal; Yun, Ho-Geun; Chun, Kyung-Hee

    2015-01-01

    Autophagy is a conserved process that contributes to cell homeostasis. It is well known that induction mainly occurs in response to nutrient starvation, such as starvation of amino acids and insulin, and its mechanisms have been extensively characterized. However, the mechanisms behind cellular glucose deprivation-induced autophagy are as of now poorly understood. In the present study, we determined a mechanism by which glucose deprivation induced the PKC-dependent proteasomal degradation of β-catenin, leading to autophagy. Glucose deprivation was shown to cause a sub-G1 transition and enhancement of the LC3-II protein levels, whereas β-catenin protein underwent degradation in a proteasome-dependent manner. Moreover, the inhibition of GSK3β was unable to abolish the glucose deprivation-mediated β-catenin degradation or up-regulation of LC3-II protein levels, which suggested GSK3β-independent protein degradation. Intriguingly, the inhibition of PKCα using a pharmacological inhibitor and transfection of siRNA for PKCα was observed to effectively block glucose deprivation-induced β-catenin degradation as well as the increase in LC3-II levels and the accumulation of a sub-G1 population. Together, our results demonstrated a molecular mechanism by which glucose deprivation can induce the GSK3β-independent protein degradation of β-catenin, leading to autophagy. PMID:25691573

  3. Effect of sulfonylureas administered centrally on the blood glucose level in immobilization stress model.

    PubMed

    Sharma, Naveen; Sim, Yun-Beom; Park, Soo-Hyun; Lim, Su-Min; Kim, Sung-Su; Jung, Jun-Sub; Hong, Jae-Seung; Suh, Hong-Won

    2015-05-01

    Sulfonylureas are widely used as an antidiabetic drug. In the present study, the effects of sulfonylurea administered supraspinally on immobilization stress-induced blood glucose level were studied in ICR mice. Mice were once enforced into immobilization stress for 30 min and returned to the cage. The blood glucose level was measured 30, 60, and 120 min after immobilization stress initiation. We found that intracerebroventricular (i.c.v.) injection with 30 µg of glyburide, glipizide, glimepiride or tolazamide attenuated the increased blood glucose level induced by immobilization stress. Immobilization stress causes an elevation of the blood corticosterone and insulin levels. Sulfonylureas pretreated i.c.v. caused a further elevation of the blood corticosterone level when mice were forced into the stress. In addition, sulfonylureas pretreated i.c.v. alone caused an elevation of the plasma insulin level. Furthermore, immobilization stress-induced insulin level was reduced by i.c.v. pretreated sulfonylureas. Our results suggest that lowering effect of sulfonylureas administered supraspinally against immobilization stress-induced increase of the blood glucose level appears to be primarily mediated via elevation of the plasma insulin level.

  4. AMPKα2 deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle.

    PubMed

    Abbott, Marcia J; Bogachus, Lindsey D; Turcotte, Lorraine P

    2011-07-01

    AMP-activated protein kinase (AMPK) is a fuel sensor in skeletal muscle with multiple downstream signaling targets that may be triggered by increases in intracellular Ca(2+) concentration ([Ca(2+)]). The purpose of this study was to determine whether increases in intracellular [Ca(2+)] induced by caffeine act solely via AMPKα(2) and whether AMPKα(2) is essential to increase glucose uptake, fatty acid (FA) uptake, and FA oxidation in contracting skeletal muscle. Hindlimbs from wild-type (WT) or AMPKα(2) dominant-negative (DN) transgene mice were perfused during rest (n = 11), treatment with 3 mM caffeine (n = 10), or muscle contraction (n = 11). Time-dependent effects on glucose and FA uptake were uncovered throughout the 20-min muscle contraction perfusion period (P < 0.05). Glucose uptake rates did not increase in DN mice during muscle contraction until the last 5 min of the protocol (P < 0.05). FA uptake rates were elevated at the onset of muscle contraction and diminished by the end of the protocol in DN mice (P < 0.05). FA oxidation rates were abolished in the DN mice during muscle contraction (P < 0.05). The DN transgene had no effect on caffeine-induced FA uptake and oxidation (P > 0.05). Glucose uptake rates were blunted in caffeine-treated DN mice (P < 0.05). The DN transgene resulted in a greater use of intramuscular triglycerides as a fuel source during muscle contraction. The DN transgene did not alter caffeine- or contraction-mediated changes in the phosphorylation of Ca(2+)/calmodulin-dependent protein kinase I or ERK1/2 (P > 0.05). These data suggest that AMPKα(2) is involved in the regulation of substrate uptake in a time-dependent manner in contracting muscle but is not necessary for regulation of FA uptake and oxidation during caffeine treatment.

  5. Hyperuricemia Is a Risk Factor for the Onset of Impaired Fasting Glucose in Men with a High Plasma Glucose Level: A Community-Based Study

    PubMed Central

    Miyake, Teruki; Kumagi, Teru; Furukawa, Shinya; Hirooka, Masashi; Kawasaki, Keitarou; Koizumi, Mitsuhito; Todo, Yasuhiko; Yamamoto, Shin; Abe, Masanori; Kitai, Kohichiro; Matsuura, Bunzo; Hiasa, Yoichi

    2014-01-01

    Background It is not clear whether elevated uric acid is a risk factor for the onset of impaired fasting glucose after stratifying by baseline fasting plasma glucose levels. We conducted a community-based retrospective longitudinal cohort study to clarify the relationship between uric acid levels and the onset of impaired fasting glucose, according to baseline fasting plasma glucose levels. Methods We enrolled 6,403 persons (3,194 men and 3,209 women), each of whom was 18–80 years old and had >2 annual check-ups during 2003–2010. After excluding persons who had fasting plasma glucose levels ≥6.11 mM and/or were currently taking anti-diabetic agents, the remaining 5,924 subjects were classified into quartiles according to baseline fasting plasma glucose levels. The onset of impaired fasting glucose was defined as fasting plasma glucose ≥6.11 mM during the observation period. Results In the quartile groups, 0.9%, 2.1%, 3.4%, and 20.2% of the men developed impaired fasting glucose, respectively, and 0.1%, 0.3%, 0.5%, and 5.6% of the women developed impaired fasting glucose, respectively (P trend <0.001). After adjusting for age, body mass index, systolic blood pressure, triacylglycerols, high density lipoprotein-cholesterol, creatinine, fatty liver, family history of diabetes, alcohol consumption, and current smoking, uric acid levels were positively associated with onset of impaired fasting glucose in men with highest-quartile fasting plasma glucose levels (adjusted hazard ratio, 1.003; 95% confidence interval, 1.0001–1.005, P = 0.041). Conclusions Among men with high fasting plasma glucose, hyperuricemia may be independently associated with an elevated risk of developing impaired fasting glucose. PMID:25237894

  6. Pro-inflammatory mediators disrupt glucose homeostasis in airway surface liquid ‡

    PubMed Central

    Garnett, James P.; Nguyen, Trang T.; Moffatt, James D.; Pelham, Elizabeth R.; Kalsi, Kameljit K.; Baker, Emma H.; Baines, Deborah L.

    2012-01-01

    The glucose concentration of the airway surface liquid (ASL) is much lower than blood and is tightly regulated by the airway epithelium. ASL glucose is elevated in patients with viral colds, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. Elevated ASL glucose is also associated with increased incidence of respiratory infection. However, the mechanism by which ASL glucose increases under inflammatory conditions is unknown. The aim of this study was to investigate the effect of pro-inflammatory mediators (PIMs) on the mechanisms governing airway glucose homeostasis in polarised monolayers of human airway (H441) and primary human bronchial epithelial (HBE) cells. Monolayers were treated with TNF-α, IFN-γ and LPS over 72 hours. PIM treatment led to increase in ASL glucose concentration and significantly reduced H441 and HBE transepithelial resistance (RT). This decline in RT was associated with an increase in paracellular permeability of glucose. Similar enhanced rates of paracellular glucose flux were also observed across excised trachea from LPS-treated mice. Interestingly, PIMs enhanced glucose uptake across the apical, but not the basolateral, membrane of H441 and HBE monolayers. This increase was predominantly via phloretin-sensitive GLUT-mediated uptake, which coincided with an increase in GLUT2 and GLUT10 abundance. In conclusion, exposure of airway epithelial monolayers to PIMs results in increased paracellular glucose flux, and apical GLUT-mediated glucose uptake. However uptake was insufficient to limit glucose accumulation in ASL. These data provide for the first time, a mechanism to support clinical findings that ASL glucose concentration is increased in patients with airway inflammation. PMID:22623330

  7. DOR(2)-selective but not DOR(1)-selective antagonist abolishes anxiolytic-like effects of the δ opioid receptor agonist KNT-127.

    PubMed

    Sugiyama, Azusa; Nagase, Hiroshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko; Saitoh, Akiyoshi

    2014-04-01

    Recently, we reported that the δ opioid receptor (DOR) agonist KNT-127 produces anxiolytic-like effects in behaving rats. Here, we report on the roles of DOR subtypes ( DOR(1) and DOR(2)) play in mediating KNT-127-induced anxiolytic-like effects. Pretreatment with the DOR(2)-selective antagonist naltriben (NTB; 0.05mg/kg, s.c.) completely abolished KNT-127 (3.0mg/kg, s.c.)-induced anxiolytic-like effects in rats performing the elevated plus-maze task. By contrast, the DOR(1)-selective antagonist 7-benzylidenenaltrexone (BNTX; 0.5mg/kg, s.c.) produced no effect at a dose that completely blocked the antinociceptive effects of KNT-127. These findings were also supported by results from a light/dark test and open-field test. We clearly demonstrated that the DOR(2)-selective antagonist, but not the DOR(1)-selective antagonist, abolishes the anxiolytic-like effects of the DOR agonist KNT-127, suggesting different roles of these DOR subtypes in anxiety. We propose that DOR(2)-selective agonists would be good candidates for future development of anxiolytic drugs. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  8. Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions.

    PubMed

    Franko, Benoit; Brault, Julie; Jouve, Thomas; Beaumel, Sylvain; Benhamou, Pierre-Yves; Zaoui, Philippe; Stasia, Marie José

    2014-09-05

    High glucose (HG) or synthetic advanced glycation end-products (AGE) conditions are generally used to mimic diabetes in cellular models. Both models have shown an increase of apoptosis, oxidative stress and pro-inflammatory cytokine production in tubular cells. However, the impact of the two conditions combined has rarely been studied. In addition, the impact of glucose level variation due to cellular consumption is not clearly characterized in such experiments. Therefore, the aim of this study was to compare the effect of HG and AGE separately and of both on tubular cell phenotype changes in the HK2 cell line. Moreover, glucose consumption was monitored every hour to maintain the glucose level by supplementation throughout the experiments. We thus observed a significant decrease of apoptosis and H2O2 production in the HK2 cell. HG or AGE treatment induced an increase of total and mitochondrial apoptosis as well as TGF-β release compared to control conditions; however, AGE or HG led to apoptosis preferentially involving the mitochondria pathway. No cumulative effect of HG and AGE treatment was observed on apoptosis. However, a pretreatment with RAGE antibodies partially abolished the apoptotic effect of HG and completely abolished the apoptotic effect of AGE. In conclusion, tubular cells are sensitive to the lack of glucose as well as to the HG and AGE treatments, the AGE effect being more deleterious than the HG effect. Absence of a potential synergistic effect of HG and AGE could indicate that they act through a common pathway, possibly via the activation of the RAGE receptors. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Continuous Glucose Monitoring in Female NOD Mice Reveals Daily Rhythms and a Negative Correlation With Body Temperature.

    PubMed

    Korstanje, Ron; Ryan, Jennifer L; Savage, Holly S; Lyons, Bonnie L; Kane, Kevin G; Sukoff Rizzo, Stacey J

    2017-09-01

    Previous studies with continuous glucose monitoring in mice have been limited to several days or weeks, with the mouse's physical attachment to the equipment affecting behavior and measurements. In the current study, we measured blood glucose and body temperature at 10-second intervals for 12 weeks in a cohort of NOD/ShiLtJ female mice using wireless telemetry. This allowed us to obtain a high-resolution profile of the circadian rhythm of these two parameters and the onset of hyperglycemic development in real time. The most striking observations were the elevated nocturnal concentrations of glucose into the diabetic range days before elevations in diurnal glucose (when glucose concentrations are historically measured) and the strong, negative correlation between elevated blood glucose concentrations and body temperature with a steady decline of the body temperature with diabetes development. Taken together, this technological advancement provides improved resolution in the study of the disease trajectory of diabetes in mouse models, including relevant translatability to the current technologies of continuous glucose monitoring now regularly used in patients. Copyright © 2017 Endocrine Society.

  10. Whole cell immobilization of refractory glucose isomerase using tris(hydroxymethyl)phosphine as crosslinker for preparation of high fructose corn syrup at elevated temperature.

    PubMed

    Jia, Dong-Xu; Wang, Teng; Liu, Zi-Jian; Jin, Li-Qun; Li, Jia-Jia; Liao, Cheng-Jun; Chen, De-Shui; Zheng, Yu-Guo

    2018-04-04

    Glucose isomerase (GI) responsible for catalyzing the isomerization from d-glucose to d-fructose, was an important enzyme for producing high fructose corn syrup (HFCS). In a quest to prepare HFCS at elevated temperature and facilitate enzymatic recovery, an effective procedure for whole cell immobilization of refractory Thermus oshimai glucose isomerase (ToGI) onto Celite 545 using tris(hydroxymethyl)phosphine (THP) as crosslinker was established. The immobilized biocatalyst showed an activity of approximate 127.3 U/(g·immobilized product) via optimization in terms of cells loading, crosslinker concentration and crosslinking time. The pH optimum of the immobilized biocatalyst was displaced from pH 8.0 of native enzyme to neutral pH 7.0. Compared with conventional glutaraldehyde (GLU)-immobilized cells, it possessed the enhanced thermostability with 70.1% residual activity retaining after incubation at 90°C for 72 h. Moreover, the THP-immobilized biocatalyst exhibited superior operational stability, in which it retained 85.8% of initial activity after 15 batches of bioconversion at 85°C. This study paved a way for reducing catalysis cost for upscale preparation of HFCS with higher d-fructose concentration. Copyright © 2018 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  11. Role of central nervous system glucagon-like Peptide-1 receptors in enteric glucose sensing.

    PubMed

    Knauf, Claude; Cani, Patrice D; Kim, Dong-Hoon; Iglesias, Miguel A; Chabo, Chantal; Waget, Aurélie; Colom, André; Rastrelli, Sophie; Delzenne, Nathalie M; Drucker, Daniel J; Seeley, Randy J; Burcelin, Remy

    2008-10-01

    Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system. We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y-and proopiomelanocortin-green fluorescent protein-expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain. Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose-sensitive c-Fos-positive cells of the arcuate nucleus colocalized with neuropeptide Y-positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression. We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.

  12. Loss of angiopoietin-like 4 (ANGPTL4) in mice with diet-induced obesity uncouples visceral obesity from glucose intolerance partly via the gut microbiota.

    PubMed

    Janssen, Aafke W F; Katiraei, Saeed; Bartosinska, Barbara; Eberhard, Daniel; Willems van Dijk, Ko; Kersten, Sander

    2018-06-01

    Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4 -/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. We chronically fed wild-type (WT) and Angptl4 -/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4 -/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4

  13. Methanolic leaf extract of Gymnema sylvestre augments glucose uptake and ameliorates insulin resistance by upregulating glucose transporter-4, peroxisome proliferator-activated receptor-gamma, adiponectin, and leptin levels in vitro.

    PubMed

    Kumar, Puttanarasaiah Mahesh; Venkataranganna, Marikunte V; Manjunath, Kirangadur; Viswanatha, Gollapalle L; Ashok, Godavarthi

    2016-01-01

    The present study was undertaken to evaluate the effect of methanolic leaf extract of Gymnema sylvestre (MLGS) on glucose transport (GLUT) and insulin resistance in vitro. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) and GLUT-4 expression were assessed in L6 myotubes for concluding the GLUT activity, and adiponectin and leptin expression was studied in 3T3 L1 murine adipocyte cell line to determine the effect of MLGS (250-750 μg/ml) on insulin resistance. The findings of the experiments have demonstrated a significant and dose-dependent increase in glucose uptake in all the tested concentrations of MLGS, further the glucose uptake activity of MLGS (750 μg/ml) was at par with rosiglitazone (50 μg/ml). Concomitantly, MLGS has shown enhanced GLUT-4 and PPAR-γ gene expressions in L6 myotubes. Furthermore, cycloheximide (CHX) had completely abolished the glucose uptake activity of MLGS when co-incubated, which further confirmed that glucose uptake activity of MLGS was linked to enhanced expression of GLUT-4 and PPAR-γ. In addition, in another experimental set, MLGS showed enhanced expression of adiponectin and leptin, thus confirms the ameliorative effect of MLGS on insulin resistance. These findings suggest that MLGS has an enhanced glucose uptake activity in L6 myotubes, and ameliorate the insulin resistance in 3T3 L1 murine adipocyte cell line in vitro.

  14. Conjoint regulation of glucagon concentrations via plasma insulin and glucose in dairy cows.

    PubMed

    Zarrin, M; Wellnitz, O; Bruckmaier, R M

    2015-04-01

    Insulin and glucagon are glucoregulatory hormones that contribute to glucose homeostasis. Plasma insulin is elevated during normoglycemia or hyperglycemia and acts as a suppressor of glucagon secretion. We have investigated if and how insulin and glucose contribute to the regulation of glucagon secretion through long term (48 h) elevated insulin concentrations during simultaneous hypoglycemia or euglycemia in mid-lactating dairy cows. Nineteen Holstein dairy cows were randomly assigned to 3 treatment groups: an intravenous insulin infusion (HypoG, n = 5) to decrease plasma glucose concentrations (2.5 mmol/L), a hyperinsulinemic-euglycemic clamp to study effects of insulin at simultaneously normal glucose concentrations (EuG, n = 6) and a 0.9% saline infusion (NaCl, n = 8). Plasma glucose was measured at 5-min intervals, and insulin and glucose infusion rates were adjusted accordingly. Area under the curve of hourly glucose, insulin, and glucagon concentrations on day 2 of infusion was evaluated by analysis of variance with treatments as fixed effect. Insulin infusion caused an increase of plasma insulin area under the curve (AUC)/h in HypoG (41.9 ± 8.1 mU/L) and EuG (57.8 ± 7.8 mU/L) compared with NaCl (13.9 ± 1.1 mU/L; P < 0.01). Induced hyperinsulinemia caused a decline of plasma glucose AUC/h to 2.3 ± 0.1 mmol/L in HypoG (P < 0.01), whereas plasma glucose AUC/h remained unchanged in EuG (3.8 ± 0.2 mmol/L) and NaCl (4.1 ± 0.1 mmol/L). Plasma glucagon AUC/h was lower in EuG (84.0 ± 6.3 pg/mL; P < 0.05) and elevated in HypoG (129.0 ± 7.0 pg/mL; P < 0.01) as compared with NaCl (106.1 ± 5.4 pg/mL). The results show that intravenous insulin infusion induces elevated glucagon concentrations during hypoglycemia, although the same insulin infusion reduces glucagon concentrations at simultaneously normal glucose concentrations. Thus, insulin does not generally have an inhibitory effect on glucagon concentrations. If simultaneously glucose is low and insulin is

  15. High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature.

    PubMed

    Li, Wei; Maloney, Ronald E; Aw, Tak Yee

    2015-08-01

    We previously demonstrated that in normal glucose (5mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG-occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG-occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  16. High glucose, glucose fluctuation and carbonyl stress enhance brain microvascular endothelial barrier dysfunction: Implications for diabetic cerebral microvasculature

    PubMed Central

    Li, Wei; Maloney, Ronald E.; Aw, Tak Yee

    2015-01-01

    We previously demonstrated that in normal glucose (5 mM), methylglyoxal (MG, a model of carbonyl stress) induced brain microvascular endothelial cell (IHEC) dysfunction that was associated with occludin glycation and prevented by N-acetylcysteine (NAC). Herein, we investigated the impact of high glucose and low GSH, conditions that mimicked the diabetic state, on MG-induced IHEC dysfunction. MG-induced loss of transendothelial electrical resistance (TEER) was potentiated in IHECs cultured for 7 or 12 days in 25 mM glucose (hyperglycemia); moreover, barrier function remained disrupted 6 h after cell transfer to normal glucose media (acute glycemic fluctuation). Notably, basal occludin glycation was elevated under these glycemic states. TEER loss was exaggerated by inhibition of glutathione (GSH) synthesis and abrogated by NAC, which corresponded to GSH decreases and increases, respectively. Significantly, glyoxalase II activity was attenuated in hyperglycemic cells. Moreover, hyperglycemia and GSH inhibition increased MG accumulation, consistent with a compromised capacity for MG elimination. α-Oxoaldehydes (MG plus glyoxal) levels were elevated in streptozotocin-induced diabetic rat plasma. Immunohistochemistry revealed a prevalence of MG-positive, but fewer occludin-positive microvessels in the diabetic brain in vivo, and Western analysis confirmed an increase in MG–occludin adducts. These results provide the first evidence that hyperglycemia and acute glucose fluctuation promote MG–occludin formation and exacerbate brain microvascular endothelial dysfunction. Low occludin expression and high glycated-occludin contents in diabetic brain in vivo are factors that would contribute to the dysfunction of the cerebral microvasculature during diabetes. PMID:25867911

  17. Intestinal Glucose Absorption Was Reduced by Vertical Sleeve Gastrectomy via Decreased Gastric Leptin Secretion.

    PubMed

    Du, Jinpeng; Hu, Chaojie; Bai, Jie; Peng, Miaomiao; Wang, Qingbo; Zhao, Ning; Wang, Yu; Wang, Guobin; Tao, Kaixiong; Wang, Geng; Xia, Zefeng

    2018-06-18

    The unique effects of gastric resection after vertical sleeve gastrectomy (VSG) on type 2 diabetes mellitus remain unclear. This work aimed to investigate the effects of VSG on gastric leptin expression and intestinal glucose absorption in high-fat diet-induced obesity. Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. HFD mice were randomized into VSG and sham-operation groups, and the relevant parameters were measured at 8 weeks postoperation. Higher gastric leptin expression and increased intestinal glucose transport were observed in the HFD mice. Furthermore, VSG reduced gastric leptin expression and the intestinal absorption of alimentary glucose. Both exogenous leptin replenishment during the oral glucose tolerance test (OGTT) and the addition of leptin into the everted isolated jejunum loops in vitro restored the glucose transport capacity in VSG-operated mice, and this effect was abolished when the glucose transporter GLUT2 was blocked with phloretin. Moreover, phloretin almost completely suppressed glucose transport in the HFD mice. Intestinal immunohistochemistry in the obese mice showed increased GLUT2 and diminished sodium glucose co-transporter 1 (SGLT-1) in the apical membrane of enterocytes. Decreased GLUT2 and enhanced SGLT1 were observed following VSG. VSG also reduced the phosphorylation status of protein kinase C isoenzyme β II (PKCβ II) in the jejunum, which was stimulated by the combination of leptin and glucose. Our data demonstrated that the decreased secretion of gastric leptin in VSG results in a decrease in intestinal glucose absorption via modulation of GLUT2 translocation.

  18. Glucose enhances tilapia against Edwardsiella tarda infection through metabolome reprogramming.

    PubMed

    Zeng, Zao-hai; Du, Chao-Chao; Liu, Shi-Rao; Li, Hui; Peng, Xuan-Xian; Peng, Bo

    2017-02-01

    We have recently reported that the survival of tilapia, Oreochromis niloticus, during Edwardsiella tarda infection is tightly associated with their metabolome, where the survived O. niloticus has distinct metabolomic profile to dying O. niloticus. Glucose is the key metabolite to distinguish the survival- and dying-metabolome. More importantly, exogenous administration of glucose to the fish greatly enhances their survival for the infection, indicating the functional roles of glucose in metabolome repurposing, known as reprogramming metabolomics. However, the underlying information for the reprogramming is not yet available. Here, GC/MS based metabolomics is used to understand the mechanisms by which how exogenous glucose elevates O. niloticus, anti-infectious ability to E. tarda. Results showed that exogenous glucose promotes stearic acid and palmitic acid biosynthesis but attenuates TCA cycle to potentiate O. niloticus against bacterial infection, which is confirmed by the fact that exogenous stearic acid increases immune protection in O. niloticus against E. tarda infection in a manner of Mx protein. These results indicate that exogenous glucose reprograms O. niloticus anti-infective metabolome that characterizes elevation of stearic acid and palmitic acid and attenuation of the TCA cycle. Therefore, our results proposed a novel mechanism that glucose promotes unsaturated fatty acid biosynthesis to cope with infection, thereby highlighting a potential way of enhancing fish immunity in aquaculture. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Brain glucose metabolism in an animal model of depression.

    PubMed

    Detka, J; Kurek, A; Kucharczyk, M; Głombik, K; Basta-Kaim, A; Kubera, M; Lasoń, W; Budziszewska, B

    2015-06-04

    An increasing number of data support the involvement of disturbances in glucose metabolism in the pathogenesis of depression. We previously reported that glucose and glycogen concentrations in brain structures important for depression are higher in a prenatal stress model of depression when compared with control animals. A marked rise in the concentrations of these carbohydrates and glucose transporters were evident in prenatally stressed animals subjected to acute stress and glucose loading in adulthood. To determine whether elevated levels of brain glucose are associated with a change in its metabolism in this model, we assessed key glycolytic enzymes (hexokinase, phosphofructokinase and pyruvate kinase), products of glycolysis, i.e., pyruvate and lactate, and two selected enzymes of the tricarboxylic acid cycle (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase) in the hippocampus and frontal cortex. Additionally, we assessed glucose-6-phosphate dehydrogenase activity, a key enzyme in the pentose phosphate pathway (PPP). Prenatal stress increased the levels of phosphofructokinase, an important glycolytic enzyme, in the hippocampus and frontal cortex. However, prenatal stress had no effect on hexokinase or pyruvate kinase levels. The lactate concentration was elevated in prenatally stressed rats in the frontal cortex, and pyruvate levels remained unchanged. Among the tricarboxylic acid cycle enzymes, prenatal stress decreased the level of pyruvate dehydrogenase in the hippocampus, but it had no effect on α-ketoglutarate dehydrogenase. Like in the case of glucose and its transporters, also in the present study, differences in markers of glucose metabolism between control animals and those subjected to prenatal stress were not observed under basal conditions but in rats subjected to acute stress and glucose load in adulthood. Glucose-6-phosphate dehydrogenase activity was not reduced by prenatal stress but was found to be even higher in animals exposed to

  20. Oxytocin increases extrapancreatic glucagon secretion and glucose production in pancreatectomized dogs

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Altszuler, N.; Puma, F.; Winkler, B.

    1986-05-01

    Infusion of oxytocin into normal dogs increases plasma levels of insulin and glucagon and glucose production and uptake. To determine whether infused oxytocin also increases glucagon secretion from extrapancreatic sites, pancreatectomized dogs, off insulin of 18 hr, were infused with oxytocin and plasma glucagon, and glucose production and uptake were measured using the (6-/sup 3/H)glucose primer-infusion technique. The diabetic dogs, in the control period, had elevated plasma glucose and glucagon levels, an increased rate of glucose production, and a relative decrease in glucose uptake (decreased clearance). Infusion of oxytocin (500 ..mu..U/kg/min) caused a rise in plasma glucagon and glucose levels,more » increased glucose production, and further decreased glucose clearance. it is concluded that oxytocin can stimulate secretion of extrapancreatic glucagon, which contributes to the increased glucose production.« less

  1. Cerebrospinal Fluid Glucose and Lactate: Age-Specific Reference Values and Implications for Clinical Practice

    PubMed Central

    Leen, Wilhelmina G.; Willemsen, Michèl A.; Wevers, Ron A.; Verbeek, Marcel M.

    2012-01-01

    Cerebrospinal fluid (CSF) analysis is an important tool in the diagnostic work-up of many neurological disorders, but reference ranges for CSF glucose, CSF/plasma glucose ratio and CSF lactate based on studies with large numbers of CSF samples are not available. Our aim was to define age-specific reference values. In 1993 The Nijmegen Observational CSF Study was started. Results of all CSF samples that were analyzed between 1993 and 2008 at our laboratory were systematically collected and stored in our computerized database. After exclusion of CSF samples with an unknown or elevated erythrocyte count, an elevated leucocyte count, elevated concentrations of bilirubin, free hemoglobin, or total protein 9,036 CSF samples were further studied for CSF glucose (n = 8,871), CSF/plasma glucose ratio (n = 4,516) and CSF lactate values (n = 7,614). CSF glucose, CSF/plasma glucose ratio and CSF lactate were age-, but not sex dependent. Age-specific reference ranges were defined as 5–95th percentile ranges. CSF glucose 5th percentile values ranged from 1.8 to 2.9 mmol/L and 95th percentile values from 3.8 to 5.6 mmol/L. CSF/plasma glucose ratio 5th percentile values ranged from 0.41 to 0.53 and 95th percentile values from 0.82 to 1.19. CSF lactate 5th percentile values ranged from 0.88 to 1.41 mmol/L and 95th percentile values from 2.00 to 2.71 mmol/L. Reference ranges for all three parameters were widest in neonates and narrowest in toddlers, with lower and upper limits increasing with age. These reference values allow a reliable interpretation of CSF results in everyday clinical practice. Furthermore, hypoglycemia was associated with an increased CSF/plasma glucose ratio, whereas hyperglycemia did not affect the CSF/plasma glucose ratio. PMID:22880096

  2. Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates Hepatic Glucose Handling.

    PubMed

    Langlet, Fanny; Haeusler, Rebecca A; Lindén, Daniel; Ericson, Elke; Norris, Tyrrell; Johansson, Anders; Cook, Joshua R; Aizawa, Kumiko; Wang, Ling; Buettner, Christoph; Accili, Domenico

    2017-11-02

    Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. ENHANCING THE EFFECTIVENESS OF A PLAY INTERVENTION BY ABOLISHING THE REINFORCING VALUE OF STEREOTYPY: A PILOT STUDY

    PubMed Central

    Lang, Russell; O'Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio E; Machalicek, Wendy; Rispoli, Mandy; White, Pamela

    2009-01-01

    An alternating treatments design compared one condition in which a child with autism was allowed to engage in stereotypy freely prior to the intervention (abolishing operation component) to a second condition without the free-access period. Levels of stereotypy and problem behavior were lower and levels of functional play were higher in the condition with the abolishing operation component. These data provide preliminary support for the use of abolishing operations in interventions to increase the play skills of children with autism. PMID:20514199

  4. Enhancing the effectiveness of a play intervention by abolishing the reinforcing value of stereotypy: a pilot study.

    PubMed

    Lang, Russell; O'Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio E; Machalicek, Wendy; Rispoli, Mandy; White, Pamela

    2009-01-01

    An alternating treatments design compared one condition in which a child with autism was allowed to engage in stereotypy freely prior to the intervention (abolishing operation component) to a second condition without the free-access period. Levels of stereotypy and problem behavior were lower and levels of functional play were higher in the condition with the abolishing operation component. These data provide preliminary support for the use of abolishing operations in interventions to increase the play skills of children with autism.

  5. Unhealthy Phenotype as Indicated by Salivary Biomarkers: Glucose, Insulin, VEGF-A, and IL-12p70 in Obese Kuwaiti Adolescents

    PubMed Central

    Hartman, Mor-Li; Goodson, J. Max; Shi, Ping; Vargas, Jorel; Yaskell, Tina; Stephens, Danielle; Cugini, Maryann; Hasturk, Hatice; Barake, Roula; Alsmadi, Osama; Al-Mutawa, Sabiha; Ariga, Jitendra; Soparkar, Pramod; Behbehani, Jawad; Behbehani, Kazem; Welty, Francine

    2016-01-01

    Objective. Here, we investigated the relationships between obesity and the salivary concentrations of insulin, glucose, and 20 metabolic biomarkers in Kuwaiti adolescents. Previously, we have shown that certain salivary metabolic markers can act as surrogates for blood concentrations. Methods. Salivary samples of whole saliva were collected from 8,317 adolescents. Salivary glucose concentration was measured by a high-sensitivity glucose oxidase method implemented on a robotic chemical analyzer. The concentration of salivary insulin and 20 other metabolic biomarkers was assayed in 744 randomly selected saliva samples by multiplexed bead-based immunoassay. Results. Obesity was seen in 26.5% of the adolescents. Salivary insulin predicting hyperinsulinemia occurred in 4.3% of normal-weight adolescents, 8.3% of overweight adolescents, and 25.7% of obese adolescents (p < 0.0001). Salivary glucose predicting hyperglycemia was found in only 3% of obese children and was not predictive (p = 0.89). Elevated salivary glucose and insulin occurring together was associated with elevated vascular endothelial growth factor and reduced salivary interleukin-12. Conclusion. Considering the surrogate nature of salivary insulin and glucose, this study suggests that elevated insulin may be a dominant sign of metabolic disease in adolescent populations. It also appears that a proangiogenic environment may accompany elevated glucose in obese adolescents. PMID:27069678

  6. Vasopressin activates Akt/mTOR pathway in smooth muscle cells cultured in high glucose concentration

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Montes, Daniela K.; Brenet, Marianne; Muñoz, Vanessa C.

    Highlights: •AVP induces mTOR phosphorylation in A-10 cells cultured in high glucose concentration. •The mTOR phosphorylation is mediated by the PI3K/Akt pathway activation. •The AVP-induced mTOR phosphorylation inhibited autophagy and stimulated cell proliferation. -- Abstract: Mammalian target of rapamycin (mTOR) complex is a key regulator of autophagy, cell growth and proliferation. Here, we studied the effects of arginine vasopressin (AVP) on mTOR activation in vascular smooth muscle cells cultured in high glucose concentration. AVP induced the mTOR phosphorylation in A-10 cells grown in high glucose, in contrast to cells cultured in normal glucose; wherein, only basal phosphorylation was observed. Themore » AVP-induced mTOR phosphorylation was inhibited by a PI3K inhibitor. Moreover, the AVP-induced mTOR activation inhibited autophagy and increased thymidine incorporation in cells grown in high glucose. This increase was abolished by rapamycin which inhibits the mTORC1 complex formation. Our results suggest that AVP stimulates mTOR phosphorylation by activating the PI3K/Akt signaling pathway and, subsequently, inhibits autophagy and raises cell proliferation in A-10 cells maintained in high glucose concentration.« less

  7. Review of Adverse Events Associated With False Glucose Readings Measured by GDH-PQQ–Based Glucose Test Strips in the Presence of Interfering Sugars

    PubMed Central

    Frias, Juan P.; Lim, Christine G.; Ellison, John M.; Montandon, Carol M.

    2010-01-01

    OBJECTIVE To assess the implications of falsely elevated glucose readings measured with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) test strips. RESEARCH DESIGN AND METHODS We conducted a review of the Food and Drug Administration's Manufacturer and User Facility Device Experience database and medical literature for adverse events (AEs) associated with falsely elevated glucose readings with GDH-PQQ test strips in the presence of interfering sugars. RESULTS Eighty-two reports were identified: 16 (20%) were associated with death, 46 (56%) with severe hypoglycemia, and 12 (15%) with nonsevere hypoglycemia. In eight reports (10%), the AE was not described. Forty-two events (51%) occurred in the U.S. Although most events occurred in hospitalized patients, at least 14 (17%) occurred in outpatients. Agents most commonly associated with AEs were icodextrin-containing peritoneal dialysate and maltose-containing intravenous immune globulin. CONCLUSIONS GDH-PQQ test strips pose a safety risk to insulin-using patients treated with agents containing or metabolized to interfering sugars. PMID:20351227

  8. ERK1/2 mediates glucose-regulated POMC gene expression in hypothalamic neurons.

    PubMed

    Zhang, Juan; Zhou, Yunting; Chen, Cheng; Yu, Feiyuan; Wang, Yun; Gu, Jiang; Ma, Lian; Ho, Guyu

    2015-04-01

    Hypothalamic glucose-sensing neurons regulate the expression of genes encoding feeding-related neuropetides POMC, AgRP, and NPY - the key components governing metabolic homeostasis. AMP-activated protein kinase (AMPK) is postulated to be the molecular mediator relaying glucose signals to regulate the expression of these neuropeptides. Whether other signaling mediator(s) plays a role is not clear. In this study, we investigated the role of ERK1/2 using primary hypothalamic neurons as the model system. The primary neurons were differentiated from hypothalamic progenitor cells. The differentiated neurons possessed the characteristic neuronal cell morphology and expressed neuronal post-mitotic markers as well as leptin-regulated orexigenic POMC and anorexigenic AgRP/NPY genes. Treatment of cells with glucose dose-dependently increased POMC and decreased AgRP/NPY expression with a concurrent suppression of AMPK phosphorylation. In addition, glucose treatment dose-dependently increased the ERK1/2 phosphorylation. Blockade of ERK1/2 activity with its specific inhibitor PD98059 partially (approximately 50%) abolished glucose-induced POMC expression, but had little effect on AgRP/NPY expression. Conversely, blockade of AMPK activity with its specific inhibitor produced a partial (approximately 50%) reversion of low-glucose-suppressed POMC expression, but almost completely blunted the low-glucose-induced AgRP/NPY expression. The results indicate that ERK1/2 mediated POMC but not AgRP/NPY expression. Confirming the in vitro findings, i.c.v. administration of PD98059 in rats similarly attenuated glucose-induced POMC expression in the hypothalamus, but again had little effect on AgRP/NPY expression. The results are indicative of a novel role of ERK1/2 in glucose-regulated POMC expression and offer new mechanistic insights into hypothalamic glucose sensing. © 2015 Society for Endocrinology.

  9. Methanolic leaf extract of Gymnema sylvestre augments glucose uptake and ameliorates insulin resistance by upregulating glucose transporter-4, peroxisome proliferator-activated receptor-gamma, adiponectin, and leptin levels in vitro

    PubMed Central

    Kumar, Puttanarasaiah Mahesh; Venkataranganna, Marikunte V.; Manjunath, Kirangadur; Viswanatha, Gollapalle L.; Ashok, Godavarthi

    2016-01-01

    Aims: The present study was undertaken to evaluate the effect of methanolic leaf extract of Gymnema sylvestre (MLGS) on glucose transport (GLUT) and insulin resistance in vitro. Materials and Methods: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) and GLUT-4 expression were assessed in L6 myotubes for concluding the GLUT activity, and adiponectin and leptin expression was studied in 3T3 L1 murine adipocyte cell line to determine the effect of MLGS (250-750 μg/ml) on insulin resistance. Results: The findings of the experiments have demonstrated a significant and dose-dependent increase in glucose uptake in all the tested concentrations of MLGS, further the glucose uptake activity of MLGS (750 μg/ml) was at par with rosiglitazone (50 μg/ml). Concomitantly, MLGS has shown enhanced GLUT-4 and PPAR-γ gene expressions in L6 myotubes. Furthermore, cycloheximide (CHX) had completely abolished the glucose uptake activity of MLGS when co-incubated, which further confirmed that glucose uptake activity of MLGS was linked to enhanced expression of GLUT-4 and PPAR-γ. In addition, in another experimental set, MLGS showed enhanced expression of adiponectin and leptin, thus confirms the ameliorative effect of MLGS on insulin resistance. Conclusion: These findings suggest that MLGS has an enhanced glucose uptake activity in L6 myotubes, and ameliorate the insulin resistance in 3T3 L1 murine adipocyte cell line in vitro. PMID:27104035

  10. PPARγ activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats.

    PubMed

    Festuccia, William T; Blanchard, Pierre-Gilles; Belchior, Thiago; Chimin, Patricia; Paschoal, Vivian A; Magdalon, Juliana; Hirabara, Sandro M; Simões, Daniel; St-Pierre, Philippe; Carpinelli, Angelo; Marette, André; Deshaies, Yves

    2014-05-01

    mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPARγ activity. Herein, we tested the hypothesis that pharmacological PPARγ activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg·kg(-1)·day(-1)) in combination or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPARγ activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake.

  11. Behavior-associated and post-consumption glucose entry into the nucleus accumbens extracellular space during glucose free-drinking in trained rats

    PubMed Central

    Wakabayashi, Ken T.; Kiyatkin, Eugene A.

    2015-01-01

    Glucose is the primary energetic substrate for the metabolic activity of brain cells and its proper delivery from the arterial blood is essential for neural activity and normal brain functions. Glucose is also a unique natural reinforcer, supporting glucose-drinking behavior without food or water deprivation. While it is known that glucose enters brain tissue via gradient-dependent facilitated diffusion, it remains unclear how glucose levels are changed during natural behavior and whether the direct central action of ingested glucose can be involved in regulating glucose-drinking behavior. Here, we used glucose biosensors with high-speed amperometry to examine the pattern of phasic and tonic changes in extracellular glucose in the nucleus accumbens (NAc) during unrestricted glucose-drinking in well-trained rats. We found that the drinking behavior is highly cyclic and is associated with relatively large and prolonged increases in extracellular glucose levels. These increases had two distinct components: a highly phasic but relatively small behavior-related rise and a larger tonic elevation that results from the arrival of consumed glucose into the brain’s extracellular space. The large post-ingestion increases in NAc glucose began minutes after the cessation of drinking and were consistently associated with periods of non-drinking, suggesting that the central action of ingested glucose could inhibit drinking behavior by inducing a pause in activity between repeated drinking bouts. Finally, the difference in NAc glucose responses found between active, behavior-mediated and passive glucose delivery via an intra-gastric catheter confirms that motivated behavior is also associated with metabolic glucose use by brain cells. PMID:26190984

  12. Ca2+ influx does not trigger glucose-induced traffic of the insulin granules and alteration of their distribution.

    PubMed

    Niki, Ichiro; Niwa, Tae; Yu, Wei; Budzko, Dorota; Miki, Takashi; Senda, Takao

    2003-11-01

    This study investigated mechanisms by which glucose increases readily releasable secretory granules via acting on preexocytotic steps, i.e., intracellular granule movement and granule access to the plasma membrane using a pancreatic beta-cell line, MIN6. Glucose-induced activation of the movement occurred at a substimulatory concentration with regard to insulin output. Glucose activation of the movement was inhibited by pretreatment with thapsigargin plus acetylcholine to suppress intracellular Ca2+ mobilization. Inhibitors of calmodulin and myosin light chain kinase also suppressed glucose activation of the movement. Simultaneous addition of glucose with Ca2+ channel blockers or the ATP-sensitive K+ channel opener diazoxide failed to suppress the traffic activation, and addition of these substances on top of glucose stimulation resulted in a further increase. Although stimulatory glucose had minimal changes in the intracellular granule distribution, inhibition of Ca2+ influx revealed increases by glucose of the granules in the cell periphery. In contrast, high K+ depolarization decreased the peripheral granules. Glucose-induced granule margination was abolished when the protein kinase C activity was downregulated. These findings indicate that preexocytotic control of insulin release is regulated by distinct mechanisms from Ca2+ influx, which triggers insulin exocytosis. The nature of the regulation by glucose may explain a part of potentiating effects of the hexose independent of the closure of the ATP-sensitive K+ channel.

  13. Blood glucose concentration and risk of liver cancer: systematic review and meta-analysis of prospective studies.

    PubMed

    Han, Hedong; Zhang, Tianyi; Jin, Zhichao; Guo, Honglei; Wei, Xin; Liu, Yuzhou; Chen, Qi; He, Jia

    2017-07-25

    The question of whether elevated blood glucose is a risk factor for liver cancer has been intensively studied, yet with inconsistent results. To explore the relationship between blood glucose concentration and risk of liver cancer, we conduct a meta-analysis of prospective studies. Literature search was comprehensively performed using database of PubMed, EMBASE and the Cochrane Library through October 2016. Random-effect models were used to combine the effect estimations. Eight articles containing ten studies with a total of 1975 liver cancer cases were included. The pooled RRs demonstrated that elevated fasting blood glucose was associated with increased risk of liver cancer (combined RRs: 1.77; 95% CI: 1.46, 2.13) with mild heterogeneity (I2 = 30.40%, P = 0.17). In sensitivity analysis, the pooled result remained significant (combined RRs: 1.33; 95% CI: 1.12, 1.59; I2 = 33.90%, P = 0.16) when we restricted blood glucose categories in the range of nondiabetic subjects. We also detected a J-shaped non-linear dose-response relationship between blood glucose concentration and risk of liver cancer. There is evidence that elevated blood glucose increases risk of liver cancer across the range of prediabetes and diabetes. Considering the rapidly increasing prevalence of prediabetes and diabetes, controlling blood glucose may lower the risk of liver cancer.

  14. A glucose-responsive insulin therapy protects animals against hypoglycemia

    PubMed Central

    Yang, Ruojing; Wu, Margaret; Lin, Songnian; Nargund, Ravi P.; Li, Xinghai; Kelly, Theresa; Yan, Lin; Dai, Ge; Qian, Ying; Dallas-yang, Qing; Fischer, Paul A.; Cui, Yan; Shen, Xiaolan; Huo, Pei; Feng, Danqing Dennis; Erion, Mark D.; Kelley, David E.

    2018-01-01

    Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose. Yet, these analogs retain capacity for binding to the insulin receptor (IR). When the blood glucose level is elevated, as in individuals with diabetes mellitus, MR binding diminishes due to glucose competition, leading to reduced MR-mediated clearance and increased partitioning for IR binding and consequent glucose lowering. These studies demonstrate that a glucose-dependent locus of insulin clearance and, hence, insulin action can be achieved by targeting MR and IR concurrently. PMID:29321379

  15. Abolish the Office of the Secretary of Defense?

    DTIC Science & Technology

    2007-01-01

    should he go, the debate should have been whether we even need the Office of the Secretary of Defense (OSD). It is perhaps time to admit that the great...source is the office itself. Simply put, the Secretary of Defense and his supporting staff are too powerful. The wisdom of the creation and relevance of...the original organization are what need to be reconsidered. The following recommendations are offered for consideration. First, abolish the Office of

  16. Artemisia princeps extract promoted glucose uptake in cultured L6 muscle cells via glucose transporter 4 translocation.

    PubMed

    Yamamoto, Norio; Ueda, Manabu; Kawabata, Kyuichi; Sato, Takuya; Kawasaki, Kengo; Hashimoto, Takashi; Ashida, Hitoshi

    2010-01-01

    Artemisia princeps is a familiar plant as a food substance and medicinal herb. In this study, we evaluated the effects of an ethanol extract of A. princeps (APE) on glucose uptake in differentiated L6 muscle cells. Treatment with APE elevated deoxyglucose uptake, and translocation of the insulin-responsive glucose transporter (GLUT4) to the plasma membrane in L6 myotubes occurred. The PI3K inhibitor LY294002 attenuated glucose uptake induced by APE. Phosphorylation of the Ser(473) residue of Akt was not observed, but phosphorylation of PI3K, Akt (Thr(308)), and atypical PKC was. In addition, APE stimulated phosphorylation of AMP-activated protein kinase (AMPK) at a level similar to 5'-amino-5-imidazolecarboxamide-riboside (AICAR). These results indicate that APE stimulates glucose uptake by inducing GLUT4 translocation, which is in part mediated by combination of the PI3K-dependent atypical PKC pathway and AMPK pathways.

  17. Blood Glucose Levels in Diabetic Patients Following Corticosteroid Injections into the Subacromial Space of the Shoulder.

    PubMed

    Aleem, Alexander W; Syed, Usman Ali M; Nicholson, Thema; Getz, Charles L; Namdari, Surena; Beredjiklian, Pedro K; Abboud, Joseph A

    2017-09-01

    Corticosteroid injections are used to treat a variety of orthopedic conditions with the goal of decreasing pain and inflammation. Administration of systemic or local corticosteroids risks temporarily increasing blood glucose levels, especially diabetic patients. The purpose of this study is to quantify the effects of corticosteroid injections on blood glucose levels in diabetic patients with shoulder pathology. Diabetic patients who regularly monitored their blood glucose levels and were indicated for a subacromial corticosteroid injection were included in this prospective investigation. The typical normal morning fasting glucose and most recent hemoglobin A1c level was recorded for each patient. After injection, patients were contacted daily to confirm their fasting morning glucose level for 10 days post-injection. Seventeen consecutive patients were enrolled. Patients with hemoglobin A1c of <7% had an average rise in blood glucose of 38 mg/dL compared to 98 mg/dL in the poorly controlled group after injection ( P <0.001). Well-controlled patients' glucose levels returned to near baseline levels around post-injection day 8, while poorly controlled patients levels remained elevated. Similarly, insulin-dependent diabetic patients had an average increase in fasting glucose level of 99 mg/dL versus 50 mg/dL in non-insulin-dependent diabetic patients ( P <0.001). After corticosteroid injection, patients with well-controlled diabetes experience smaller elevations and faster return to baseline glucose levels than patients with poor control. Insulin dependent diabetics experienced similar findings as patients with poor control. Future studies are needed to evaluate dosing to optimize the risks of blood glucose elevation while maintaining therapeutic benefit.

  18. Role of glucose utilization in the restoration of hypophysectomy-induced hepatic cytochrome P450 2E1 by growth hormone in rats.

    PubMed

    Son, M H; Kang, K W; Kim, E J; Ryu, J H; Cho, H; Kim, S H; Kim, W B; Kim, S G

    2000-06-15

    Growth hormone and insulin are the primary determinants for cytochrome P450 2E1 (CYP2E1) expression. The role of glucose on the induction of CYP2E1 by hypophysectomy and on the restorative effect by growth hormone was investigated in the rat liver. Western and Northern blot analyses revealed that hypophysectomy induced CYP2E1 by 5-fold at 1-4 weeks, relative to control, with a concomitant increase in CYP2E1 mRNA. Hypophysectomized rats (HXR) showed a 20% reduction in the plasma glucose level. Hypophysectomy-induced increase in the CYP2E1 mRNA was completely abolished by glucose feeding in drinking water (10%) for 7 days. Treatment of HXR with hGH (2 I.U./kg, twice a day, for 7 days) inhibited the increases in CYP2E1 protein and mRNA levels with restoration of the plasma glucose level. In contrast to the effect of human growth hormone (hGH) on CYP2E1 in HXR with free access to foods, CYP2E1 expression failed to be restored by hGH in starving HXR. However, glucose feeding of starving HXR abolished the induction of CYP2E1. Effects of hypophysectomy and hGH treatment were studied in streptozotocin-induced diabetic rats. Insulin, but not hGH, prevented an increase in CYP2E1 mRNA in diabetic rats. The hepatic CYP2E1 induction in hypophysectomized diabetic rats was inhibited by hGH treatment, indicating that the hGH effect on CYP2E1 expression did not involve insulin production. These results provide evidence that the induction of hepatic CYP2E1 by hypophysectomy may result from reduced glucose utilization, and that the effect of hGH on CYP2E1 expression may be mediated with enhanced glucose utilization, but not with insulin production.

  19. Predicted Blood Glucose from Insulin Administration Based on Values from Miscoded Glucose Meters

    PubMed Central

    Raine, Charles H.; Pardo, Scott; Parkes, Joan Lee

    2008-01-01

    Objectives The proper use of many types of self-monitored blood glucose (SMBG) meters requires calibration to match strip code. Studies have demonstrated the occurrence and impact on insulin dose of coding errors with SMBG meters. This paper reflects additional analyses performed with data from Raine et al. (JDST, 2:205–210, 2007). It attempts to relate potential insulin dose errors to possible adverse blood glucose outcomes when glucose meters are miscoded. Methods Five sets of glucose meters were used. Two sets of meters were autocoded and therefore could not be miscoded, and three sets required manual coding. Two of each set of manually coded meters were deliberately miscoded, and one from each set was properly coded. Subjects (n = 116) had finger stick blood glucose obtained at fasting, as well as at 1 and 2 hours after a fixed meal (Boost®; Novartis Medical Nutrition U.S., Basel, Switzerland). Deviations of meter blood glucose results from the reference method (YSI) were used to predict insulin dose errors and resultant blood glucose outcomes based on these deviations. Results Using insulin sensitivity data, it was determined that, given an actual blood glucose of 150–400 mg/dl, an error greater than +40 mg/dl would be required to calculate an insulin dose sufficient to produce a blood glucose of less than 70 mg/dl. Conversely, an error less than or equal to -70 mg/dl would be required to derive an insulin dose insufficient to correct an elevated blood glucose to less than 180 mg/dl. For miscoded meters, the estimated probability to produce a blood glucose reduction to less than or equal to 70 mg/dl was 10.40%. The corresponding probabilities for autocoded and correctly coded manual meters were 2.52% (p < 0.0001) and 1.46% (p < 0.0001), respectively. Furthermore, the errors from miscoded meters were large enough to produce a calculated blood glucose outcome less than or equal to 50 mg/dl in 42 of 833 instances. Autocoded meters produced zero (0) outcomes

  20. Predicted blood glucose from insulin administration based on values from miscoded glucose meters.

    PubMed

    Raine, Charles H; Pardo, Scott; Parkes, Joan Lee

    2008-07-01

    The proper use of many types of self-monitored blood glucose (SMBG) meters requires calibration to match strip code. Studies have demonstrated the occurrence and impact on insulin dose of coding errors with SMBG meters. This paper reflects additional analyses performed with data from Raine et al. (JDST, 2:205-210, 2007). It attempts to relate potential insulin dose errors to possible adverse blood glucose outcomes when glucose meters are miscoded. Five sets of glucose meters were used. Two sets of meters were autocoded and therefore could not be miscoded, and three sets required manual coding. Two of each set of manually coded meters were deliberately miscoded, and one from each set was properly coded. Subjects (n = 116) had finger stick blood glucose obtained at fasting, as well as at 1 and 2 hours after a fixed meal (Boost((R)); Novartis Medical Nutrition U.S., Basel, Switzerland). Deviations of meter blood glucose results from the reference method (YSI) were used to predict insulin dose errors and resultant blood glucose outcomes based on these deviations. Using insulin sensitivity data, it was determined that, given an actual blood glucose of 150-400 mg/dl, an error greater than +40 mg/dl would be required to calculate an insulin dose sufficient to produce a blood glucose of less than 70 mg/dl. Conversely, an error less than or equal to -70 mg/dl would be required to derive an insulin dose insufficient to correct an elevated blood glucose to less than 180 mg/dl. For miscoded meters, the estimated probability to produce a blood glucose reduction to less than or equal to 70 mg/dl was 10.40%. The corresponding probabilities for autocoded and correctly coded manual meters were 2.52% (p < 0.0001) and 1.46% (p < 0.0001), respectively. Furthermore, the errors from miscoded meters were large enough to produce a calculated blood glucose outcome less than or equal to 50 mg/dl in 42 of 833 instances. Autocoded meters produced zero (0) outcomes less than or equal to 50 mg

  1. An elevated gap between admission and A1C-derived average glucose levels is associated with adverse outcomes in diabetic patients with pyogenic liver abscess.

    PubMed

    Liao, Wen-I; Sheu, Wayne Huey-Herng; Chang, Wei-Chou; Hsu, Chin-Wang; Chen, Yu-Long; Tsai, Shih-Hung

    2013-01-01

    To assess whether chronic glycemic control and stress-induced hyperglycemia, determined by the gap between admission glucose levels and A1C-derived average glucose (ADAG) levels adversely affects outcomes in diabetic patients with pyogenic liver abscess (PLA). Clinical, laboratory, and multi-detector computed tomography (MDCT) findings of 329 PLA patients (2004-2010) were retrospectively reviewed. HbA1C levels were used to determine long-term glycemic control status, which were then converted to estimated average glucose values. For the gap between admission glucose levels and ADAG levels, we used receiver operating characteristic (ROC) curve to determine the optimal cut-off values predicting adverse outcomes. Univariate and multivariate logistic regressions were used to identify predictors of adverse outcomes. Diabetic PLA patients with poorer glycemic control had significantly higher Klebsiella pneumoniae (KP) infection rates, lower albumin levels, and longer hospital stays than those with suboptimal and good glycemic control. The ROC curve showed that a glycemic gap of 72 mg/dL was the optimal cut-off value for predicting adverse outcomes and showed a 22.3% relative increase in adverse outcomes compared with a glycemic gap<72 mg/dL. Multivariate analysis revealed that an elevated glycemic gap≥72 mg/dL was important predictor of adverse outcomes. A glycemic gap≥72 mg/dL, rather than admission hyperglycemia or chronic glycemic control, was significantly correlated with adverse outcomes in diabetic PLA patients. Poorer chronic glycemic control in diabetic PLA patients is associated with high incidence of KP infection, hypoalbuminemia and longer hospital stay.

  2. Protein Kinase Cζ Mediates Insulin-induced Glucose Transport through Actin Remodeling in L6 Muscle Cells

    PubMed Central

    Liu, Li-Zhong; Zhao, Hai-Lu; Zuo, Jin; Ho, Stanley K.S.; Chan, Juliana C.N.; Meng, Yan; Fang, Fu-De; Tong, Peter C.Y.

    2006-01-01

    Protein kinase C (PKC) ζ has been implicated in insulin-induced glucose uptake in skeletal muscle cell, although the underlying mechanism remains unknown. In this study, we investigated the effect of PKCζ on actin remodeling and glucose transport in differentiated rat L6 muscle cells expressing myc-tagged glucose transporter 4 (GLUT4). On insulin stimulation, PKCζ translocated from low-density microsomes to plasma membrane accompanied by increase in GLUT4 translocation and glucose uptake. Z-scan confocal microscopy revealed a spatial colocalization of relocated PKCζ with the small GTPase Rac-1, actin, and GLUT4 after insulin stimulation. The insulin-mediated colocalization, PKCζ distribution, GLUT4 translocation, and glucose uptake were inhibited by wortmannin and cell-permeable PKCζ pseudosubstrate peptide. In stable transfected cells, overexpression of PKCζ caused an insulin-like effect on actin remodeling accompanied by a 2.1-fold increase in GLUT4 translocation and 1.7-fold increase in glucose uptake in the absence of insulin. The effects of PKCζ overexpression were abolished by cell-permeable PKCζ pseudosubstrate peptide, but not wortmannin. Transient transfection of constitutively active Rac-1 recruited PKCζ to new structures resembling actin remodeling, whereas dominant negative Rac-1 prevented the insulin-mediated PKCζ translocation. Together, these results suggest that PKCζ mediates insulin effect on glucose transport through actin remodeling in muscle cells. PMID:16525020

  3. Elevated atmospheric CO2 increases microbial growth rates and enzymes activity in soil

    NASA Astrophysics Data System (ADS)

    Blagodatskaya, Evgenia; Blagodatsky, Sergey; Dorodnikov, Maxim; Kuzyakov, Yakov

    2010-05-01

    Increasing the belowground translocation of assimilated carbon by plants grown under elevated CO2 can cause a shift in the structure and activity of the microbial community responsible for the turnover of organic matter in soil. We investigated the long-term effect of elevated CO2 in the atmosphere on microbial biomass and specific growth rates in root-free and rhizosphere soil. The experiments were conducted under two free air carbon dioxide enrichment (FACE) systems: in Hohenheim and Braunschweig, as well as in the intensively managed forest mesocosm of the Biosphere 2 Laboratory (B2L) in Oracle, AZ. Specific microbial growth rates (μ) were determined using the substrate-induced respiration response after glucose and/or yeast extract addition to the soil. We evaluated the effect of elevated CO2 on b-glucosidase, chitinase, phosphatase, and sulfatase to estimate the potential enzyme activity after soil amendment with glucose and nutrients. For B2L and both FACE systems, up to 58% higher μ were observed under elevated vs. ambient CO2, depending on site, plant species and N fertilization. The μ-values increased linearly with atmospheric CO2 concentration at all three sites. The effect of elevated CO2 on rhizosphere microorganisms was plant dependent and increased for: Brassica napus=Triticum aestivumglucose, i.e. the effect of elevated CO2 was smoothed on rich vs. simple substrate. So, the r/K strategies ratio can be better revealed by studying growth on simple (glucose) than on rich substrate mixtures (yeast extract). After adding glucose, enzyme activities under elevated CO2 were

  4. Slightly elevated high-sensitivity C-reactive protein (hsCRP) concentrations are associated with carotid atherosclerosis in women with varying degrees of glucose tolerance.

    PubMed

    Prahl, Ulrica; Wikstrand, John; Bergström, Göran M L; Behre, Carl Johan; Hulthe, Johannes; Fagerberg, Björn

    2010-11-01

    We examined whether high-sensitivity C-reactive protein (hsCRP) ≥2.0 mg/L was associated with increased intima-media thickness (IMT), plaque burden, and plaque echolucency in carotid arteries. Women (n = 635) from a population sample of 64-year-old females with varying degrees of glucose tolerance underwent risk factor assessment, measurement of hsCRP, and ultrasound examinations of the carotid arteries. Participants with hsCRP levels ≥2.0 mg/L had elevated carotid bulb IMT independently of other cardiovascular risk factors compared with those with hsCRP <2.0 mg/L. The participants with plaques in the highhsCRP group had larger total plaque area compared to those with plaque in the lower hsCRP group. Plaque echolucency did not differ between groups. High-sensitivity CRP levels ≥2.0 mg/L were accompanied by elevated IMT in the carotid bulbs independently of other cardiovascular risk factors. Total plaque area was larger among women with plaques in the high hsCRP group versus the lower hsCRP group.

  5. Increased cerebellar PET glucose metabolism corresponds to ataxia in Wernicke-Korsakoff syndrome.

    PubMed

    Fellgiebel, Andreas; Siessmeier, Thomas; Winterer, Georg; Lüddens, Hartmut; Mann, Klaus; Schmidt, Lutz G; Bartenstein, Peter

    2004-01-01

    To investigate a possible relationship between cerebellar glucose metabolism and recovery from ataxia in the first months of acute Wernicke-Korsakoff syndrome. Two cases of alcoholic Wernicke-Korsakoff syndrome were followed up with the clinical status and cerebral glucose metabolism over a 4- and 9-month period. Initially both patients showed severe ataxia and elevated cerebellar glucose metabolism that decreased corresponding to the restitution of stance and gait. Increased cerebellar glucose metabolism at the onset of the illness may reflect the reorganization process of disturbed motor skills and may indicate cerebellar plasticity.

  6. Fluctuations in Nucleus Accumbens Extracellular Glutamate and Glucose during Motivated Glucose-drinking Behavior: Dissecting the Neurochemistry of Reward

    PubMed Central

    Wakabayashi, Ken T.; Myal, Stephanie E.; Kiyatkin, Eugene A.

    2015-01-01

    While motivated behavior involves multiple neurochemical systems, few studies have focused on the role of glutamate, the brain’s excitatory neurotransmitter, and glucose, the energetic substrate of neural activity in reward-related neural processes. Here, we used high-speed amperometry with enzyme-based substrate-sensitive and control, enzyme-free biosensors to examine second-scale fluctuations in the extracellular levels of these substances in the nucleus accumbens shell during glucose-drinking behavior in trained rats. Glutamate rose rapidly after the presentation of a glucose-containing cup and before the initiation of drinking (reward seeking), decreased more slowly to levels below baseline during consumption (sensory reward), and returned to baseline when the ingested glucose reached the brain (metabolic reward). When water was substituted for glucose, glutamate rapidly increased with cup presentation and in contrast to glucose drinking, increased above baseline after rats tasted the water and refused to drink further. Therefore, extracellular glutamate show distinct changes associated with key events of motivated drinking behavior and opposite dynamics during sensory and metabolic components of reward. In contrast to glutamate, glucose increased at each stimulus and behavioral event, showing a sustained elevation during the entire behavior and a robust post-ingestion rise that correlated with the gradual return of glutamate levels to their baseline. By comparing active drinking with passive intra-gastric glucose delivery, we revealed that fluctuations in extracellular glucose are highly dynamic, reflecting a balance between rapid delivery due to neural activity, intense metabolism, and the influence of ingested glucose reaching the brain. PMID:25393775

  7. Elevated 1-hour postload plasma glucose levels identify subjects with normal glucose tolerance but impaired β-cell function, insulin resistance, and worse cardiovascular risk profile: the GENFIEV study.

    PubMed

    Bianchi, Cristina; Miccoli, Roberto; Trombetta, Maddalena; Giorgino, Francesco; Frontoni, Simona; Faloia, Emanuela; Marchesini, Giulio; Dolci, Maria A; Cavalot, Franco; Cavallo, Gisella; Leonetti, Frida; Bonadonna, Riccardo C; Del Prato, Stefano

    2013-05-01

    In subjects with normal glucose tolerance (NGT) 1-hour postload plasma glucose (1-h oral glucose tolerance test [OGTT]) of >155 mg/dL predicts type 2 diabetes (T2DM) and is associated with subclinical atherosclerosis. The purpose of this study was to evaluate β-cell function, insulin resistance, and cardiovascular risk profile in subjects with NGT with a 1-h OGTT glucose of >155 mg/dL. The GENFIEV (Genetics, PHYsiopathology, and Evolution of Type 2 diabetes) study is a multicenter study recruiting individuals at high risk of T2DM. A total of 926 subjects underwent a 75-g OGTT for assessment of plasma glucose and C-peptide for mathematical modeling of β-cell function (derivative and proportional control). Fasting insulin, lipid profile, and clinical parameters were determined as well. A 1-hour OGTT glucose of >155 mg/dL was found in 39% of subjects with NGT, 76% with impaired fasting glucose (IFG), 90% with impaired glucose tolerance (IGT), and 99% and 98% with IFG + IGT or newly diagnosed T2DM, respectively. Among subjects with NGT (n = 474), those with 1-hour OGTT glucose of >155 mg/dL were more insulin-resistant and had worse β-cell function than those with 1-hour OGTT glucose of ≤155 mg/dL. Moreover, glycosylated hemoglobin, blood pressure, low-density lipoprotein cholesterol, and triglycerides were higher in subjects with NGT with 1-hour OGTT glucose of >155 mg/dL, whereas high-density lipoprotein cholesterol was lower compared with that in subjects with NGT with 1-hour OGTT glucose of ≤155 mg/dL. Compared with subjects with IGT, those with NGT with 1-hour OGTT glucose of >155 mg/dL had comparable cardiovascular risk profile and insulin resistance but slightly better β-cell function. Among subjects with NGT, those with 1-hour OGTT glucose of >155 mg/dL showed lower insulin sensitivity, impaired β-cell function, and worse cardiovascular risk profile and therefore are at greater risk of developing T2DM and cardiovascular disease.

  8. Elevated admission glucose is associated with increased long-term mortality in myocardial infarction patients, irrespective of the initially applied reperfusion strategy.

    PubMed

    de Mulder, Maarten; Cornel, Jan-Hein; van der Ploeg, Tjeerd; Boersma, Eric; Umans, Victor A

    2010-09-01

    It is uncertain if elevated admission plasma glucose (APG) remains an independent determinant of longer-term mortality in myocardial infarction (MI) patients with early restoration of coronary reperfusion by primary percutaneous coronary intervention. The objective of the study was to describe the relation between elevated APG and long-term mortality in MI patients undergoing invasive management. We studied 1,185 consecutive MI patients treated in the Medical Center Alkmaar in the separate years 1996 and 1999 (preinvasive era) and 2003 and 2006 (invasive era). In both eras, APG was derived according to a standard protocol. A multivariate Cox regression model was created to study the relation between APG, reperfusion era, and 5-year mortality. During a median follow-up of 63 months, 261 patients had died. Mortality was lower in the invasive (19%) than in the preinvasive era (28%). Increased APG was associated with increased mortality, irrespective of the initial reperfusion strategy, although the relation was more pronounced in the preinvasive era (P value for heterogeneity of effects < .001). Each millimole-per-liter APG increase corresponded to a 7% increased mortality (adjusted hazard ratio 1.07, 95% CI 1.04-1.10). Patients with an APG >11 mmol/L had nearly 2-fold higher mortality (hazard ratio 1.9, 95% CI 1.3-2.7) than those with lower values. Elevated APG remains a determinant of long-term mortality in MI patients, irrespective of the advances that have been made in reperfusion therapy. 2010 Mosby, Inc. All rights reserved.

  9. Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study.

    PubMed

    Nygren, Karina; Hammarström, Anne; Rolandsson, Olov

    2017-06-08

    Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.

  10. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice.

    PubMed

    Coomans, Claudia P; Biermasz, Nienke R; Geerling, Janine J; Guigas, Bruno; Rensen, Patrick C N; Havekes, Louis M; Romijn, Johannes A

    2011-12-01

    Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated tissue-specific glucose uptake. Tolbutamide, an inhibitor of ATP-sensitive K(+) channels (K(ATP) channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with diet-induced obesity. Whole-body glucose uptake was measured by d-[(14)C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-d-[(3)H]glucose uptake. During clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ∼20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ∼59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle. Insulin stimulates glucose uptake in muscle in part through effects via K(ATP) channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. High-fat diet-induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistance.

  11. High glucose augments angiotensinogen in human renal proximal tubular cells through hepatocyte nuclear factor-5

    PubMed Central

    Wang, Juan; Shibayama, Yuki; Kobori, Hiroyuki; Liu, Ya; Kobara, Hideki; Masaki, Tsutomu; Wang, Zhiyu

    2017-01-01

    High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5’-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy. PMID:29053707

  12. Consequences of organizational commitment in abolished company sports team - a case study in Japan.

    PubMed

    Honda, Yuki; Hochi, Yasuyuki; Mizuno, Motoki

    2012-01-01

    The purpose of this study was to show that how the abolishment of company sports team influenced the organizational commitment in employees. In this study, Three-Component Model of Organizational Commitment (Meyer and Allen, 1997) was tested with 16 employees (10 males, 6 females) of T Company in NAGANO prefecture. The average age of the participants was 44, 50 years (SD=±0.85). And from 16 employees, 3 male employees were measured on organizational commitment with interview test. According to the analysis, the relation between organizational commitment in employees and the abolishment of company sports team was not positive significant correlation. Furthermore, results of interview test did not show the relation between organizational commitment in employees and the abolishment of company sports team. However, results of interview test showed the relation with organizational commitment of players in T Company sports team. Consequently, the goal to possess a sports team in T Company was not to boost organizational commitment in employees. In addition, it is necessary to reconsider the correlation among employees engaged in T Company in the future.

  13. Elevated Fasting Blood Glucose Is Predictive of Poor Outcome in Non-Diabetic Stroke Patients: A Sub-Group Analysis of SMART.

    PubMed

    Yao, Ming; Ni, Jun; Zhou, Lixin; Peng, Bin; Zhu, Yicheng; Cui, Liying

    2016-01-01

    Although increasing evidence suggests that hyperglycemia following acute stroke adversely affects clinical outcome, whether the association between glycaemia and functional outcome varies between stroke patients with\\without pre-diagnosed diabetes remains controversial. We aimed to investigate the relationship between the fasting blood glucose (FBG) and the 6-month functional outcome in a subgroup of SMART cohort and further to assess whether this association varied based on the status of pre-diagnosed diabetes. Data of 2862 patients with acute ischemic stroke (629 with pre-diagnosed diabetics) enrolled from SMART cohort were analyzed. Functional outcome at 6-month post-stroke was measured by modified Rankin Scale (mRS) and categorized as favorable (mRS:0-2) or poor (mRS:3-5). Binary logistic regression model, adjusting for age, gender, educational level, history of hypertension and stroke, baseline NIHSS and treatment group, was used in the whole cohort to evaluate the association between admission FBG and functional outcome. Stratified logistic regression analyses were further performed based on the presence/absence of pre-diabetes history. In the whole cohort, multivariable logistical regression showed that poor functional outcome was associated with elevated FBG (OR1.21 (95%CI 1.07-1.37), p = 0.002), older age (OR1.64 (95% CI1.38-1.94), p<0.001), higher NIHSS (OR2.90 (95%CI 2.52-3.33), p<0.001) and hypertension (OR1.42 (95%CI 1.13-1.98), p = 0.04). Stratified logistical regression analysis showed that the association between FBG and functional outcome remained significant only in patients without pre-diagnosed diabetes (OR1.26 (95%CI 1.03-1.55), p = 0.023), but not in those with premorbid diagnosis of diabetes (p = 0.885). The present results demonstrate a significant association between elevated FBG after stroke and poor functional outcome in patients without pre-diagnosed diabetes, but not in diabetics. This finding confirms the importance of glycemic

  14. Blood glucose control for patients with acute coronary syndromes in Qatar.

    PubMed

    Wilby, Kyle John; Elmekaty, Eman; Abdallah, Ibtihal; Habra, Masa; Al-Siyabi, Khalid

    2016-01-01

    Blood glucose is known to be elevated in patients presenting with acute coronary syndromes. However a gap in knowledge exists regarding effective management strategies once admitted to acute care units. It is also unknown what factors (if any) predict elevated glucose values during initial presentation. OBJECTIVES of the study were to characterize blood glucose control in patients admitted to the cardiac care unit (CCU) in Qatar and to determine predictive factors associated with high glucose levels (>10 mmol/l) on admission to the CCU. All data for this study were obtained from the CCU at Heart Hospital in Doha, Qatar. A retrospective chart review was completed for patients admitted to the CCU in Qatar from October 1st, 2012 to March 31st, 2013, of which 283 were included. Baseline characteristics (age, gender, nationality, medical history, smoking status, type of acute coronary syndrome), capillary and lab blood glucose measurements, and use of insulin were extracted. Time spent in glucose ranges of <4, 4 to <8, 8 to <10, and >10 mmol/1 was calculated manually. Univariate and multivariate logistic regression were performed to assess factors associated with high glucose on admission. The primary analysis was completed with capillary data and a sensitivity analysis was completed using laboratory data. Blood glucose values measured on admission and throughout length of stay in the CCU. Capillary blood glucose data showed majority of time was spent in the range of >10 mmol/l (41.95%), followed by 4-8 mmol/l (35.44%), then 8-10 mmol/l (21.45%), and finally <4 mmol/l (1.16%). As a sensitivity analysis, laboratory data showed very similar findings. Diabetes, hypertension, and non-smoker status predicted glucose values >10 mmol/l on admission (p < 0.05) in a univariate analysis but only diabetes remained significant in a multivariate model (OR 23.3; 95% CI, 11.5-47.3). Diabetes predicts high glucose values on hospital admission for patients with ACS and patients

  15. Glucose Levels and Risk of Frailty.

    PubMed

    Zaslavsky, Oleg; Walker, Rod L; Crane, Paul K; Gray, Shelly L; Larson, Eric B

    2016-09-01

    The association between glucose levels and incident frailty in older persons remains unclear. We examined the extent to which higher glucose levels in older adults with and without diabetes are related to risk of frailty. The data are from the Adult Changes in Thought study. We identified 1,848 individuals aged 65+ without dementia for whom glucose levels from laboratory measurements of glucose and glycated hemoglobin were available. Physical frailty using modified Fried's criteria was determined from biennial assessments. Frailty hazard was modeled as a function of time-varying measures of diabetes and average glucose levels using Cox regression. A total of 578 incident frailty cases (94 with diabetes, 484 without) occurred during a median follow-up of 4.8 years. The adjusted hazard ratio for frailty comparing those with and without diabetes was 1.52 (95% confidence interval = 1.19-1.94). In participants without diabetes, modeling suggested elevated frailty risk with greater average glucose levels (p = .019); for example, a glucose level of 110mg/dL compared with 100mg/dL yielded a hazard ratio of 1.32 (95% confidence interval = 1.09-1.59). In participants with diabetes, glucose levels less than 160mg/dL and greater than 180mg/dL were related to increased risk of frailty (p = .001). Higher glucose levels may be a risk factor for frailty in older adults without diabetes. The apparent U-shape association between glucose levels and frailty in people with diabetes is consistent with the literature on glycemia and mortality and deserves further examination. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Diadenosine tetraphosphate (Ap4A) induces a diabetogenic situation: its impact on blood glucose, plasma insulin, gluconeogenesis, glucose uptake and GLUT-4 transporters.

    PubMed

    Verspohl, E J; Hohmeier, N; Lempka, M

    2003-12-01

    Diadenosine polyphosphates such as Ap4A are physiologically released compounds for which both receptors as well as a role as second messengers for influencing insulin release have been shown. So far little is known about their pathophysiological impact on diabetes with respect to blood glucose and plasma insulin, glucose production via gluconeogenesis, glucose uptake and GLUT-4 expression. Rats given an intravenous bolus of Ap4A (0.75 mg/kg) developed a rapid and dramatic increase in blood glucose. Plasma insulin was only transiently increased (for 4 min), but did not follow the normally stimulatory effect of the elevated blood glucose. A bolus of 25 microg Ap4A quickly increased glucose release from perfused rat liver. Glucose uptake was reduced in 3T3 adipocytes. Reduced amounts of translocated GLUT-4 were found in 3T3 cell membranes incubated with 10 microM Ap4A. Thus, Ap4A itself induces a diabetic situation which is likely to be mediated by an increase in gluconeogenesis and/or an insulin resistance caused by a decrease in GLUT-4 and an attenuation of glucose uptake.

  17. Fluctuations in nucleus accumbens extracellular glutamate and glucose during motivated glucose-drinking behavior: dissecting the neurochemistry of reward.

    PubMed

    Wakabayashi, Ken T; Myal, Stephanie E; Kiyatkin, Eugene A

    2015-02-01

    While motivated behavior involves multiple neurochemical systems, few studies have focused on the role of glutamate, the brain's excitatory neurotransmitter, and glucose, the energetic substrate of neural activity in reward-related neural processes. Here, we used high-speed amperometry with enzyme-based substrate-sensitive and control, enzyme-free biosensors to examine second-scale fluctuations in the extracellular levels of these substances in the nucleus accumbens shell during glucose-drinking behavior in trained rats. Glutamate rose rapidly after the presentation of a glucose-containing cup and before the initiation of drinking (reward seeking), decreased more slowly to levels below baseline during consumption (sensory reward), and returned to baseline when the ingested glucose reached the brain (metabolic reward). When water was substituted for glucose, glutamate rapidly increased with cup presentation and in contrast to glucose drinking, increased above baseline after rats tasted the water and refused to drink further. Therefore, extracellular glutamate show distinct changes associated with key events of motivated drinking behavior and opposite dynamics during sensory and metabolic components of reward. In contrast to glutamate, glucose increased at each stimulus and behavioral event, showing a sustained elevation during the entire behavior and a robust post-ingestion rise that correlated with the gradual return of glutamate levels to their baseline. By comparing active drinking with passive intra-gastric glucose delivery, we revealed that fluctuations in extracellular glucose are highly dynamic, reflecting a balance between rapid delivery because of neural activity, intense metabolism, and the influence of ingested glucose reaching the brain. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  18. Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics

    PubMed Central

    Povlsen, Bo; Povlsen, Sebastian D

    2014-01-01

    Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0–10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis. PMID:25199186

  19. Steroid injection for shoulder pain causes prolonged increased glucose level in type 1 diabetics.

    PubMed

    Povlsen, Bo; Povlsen, Sebastian D

    2014-09-08

    Shoulder pain is very common in diabetic patients and often treated with steroid injections, with subsequent increases in blood glucose levels or the need for additional insulin being questioned. We report a case of significant and prolonged elevation of blood glucose levels and resultant insulin requirement in a type 1 diabetic man after a single 40 mg injection of triamcinolone for shoulder pain. Within 48 h, the shoulder pain as assessed by a visual analogue scale (0-10) was reduced to zero, but the elevated insulin requirements continued for 4 weeks after the injection. This finding suggests that steroid injections for shoulder pain in diabetics may not always be as safe as previously thought. We propose that medical practitioners advise their patients to monitor their glucose levels more carefully after such injections and that caution is exercised when considering administrating these injections to those who have poorly controlled blood glucose levels preinjection to avoid ketoacidosis. 2014 BMJ Publishing Group Ltd.

  20. Exercising Tactically for Taming Postmeal Glucose Surges.

    PubMed

    Chacko, Elsamma

    2016-01-01

    This review seeks to synthesize data on the timing, intensity, and duration of exercise found scattered over some 39 studies spanning 3+ decades into optimal exercise conditions for controlling postmeal glucose surges. The results show that a light aerobic exercise for 60 min or moderate activity for 20-30 min starting 30 min after meal can efficiently blunt the glucose surge, with minimal risk of hypoglycemia. Exercising at other times could lead to glucose elevation caused by counterregulation. Adding a short bout of resistance exercise of moderate intensity (60%-80%  VO2max) to the aerobic activity, 2 or 3 times a week as recommended by the current guidelines, may also help with the lowering of glucose surges. On the other hand, high-intensity exercise (>80%  VO2max) causes wide glucose fluctuations and its feasibility and efficacy for glucose regulation remain to be ascertained. Promoting the kind of physical activity that best counters postmeal hyperglycemia is crucial because hundreds of millions of diabetes patients living in developing countries and in the pockets of poverty in the West must do without medicines, supplies, and special diets. Physical activity is the one tool they may readily utilize to tame postmeal glucose surges. Exercising in this manner does not violate any of the current guidelines, which encourage exercise any time.

  1. The modulatory role of spinally located histamine receptors in the regulation of the blood glucose level in d-glucose-fed mice.

    PubMed

    Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

    2014-02-01

    The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

  2. Effect of GABA receptor agonists or antagonists injected spinally on the blood glucose level in mice.

    PubMed

    Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

    2013-05-01

    The possible roles of gamma-amino butyric acid (GABA) receptors located in the spinal cord for the regulation of the blood glucose level were studied in ICR mice. We found in the present study that intrathecal (i.t.) injection with baclofen (a GABAB receptor agonist; 1-10 μg/5 μl) or bicuculline (a GABAA receptor antagonist; 1-10 μg/5 μl) caused an elevation of the blood glucose level in a dose-dependent manner. The hyperglycemic effect induced by baclofen was more pronounced than that induced by bicuculline. However, muscimol (a GABAA receptor agonist; 1-5 μg/5 μl) or phaclofen (a GABAB receptor antagonist; 5-10 μg/5 μl) administered i.t. did not affect the blood glucose level. Baclofen-induced elevation of the blood glucose was dose-dependently attenuated by phaclofen. Furthermore, i.t. pretreatment with pertussis toxin (PTX; 0.05 or 0.1 μg/5 μl) for 6 days dose-dependently reduced the hyperglycemic effect induced by baclofen. Our results suggest that GABAB receptors located in the spinal cord play important roles for the elevation of the blood glucose level. Spinally located PTX-sensitive G-proteins appear to be involved in hyperglycemic effect induced by baclofen. Furthermore, inactivation of GABAA receptors located in the spinal cord appears to be responsible for tonic up-regulation of the blood glucose level.

  3. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhang, Yu-Kun Jennifer; Wu, Kai Connie; Liu, Jie

    Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulatingmore » glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. -- Highlights: ► Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. ► The anti-diabetic hormone, Fgf21, is highly expressed in livers of Nrf2-null mice. ► The absence of Nrf2 increases the insulin-regulated Igfbp-1 mRNA in

  4. Astrocyte glycogen as an emergency fuel under conditions of glucose deprivation or intense neural activity.

    PubMed

    Brown, Angus M; Ransom, Bruce R

    2015-02-01

    Energy metabolism in the brain is a complex process that is incompletely understood. Although glucose is agreed as the main energy support of the brain, the role of glucose is not clear, which has led to controversies that can be summarized as follows: the fate of glucose, once it enters the brain is unclear. It is not known the form in which glucose enters the cells (neurons and glia) within the brain, nor the degree of metabolic shuttling of glucose derived metabolites between cells, with a key limitation in our knowledge being the extent of oxidative metabolism, and how increased tissue activity alters this. Glycogen is present within the brain and is derived from glucose. Glycogen is stored in astrocytes and acts to provide short-term delivery of substrates to neural elements, although it may also contribute an important component to astrocyte metabolism. The roles played by glycogen awaits further study, but to date its most important role is in supporting neural elements during increased firing activity, where signaling molecules, proposed to be elevated interstitial K(+), indicative of elevated neural firing rates, activate glycogen phosphorylase leading to increased production of glycogen derived substrate.

  5. Anxiolytic Effect of Exogenous Ketone Supplementation Is Abolished by Adenosine A1 Receptor Inhibition in Wistar Albino Glaxo/Rijswijk Rats.

    PubMed

    Kovács, Zsolt; D'Agostino, Dominic P; Ari, Csilla

    2018-01-01

    Anxiety disorders are one of the most common mental health problems worldwide, but the exact pathophysiology remains largely unknown. It has been demonstrated previously that administration of exogenous ketone supplement KSMCT (ketone salt/KS + medium chain triglyceride/MCT oil) by intragastric gavage for 7 days decreased the anxiety level in genetically absence epileptic Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. To investigate the potential role of the adenosinergic system in the pathomechanism of anxiety we tested whether the inhibition of adenosine A 1 receptors (A 1 Rs) influence the anxiolytic effect of the exogenous ketone supplement. As A 1 Rs may mediate such an effect, in the present study we used a specific A 1 R antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine) to test whether it modulates the anxiolytic effect of sub-chronically (7 days) applied KSMCT in the previously tested animal model by using elevated plus maze (EPM) test. We administered KSMCT (2.5 g/kg/day) alone by intragastric gavage and in combination with intraperitoneally (i.p.) injected of DPCPX in two doses (lower: 0.15 mg/kg, higher: 0.25 mg/kg). Control groups represented i.p saline and water gavage with or without i.p. DPCPX administration (2.5 g/kg/day). After treatments, the level of blood glucose and beta-hydroxybutyrate (βHB), as well as body weight were recorded. KSMCT alone significantly increased the time spent in the open arms and decreased the time spent in the closed arms, supporting our previous results. Injection of lower dose of DPCPX decreased, while higher dose of DPCPX abolished the effect of KSMCT administration on EPM. Blood βHB levels were significantly increased after administration of KSMCT, while DPCPX did not change the KSMCT induced increase in blood βHB levels. These results demonstrate that A 1 R inhibition modified (decreased) the anti-anxiety effect of KSMCT administration implying that the adenosinergic system, likely via A 1 Rs, may modulate the

  6. Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation

    PubMed Central

    2017-01-01

    The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose. PMID:28072818

  7. Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation.

    PubMed

    Marroquin-Guzman, Margarita; Sun, Guangchao; Wilson, Richard A

    2017-01-01

    The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose.

  8. Vitamin E and Vitamin C supplementation does not prevent glucose intolerance in obese-prone rats

    USDA-ARS?s Scientific Manuscript database

    Obesity-induced glucose intolerance affects over 70 million Americans. Elevated oxidative stress is associated with development of glucose intolerance. In this work, we tested the hypothesis that supplementation with the anti-oxidants vitamin E (d-alpha-tocopherol acetate; 0.4 g/kg diet) and vitamin...

  9. Impaired fasting glucose and the metabolic syndrome in an indigenous Siberian population.

    PubMed

    Snodgrass, J Josh; Leonard, William R; Tarskaia, Larissa A; Egorova, Aitalina G; Maharova, Natalia V; Pinigina, Irina A; Halyev, Simeon D; Matveeva, Niurguyana P; Romanova, Anna N

    2010-02-01

    This study investigated the lifestyle and anthropometric correlates of impaired fasting glucose and the presence of metabolic syndrome (MetS) among an Indigenous high-latitude herding population from north-eastern Siberia. Cross-sectional study of Yakut (Sakha) adult volunteers. We collected health, lifestyle and anthropometric data among 166 Yakut adults (>or=18 years old; 101 females, 65 males) from the rural village of Tyungyulyu (62 degrees N, 130 degrees E; population 2,500), Sakha Republic (Yakutia), Russia. Measurements of fasting glucose, triglycerides, HDL cholesterol, blood pressure and waist circumference were used to document the presence of MetS based on the updated Adult Treatment Panel (ATP) III definition. Metabolic syndrome was relatively uncommon among study participants, with only 10% of participants classified as having MetS, including 8% of females and 12% of males. Elevated blood pressure and low HDL cholesterol were the most common features of MetS in Yakut men and women, while elevated fasting glucose and high triglycerides were uncommon in both sexes. Relatively low mean fasting glucose concentrations were documented among Yakut women (4.46+/-0.65 mmol/L) and men (4.41+/-0.76 mmol/L); no participants were classified as diabetic. Fasting glucose and MetS are at relatively low levels in this population; however, rising rates of obesity are likely to lead to future increases in MetS and impaired fasting glucose in this population. Further, increasing consumption of market foods, many high in refined sugars, is likely to contribute to an increased presence of impaired fasting glucose and MetS.

  10. Elevated and super-elevated CO2 differ in their interactive effects with nitrogen availability on fruit yield and quality of cucumber.

    PubMed

    Dong, Jinlong; Xu, Qiao; Gruda, Nazim; Chu, Wenying; Li, Xun; Duan, Zengqiang

    2018-02-25

    Elevated carbon dioxide (CO 2 ) and nitrogen (N) availability can interactively promote cucumber yield, but how the yield increase is realized remains unclear, whilst the interactive effects on fruit quality are unknown. In this study, cucumber plants (Cucumis sativus L. cv. Jinmei No. 3) were grown in a paddy soil under three CO 2 concentrations - 400 (ambient CO 2 ), 800 (elevated CO 2 , eCO 2 ) and 1200 µmol mol -1 (super-elevated CO 2 ) - and two N applications - 0.06 (low N) and 0.24 g N kg -1 soil (high N). Compared with ambient CO 2 , eCO 2 increased yield by 106% in high N but the increase in total biomass was only 33%. This can result from greater carbon translocation to fruits from other organs, indicated by the increased biomass allocation from stems and leaves, particularly source leaves, to fruits and the decreased concentrations of fructose and glucose in source leaves. Super-elevated CO 2 reduced the carbon allocation to fruits thus yield increase (71%). Additionally, eCO 2 also increased the concentrations of fructose and glucose in fruits, maintained the concentrations of dietary fiber, phosphorus, potassium, calcium, magnesium, sulfur, manganese, copper, molybdenum and sodium, whilst it decreased the concentrations of nitrate, protein, iron, and zinc in high N. Compared with eCO 2 , super-elevated CO 2 can still improve the fruit quality to some extent in low N availability. Elevated CO 2 promotes cucumber yield largely by carbon allocation from source leaves to fruits in high N availability. Besides a dilution effect, carbon allocation to fruits, carbohydrate transformation, and nutrient uptake and assimilation can affect the fruit quality. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

  11. [The impaired glucose tolerance in the pathogenesis of dyslipidemia].

    PubMed

    Ikoue, I; Takahashi, K; Katayama, S

    1996-10-01

    It is well known that hyperlipidemia is often present in patient with impaired glucose tolerance, obesity and/or hypertension. All of these are risk factors for coronary artery disease (CAD). The coexistence of these risk factors markedly increase the likelihood of CAD. Recently, it has been reported that the impaired glucose tolerance and insulin resistence are associated with the increased proinsulin, which is linked to the risk of CAD. We review that the impaired glucose tolerance is an important factor causing dyslipidemia. The characteristic of dyslipidemia associated with the impaired glucose tolerance include hypertriglyceridemia, high level of VLDL and low level of HDL cholesterol. They also associate with accumulation of remnant lipoproteins and appearance of small dense LDL. In addition, we pointed out that the increased number of risk factors is associated with elevated insulin and proinsulin level.

  12. An elevated blood glucose level and increased incidence of gestational diabetes mellitus in pregnant women with latent toxoplasmosis.

    PubMed

    Kankova, Sarka; Flegr, Jaroslav; Calda, Pavel

    2015-09-21

    About 30-50% of the world human population are infected with the protozoan parasite Toxoplasma gondii (Nicolle et Manceaux, 1908). Latent toxoplasmosis has many specific behavioural and physiological effects on the human body and influences the course of pregnancy, including secondary sex ratio of children of infected mothers. It was suggested that an increased concentration of glucose could be the proximate cause of increased sex ratio. There are some indirect indications of possible association between toxoplasmosis and certain forms of diabetes. Here we searched for a possible link between latent toxoplasmosis and the level of glucose in the blood. In a cross-sectional study, we found that pregnant women with latent toxoplasmosis had significantly higher blood glucose levels during the oral glucose tolerance test (n = 191, p = 0.010; the level of fasting plasma glucose: mean = 5.04 mmol/l vs mean = 4.88 mmol/l; blood glucose level at 1 hour mean = 7.73 mmol/l vs mean = 6.89 mmol/l and blood glucose level at two hours mean = 6.43 mmol/l vs mean = 5.74 mmol/l) and higher prevalence (19.5 %) of gestational diabetes mellitus (n = 532, p = 0.033, odds ratio = 1.78) in the 24-28th gestational weeks than T. gondii-free women (12.0 %). Increased level of glucose and increased incidence of gestational diabetes mellitus could have considerable clinical impact as contributors to the development of the metabolic syndrome and type 2 diabetes in T. gondii-infected women. Our results also brought the first empirical support for the hypothesis that the glucose concentration may play a role in T. gondii-associated offspring sex ratio shifts.

  13. Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study

    PubMed Central

    Brutsaert, Erika F; Shitole, Sanyog; Biggs, Mary Lou; Mukamal, Kenneth J; deBoer, Ian H; Thacker, Evan L; Barzilay, Joshua I; Djoussé, Luc; Ix, Joachim H; Smith, Nicholas L; Kaplan, Robert C; Siscovick, David S; Psaty, Bruce M; Kizer, Jorge R

    2016-01-01

    Abstract Background Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. Methods Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996–1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. Results Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03–1.25] and 1.17 [1.07–1.28], respectively) and all-cause mortality (HR 1.12 [1.07–1.18] and 1.14 [1.08–1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. Conclusion In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life. PMID:26314953

  14. Aqueous fraction of Beta vulgaris ameliorates hyperglycemia in diabetic mice due to enhanced glucose stimulated insulin secretion, mediated by acetylcholine and GLP-1, and elevated glucose uptake via increased membrane bound GLUT4 transporters.

    PubMed

    Ul Kabir, Ashraf; Samad, Mehdi Bin; Ahmed, Arif; Jahan, Mohammad Rajib; Akhter, Farjana; Tasnim, Jinat; Hasan, S M Nageeb; Sayfe, Sania Sarker; Hannan, J M A

    2015-01-01

    The study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris. Aqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05). Findings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in the anti-hyperglycemic activity of B. Vulgaris.

  15. Aqueous Fraction of Beta vulgaris Ameliorates Hyperglycemia in Diabetic Mice due to Enhanced Glucose Stimulated Insulin Secretion, Mediated by Acetylcholine and GLP-1, and Elevated Glucose Uptake via Increased Membrane Bound GLUT4 Transporters

    PubMed Central

    Kabir, Ashraf Ul; Samad, Mehdi Bin; Ahmed, Arif; Jahan, Mohammad Rajib; Akhter, Farjana; Tasnim, Jinat; Hasan, S. M. Nageeb; Sayfe, Sania Sarker; Hannan, J. M. A.

    2015-01-01

    Background The study was designed to investigate the probable mechanisms of anti-hyperglycemic activity of B. Vulgaris. Methodology/Principal Findings Aqueous fraction of B. Vulgaris extract was the only active fraction (50mg/kg). Plasma insulin level was found to be the highest at 30 mins after B. Vulgaris administration at a dose of 200mg/kg. B. Vulgaris treated mice were also assayed for plasma Acetylcholine, Glucagon Like Peptide-1 (GLP-1), Gastric Inhibitory Peptide (GIP), Vasoactive Intestinal Peptide, Pituitary Adenylate Cyclase-Activating Peptide (PACAP), Insulin Like Growth Factor-1 (IGF-1), Pancreatic Polypeptides (PP), and Somatostatin, along with the corresponding insulin levels. Plasma Acetylcholine and GLP-1 significantly increased in B. Vulgaris treated animals and were further studied. Pharmacological enhancers, inhibitors, and antagonists of Acetylcholine and GLP-1 were also administered to the test animals, and corresponding insulin levels were measured. These studies confirmed the role of acetylcholine and GLP-1 in enhanced insulin secretion (p<0.05). Principal signaling molecules were quantified in isolated mice islets for the respective pathways to elucidate their activities. Elevated concentrations of Acetylcholine and GLP-1 in B. Vulgaris treated mice were found to be sufficient to activate the respective pathways for insulin secretion (p<0.05). The amount of membrane bound GLUT1 and GLUT4 transporters were quantified and the subsequent glucose uptake and glycogen synthesis were assayed. We showed that levels of membrane bound GLUT4 transporters, glucose-6-phosphate in skeletal myocytes, activity of glycogen synthase, and level of glycogen deposited in the skeletal muscles all increased (p<0.05). Conclusion Findings of the present study clearly prove the role of Acetylcholine and GLP-1 in the Insulin secreting activity of B. Vulgaris. Increased glucose uptake in the skeletal muscles and subsequent glycogen synthesis may also play a part in

  16. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes.

    PubMed

    Jabbour, S A; Goldstein, B J

    2008-08-01

    The kidney plays a central role in the regulation of plasma glucose levels, although until recently this has not been widely appreciated or considered a target for therapeutic intervention. The sodium glucose co-transporter type 2 (SGLT2) located in the plasma membrane of cells lining the proximal tubule mediates the majority of renal glucose reabsorption from the tubular fluid, which normally prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 that provoke the renal excretion of glucose have been discovered, thereby providing a unique mechanism to potentially lower the elevated blood glucose levels in patients with diabetes. To explore the physiology of SGLT2 action and discuss several SGLT2 inhibitors that have entered early clinical development. All publicly available data were identified by searching the internet for 'SGLT2' and 'SGLT2 inhibitor' through 1 November 2007. Published articles, press releases and abstracts presented at national and international meetings were considered. Sodium glucose co-transporter type 2 inhibition is a novel treatment option for diabetes, which has been studied in preclinical models and a few potent and selective SGLT2 inhibitors have been reported and are currently in clinical development. These agents appear to be safe and generally well tolerated, and will potentially be a beneficial addition to the growing battery of oral antihyperglycaemic agents.

  17. MicroRNA-29a is up-regulated in beta-cells by glucose and decreases glucose-stimulated insulin secretion

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bagge, Annika; Clausen, Trine R.; Larsen, Sylvester

    Highlights: Black-Right-Pointing-Pointer MicroRNA-29a (miR-29a) levels are increased by glucose in human and rat islets and INS-1E cells. Black-Right-Pointing-Pointer miR-29a increases proliferation of INS-1E beta-cells. Black-Right-Pointing-Pointer Forced expression of miR-29a decreases glucose-stimulated insulin secretion (GSIS). Black-Right-Pointing-Pointer Depletion of beta-cell miR-29a improves GSIS. Black-Right-Pointing-Pointer miR-29a may be a mediator of glucose toxicity in beta-cells. -- Abstract: Chronically elevated levels of glucose impair pancreatic beta-cell function while inducing beta-cell proliferation. MicroRNA-29a (miR-29a) levels are increased in several tissues in diabetic animals and mediate decreased insulin-stimulated glucose-transport of adipocytes. The aim was to investigate the impact of glucose on miR-29a levels in INS-1E beta-cellsmore » and in human islets of Langerhans and furthermore to evaluate the impact of miR-29a on beta-cell function and proliferation. Increased glucose levels up-regulated miR-29a in beta-cells and human and rat islets of Langerhans. Glucose-stimulated insulin-secretion (GSIS) of INS-1E beta-cells was decreased by forced expression of miR-29a, while depletion of endogenous miR-29a improved GSIS. Over-expression of miR-29a increased INS-1E proliferation. Thus, miR-29a up-regulation is involved in glucose-induced proliferation of beta-cells. Furthermore, as depletion of miR-29a improves beta-cell function, miR-29a is a mediator of glucose-induced beta-cell dysfunction. Glucose-induced up-regulation of miR-29a in beta-cells could be implicated in progression from impaired glucose tolerance to type 2 diabetes.« less

  18. Fetal and neonatal responses to maternal canine starvation: circulating fuels and neonatal glucose production.

    PubMed

    Kliegman, R M; Miettinen, E L; Adam, P A

    1981-06-01

    Pregnant dogs were starved for 72 hr while controls were fasted overnight. Maternal starvation significantly reduced fetal birth weight (269 +/- 7.2 versus 294 +/- 4.4 g). Total caloric deprivation had no effect on maternal or fetal blood glucose concentration at the time of delivery; however, fasting neonatal blood glucose levels were depressed during the first 9 hr of life. Starvation produced a large elevation of maternal free fatty acids (1.68 +/- 0.39 versus 0.74 +/- 0.2 mM) and ketone bodies (2.99 +/- 0.70 versus 1.04 +/- 0.48). Although fetal free fatty acids increased minimally (0.39 +/- 0.03 versus 0.22 +/- 0.07), ketone body levels were markedly elevated (2.53 +/- 0.35 versus 1.01 +/- 0.32). After birth, plasma-free fatty acid and beta-hydroxybutyrate levels were lower in pups of starved mothers at 3 hr, and acetoacetate was lower at 6 and 9 hr. Other alternate fuels such as amino acids demonstrated lower levels of glutamine in pups of starved mothers throughout the day (except 3 hr), whereas alanine levels declined significantly only at 24 hr (114.9 +/- 15 versus 187.6 +/- 26 microM. Glucose production was significantly depressed in pups of starved mothers at 3 (13.7 +/- 1.4 versus 22.7 +/- 3) and 9 hr (17.5 +/- 2.2 versus 26.0 +/- 2.8 mumoles/kg/min), whereas glucose clearance rates were elevated at 3, 6 and 9 hr of age. Lactate carbon incorporation into glucose increased throughout the day but was not significantly affected by prior maternal starvation.

  19. Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure.

    PubMed

    Olatunji, Lawrence A; Usman, Taofeek O; Akinade, Aminat I; Adeyanju, Oluwaseun A; Kim, InKyeom; Soladoye, Ayodele O

    2017-12-01

    Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. Pregnant Wistar rats received vehicle, testosterone (0.5 mg/kg; sc), spironolactone (0.5 mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

  20. Glucose Administration Enhances fMRI Brain Activation and Connectivity Related to Episodic Memory Encoding for Neutral and Emotional Stimuli

    ERIC Educational Resources Information Center

    Parent, Marise B.; Krebs-Kraft, Desiree L.; Ryan, John P.; Wilson, Jennifer S.; Harenski, Carla; Hamann, Stephan

    2011-01-01

    Glucose enhances memory in a variety of species. In humans, glucose administration enhances episodic memory encoding, although little is known regarding the neural mechanisms underlying these effects. Here we examined whether elevating blood glucose would enhance functional MRI (fMRI) activation and connectivity in brain regions associated with…

  1. Spleen tyrosine kinase mediates high glucose-induced transforming growth factor-{beta}1 up-regulation in proximal tubular epithelial cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yang, Won Seok; Chang, Jai Won; Han, Nam Jeong

    The role of spleen tyrosine kinase (Syk) in high glucose-induced intracellular signal transduction has yet to be elucidated. We investigated whether Syk is implicated in high glucose-induced transforming growth factor-{beta}1 (TGF-{beta}1) up-regulation in cultured human proximal tubular epithelial cells (HK-2 cell). High glucose increased TGF-{beta}1 gene expression through Syk, extracellular signal-regulated kinase (ERK), AP-1 and NF-{kappa}B. High glucose-induced AP-1 DNA binding activity was decreased by Syk inhibitors and U0126 (an ERK inhibitor). Syk inhibitors suppressed high glucose-induced ERK activation, whereas U0126 had no effect on Syk activation. High glucose-induced NF-{kappa}B DNA binding activity was also decreased by Syk inhibitors. Highmore » glucose increased nuclear translocation of p65 without serine phosphorylation of I{kappa}B{alpha} and without degradation of I{kappa}B{alpha}, but with an increase in tyrosine phosphorylation of I{kappa}B{alpha} that may account for the activation of NF-{kappa}B. Both Syk inhibitors and Syk-siRNA attenuated high glucose-induced I{kappa}B{alpha} tyrosine phosphorylation and p65 nuclear translocation. Depletion of p21-activated kinase 2 (Pak2) by transfection of Pak2-siRNA abolished high glucose-induced Syk activation. In summary, high glucose-induced TGF-{beta}1 gene transcription occurred through Pak2, Syk and subsequent ERK/AP-1 and NF-{kappa}B pathways. This suggests that Syk might be implicated in the diabetic kidney disease.« less

  2. Portal hemodynamic responses after oral intake of glucose in patients with cirrhosis.

    PubMed

    Tsunoda, T; Ohnishi, K; Tanaka, H

    1988-04-01

    Changes of portal, superior mesenteric, and splenic venous flows, and portohepatic gradient (portal vein pressure minus free hepatic vein pressure) after a meal were studied in patients with cirrhosis using the duplex ultrasonic Doppler flowmeter, and portal and hepatic vein catheterizations after ingestion of 227 ml of 33% glucose solution (300 kcal). As a control, changes of portal venous flow and portohepatic gradient after drinking 227 ml of water, were studied. Portal and superior mesenteric venous flows increased significantly at 30 min after glucose intake, and they returned gradually to the basal values, whereas no significant postprandial change occurred in splenic venous flow. The sum of superior mesenteric and splenic venous flows was greater than the estimated portal venous flow before glucose intake, and the difference widened during post-prandial mesenteric hyperemia, indicating an increase of blood flow into the portal-systemic shunts. After glucose intake, portohepatic gradient elevated immediately, in parallel with an increase of portal venous flow, and these changes persisted for the 30 min studied; however, no significant change occurred in these parameters after drinking water. 1) In patients with cirrhosis, hyperemia occurs in the intestine but not in the spleen after glucose intake, and 2) postprandial mesenteric hyperemia causes an increase of portal venous inflow, portal-systemic collateral flow, portal venous flow, and an elevation of portohepatic gradient.

  3. Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hill, Denise S.; Wlodarczyk, Bogdan J.; Mitchell, Laura E.

    Background: Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals. Objectives: We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic's teratogenicity in early neurodevelopment. Methods: We evaluated maternal intraperitoneal (IP) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selectedmore » compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-{alpha}-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate's effects. Results: Arsenate caused significant glucose elevation during an IP glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p = 0.0260). Arsenate caused NTDs (100%, p < 0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%. Conclusions: IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin's success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.« less

  4. Glucose Oscillations Can Activate an Endogenous Oscillator in Pancreatic Islets

    PubMed Central

    Mukhitov, Nikita; Roper, Michael G.; Bertram, Richard

    2016-01-01

    Pancreatic islets manage elevations in blood glucose level by secreting insulin into the bloodstream in a pulsatile manner. Pulsatile insulin secretion is governed by islet oscillations such as bursting electrical activity and periodic Ca2+ entry in β-cells. In this report, we demonstrate that although islet oscillations are lost by fixing a glucose stimulus at a high concentration, they may be recovered by subsequently converting the glucose stimulus to a sinusoidal wave. We predict with mathematical modeling that the sinusoidal glucose signal’s ability to recover islet oscillations depends on its amplitude and period, and we confirm our predictions by conducting experiments with islets using a microfluidics platform. Our results suggest a mechanism whereby oscillatory blood glucose levels recruit non-oscillating islets to enhance pulsatile insulin output from the pancreas. Our results also provide support for the main hypothesis of the Dual Oscillator Model, that a glycolytic oscillator endogenous to islet β-cells drives pulsatile insulin secretion. PMID:27788129

  5. Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 in livers of zucker diabetic fatty rats.

    PubMed

    Jain, Sushil K; Croad, Jennifer L; Velusamy, Thirunavukkarasu; Rains, Justin L; Bull, Rebeca

    2010-09-01

    Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in Zucker diabetic fatty (ZDF) rats. Starting at the age of 6 wk, ZDF rats were supplemented orally (daily gavages for 8 more weeks) with saline-placebo (D) or chromium (400 microg Cr/Kg body weight) as chromium dinicocysteinate (CDNC), chromium dinicotinate (CDN) or chromium picolinate (CP) or equimolar L-cysteine (LC, img/Kg body weight), and fed Purina 5008 diet for 8 wk. ZDF rats of 6 wk age before any supplementations and onset of diabetes were considered as baseline. D rats showed elevated levels of fasting blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and oxidative stress (lipid peroxidation) and lower adiponectin and vitamin C, when compared with baseline rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA(1), CRP, MCP-1, ICAM-1 and lipid peroxidation and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkappaB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium. CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats.

  6. Blood Glucose, Diet-Based Glycemic Load and Cognitive Aging Among Dementia-Free Older Adults

    PubMed Central

    Andel, Ross; McEvoy, Cathy; Dahl Aslan, Anna K.; Finkel, Deborah; Pedersen, Nancy L.

    2015-01-01

    Background. Although evidence indicates that Type II Diabetes is related to abnormal brain aging, the influence of elevated blood glucose on long-term cognitive change is unclear. In addition, the relationship between diet-based glycemic load and cognitive aging has not been extensively studied. The focus of this study was to investigate the influence of diet-based glycemic load and blood glucose on cognitive aging in older adults followed for up to 16 years. Methods. Eight-hundred and thirty-eight cognitively healthy adults aged ≥50 years (M = 63.1, SD = 8.3) from the Swedish Adoption/Twin Study of Aging were studied. Mixed effects growth models were utilized to assess overall performance and change in general cognitive functioning, perceptual speed, memory, verbal ability, and spatial ability as a function of baseline blood glucose and diet-based glycemic load. Results. High blood glucose was related to poorer overall performance on perceptual speed as well as greater rates of decline in general cognitive ability, perceptual speed, verbal ability, and spatial ability. Diet-based glycemic load was related to poorer overall performance in perceptual speed and spatial ability. Conclusion. Diet-based glycemic load and, in particular, elevated blood glucose appear important for cognitive performance/cognitive aging. Blood glucose control (perhaps through low glycemic load diets) may be an important target in the detection and prevention of age-related cognitive decline. PMID:25149688

  7. Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats

    NASA Technical Reports Server (NTRS)

    Henriksen, Erik J.; Halseth, Amy E.

    1994-01-01

    Voluntary wheel running (WR) by juvenile female rats was used as a noninterventional model of soleus muscle functional overload to study the regulation of insulin-stimulated glucose transport activity by the glucose transporter (GLUT-4 isoform) protein level and glycogen concentration. Soleus total protein content was significantly greater (+18%;P greater than 0.05) than in age-matched controls after 1 wk of WR, and this hypertrophic response continued in weeks 2-4 (+24-32%). GLUT-4 protein was 39% greater than in controls in 1-wk WR soleus, and this adaptation was accompanied by a similar increase in in vitro insulin-stimulated glucose transport activity(+29%). After 2 and 4 wk of WR, however, insulin-stimulated glucose transport activity had returned to control levels, despite a continued elevation (+25-28%) of GLUT-4 protein. At these two time points, glycogen concentration was significantly enhanced in WR soleus (+21-42%), which coincided with significant reductions in glycogen synthase activity ratios (-23 to-41%). These results indicate that, in this model of soleus muscle functional overload, the GLUT-4 protein level may initially regulate insulin-stimulated glucose transport activity in the absence of changes in other modifying factors. However,this regulation of glucose transport activity by GLUT-4 protein may be subsequently overridden by elevated glycogen concentration.

  8. Effect of Global ATGL Knockout on Murine Fasting Glucose Kinetics.

    PubMed

    Coelho, Margarida; Nunes, Patricia; Mendes, Vera M; Manadas, Bruno; Heerschap, Arend; Jones, John G

    2015-01-01

    Mice deficient in adipose triglyceride lipase (ATGL(-/-)) present elevated ectopic lipid levels but are paradoxically glucose-tolerant. Measurement of endogenous glucose production (EGP) and Cori cycle activity provide insights into the maintenance of glycemic control in these animals. These parameters were determined in 7 wild-type (ATGL(+/-)) and 6 ATGL(-/-) mice by a primed-infusion of [U-(13)C6]glucose followed by LC-MS/MS targeted mass-isotopomer analysis of blood glucose. EGP was quantified by isotope dilution of [U-(13)C6]glucose while Cori cycling was estimated by analysis of glucose triose (13)C-isotopomers. Fasting plasma free fatty-acids were significantly lower in ATGL(-/-) versus control mice (0.43 ± 0.05 mM versus 0.73 ± 0.11 mM, P < 0.05). Six-hour fasting EGP rates were identical for both ATGL(-/-) and control mice (79 ± 11 versus 71 ± 7 μmol/kg/min, resp.). Peripheral glucose metabolism was dominated by Cori cycling (80 ± 2% and 82 ± 7% of glucose disposal for ATGL(-/-) and control mice, resp.) indicating that peripheral glucose oxidation was not significantly upregulated in ATGL(-/-) mice under these conditions. The glucose (13)C-isotopomer distributions in both ATGL(-/-) and control mice were consistent with extensive hepatic pyruvate recycling. This suggests that gluconeogenic outflow from the Krebs cycle was also well compensated in ATGL(-/-) mice.

  9. Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study.

    PubMed

    Brutsaert, Erika F; Shitole, Sanyog; Biggs, Mary Lou; Mukamal, Kenneth J; deBoer, Ian H; Thacker, Evan L; Barzilay, Joshua I; Djoussé, Luc; Ix, Joachim H; Smith, Nicholas L; Kaplan, Robert C; Siscovick, David S; Psaty, Bruce M; Kizer, Jorge R

    2016-03-01

    Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse. Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic. Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models. In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  10. Impaired glucose tolerance in patients with amyotrophic lateral sclerosis.

    PubMed

    Pradat, Pierre-Francois; Bruneteau, Gaelle; Gordon, Paul H; Dupuis, Luc; Bonnefont-Rousselot, Dominique; Simon, Dominique; Salachas, Francois; Corcia, Philippe; Frochot, Vincent; Lacorte, Jean-Marc; Jardel, Claude; Coussieu, Christiane; Le Forestier, Nadine; Lacomblez, Lucette; Loeffler, Jean-Philippe; Meininger, Vincent

    2010-01-01

    Our objectives were to analyse carbohydrate metabolism in a series of ALS patients and to examine potential association with parameters of lipid metabolism and clinical features. Glucose tolerance was assessed by the oral glucose tolerance test in 21 non-diabetic ALS patients and compared with 21 age- and sex-matched normal subjects. Lipids and lactate/pyruvate ratio, levels of pro-inflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) and adipocytokines (leptin and adiponectin) were also measured in ALS patients. Mann-Whitney U-tests analysed continuous data and Fisher's exact tests assessed categorical data. Blood glucose determined 120 min after the glucose bolus was significantly higher in patients with ALS (7.41 mmol/l+/-1.68) compared to controls (6.05+/-1.44, p=0.006). ALS patients with impaired glucose tolerance (IGT) according to WHO criteria (n=7, 33%) were more likely to have elevated free fatty acids (FFA) levels compared to patients with normal glucose tolerance (0.77 nmol/l+/-0.30 vs. 0.57+/-0.19, p=0.04). IGT was not associated with disease duration or severity. In conclusion, patients with ALS show abnormal glucose tolerance that could be associated with increased FFA levels, a key determinant of insulin resistance. The origin of glucose homeostasis abnormalities in ALS may be multifactorial and deserves further investigation.

  11. Associations of Metabolic Syndrome, Elevated C-Reactive Protein, and Physical Activity in U.S. Adolescents.

    PubMed

    Williams, Bethany D; Richardson, Michael R; Johnson, Tammie M; Churilla, James R

    2017-12-01

    The aim was to estimate the prevalence of metabolic syndrome (MetS) criteria, elevated C-reactive protein (CRP), and physical activity (PA) as well as the odds of MetS criteria in those active versus inactive utilizing a representative sample of U.S. adolescents. The study sample (n = 676) included male and female adolescent (12-17 years) participants in the 2007-2010 National Health and Nutrition Examination Survey. The criteria analyzed were based on a modified definition of MetS using the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Current adult cut points were used to determine elevated CRP. Activity was estimated using reported days per week and minutes per day of moderate/vigorous PA. The MetS criteria with the highest and lowest overall prevalence estimates were elevated fasting glucose and elevated blood pressure (20.7% [95% confidence interval, 17.02-24.38] and 5.7% [95% confidence interval, 3.70-7.70], respectively). The prevalence of elevated CRP was 7.1% (6.3% and 7.8% in males and females, respectively; p = .42). The prevalence of insufficient PA was 75.0%. Odds of low high-density lipoprotein cholesterol were significantly lower in active adolescents when compared with inactive adolescents (odds ratio = .39, p < .05). In a representative sample of U.S. adolescents, elevated fasting glucose is the most prevalent MetS criterion. One out of five U.S. adolescents has elevated fasting glucose, and three out four do not meet the daily federal PA recommendations. Adolescents meeting the federal PA recommendation demonstrate approximately 60% lower odds of having low high-density lipoprotein cholesterol. Copyright © 2017 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  12. Functional analysis of mutations in a severe congenital neutropenia syndrome caused by glucose-6-phosphatase-β deficiency

    PubMed Central

    Lin, Su Ru; Pan, Chi-Jiunn; Mansfield, Brian C.; Chou, Janice Yang

    2016-01-01

    Glucose-6-phosphatase-β (G6Pase-β or G6PC3) deficiency is characterized by neutropenia and dysfunction in both neutrophils and macrophages. G6Pase-β is an enzyme embedded in the endoplasmic reticulum membrane that catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate. To date, 33 separate G6PC3 mutations have been identified in G6Pase-β-deficient patients but only the p.R253H and p.G260R missense mutations have been characterized functionally for pathogenicity. Here we functionally characterize 16 of the 19 known missense mutations using a sensitive assay, based on a recombinant adenoviral vector-mediated expression system, to demonstrate pathogenicity. Fourteen missense mutations completely abolish G6Pase-β enzymatic activity while the p.S139I and p.R189Q mutations retain 49% and 45%, respectively of wild type G6Pase-β activity. A database of residual enzymatic activity retained by the G6Pase-β mutations will serve as a reference for evaluating genotype-phenotype relationships. PMID:25492228

  13. Trinucleotide Insertions, Deletions, and Point Mutations in Glucose Transporters Confer K+ Uptake in Saccharomyces cerevisiae

    PubMed Central

    Liang, Hong; Ko, Christopher H.; Herman, Todd; Gaber, Richard F.

    1998-01-01

    Deletion of TRK1 and TRK2 abolishes high-affinity K+ uptake in Saccharomyces cerevisiae, resulting in the inability to grow on typical synthetic growth medium unless it is supplemented with very high concentrations of potassium. Selection for spontaneous suppressors that restored growth of trk1Δ trk2Δ cells on K+-limiting medium led to the isolation of cells with unusual gain-of-function mutations in the glucose transporter genes HXT1 and HXT3 and the glucose/galactose transporter gene GAL2. 86Rb uptake assays demonstrated that the suppressor mutations conferred increased uptake of the ion. In addition to K+, the mutant hexose transporters also conferred permeation of other cations, including Na+. Because the selection strategy required such gain of function, mutations that disrupted transporter maturation or localization to the plasma membrane were avoided. Thus, the importance of specific sites in glucose transport could be independently assessed by testing for the ability of the mutant transporter to restore glucose-dependent growth to cells containing null alleles of all of the known functional glucose transporter genes. Twelve sites, most of which are conserved among eukaryotic hexose transporters, were revealed to be essential for glucose transport. Four of these have previously been shown to be essential for glucose transport by animal or plant transporters. Eight represented sites not previously known to be crucial for glucose uptake. Each suppressor mutant harbored a single mutation that altered an amino acid(s) within or immediately adjacent to a putative transmembrane domain of the transporter. Seven of 38 independent suppressor mutations consisted of in-frame insertions or deletions. The nature of the insertions and deletions revealed a striking DNA template dependency: each insertion generated a trinucleotide repeat, and each deletion involved the removal of a repeated nucleotide sequence. PMID:9447989

  14. Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells

    PubMed Central

    Lin, Yi

    2012-01-01

    Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane levels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 β-cells. PMID:22597535

  15. Antiaging gene Klotho enhances glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 in MIN6 β-cells.

    PubMed

    Lin, Yi; Sun, Zhongjie

    2012-07-01

    Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane levels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 β-cells.

  16. Comparison of the clinical information provided by the FreeStyle Navigator continuous interstitial glucose monitor versus traditional blood glucose readings.

    PubMed

    McGarraugh, Geoffrey V; Clarke, William L; Kovatchev, Boris P

    2010-05-01

    The purpose of the analysis was to compare the clinical utility of data from traditional self-monitoring of blood glucose (SMBG) to that of continuous glucose monitoring (CGM). A clinical study of the clinical accuracy of the FreeStyle Navigator CGM System (Abbott Diabetes Care, Alameda, CA), which includes SMBG capabilities, was conducted by comparison to the YSI blood glucose analyzer (YSI Inc., Yellow Springs, OH) using 58 subjects with type 1 diabetes. The Continuous Glucose-Error Grid Analysis (CG-EGA) was used as the analytical tool. Using CG-EGA, the "clinically accurate," "benign errors," and "clinical errors" were 86.8%, 8.7%, and 4.5% for SMBG and 92.7%, 3.7%, and 3.6% for CGM, respectively. If blood glucose is viewed as a process in time, SMBG would provide accurate information about this process 86.8% of the time, whereas CGM would provide accurate information about this process 92.7% of the time (P < 0.0001). In the hypoglycemic range, however, SMBG is more accurate as the "clinically accurate," "benign errors," and "clinical errors" were 83.5%, 6.4%, and 10.1% for SMBG and 57.1%, 8.4%, and 34.5% (P < 0.0001) for CGM, respectively. While SMBG produces more accurate instantaneous glucose values than CGM, control of blood glucose involves a system in flux, and CGM provides more detailed insight into the dynamics of that system. In the normal and elevated glucose ranges, the additional information about the direction and rate of glucose change provided by the FreeStyle Navigator CGM System increases the ability to make correct clinical decisions when compared to episodic SMBG tests.

  17. Time-dependent Mechanisms in Beta-cell Glucose Sensing

    PubMed Central

    Vagn Korsgaard, Thomas

    2006-01-01

    The relation between plasma glucose and insulin release from pancreatic beta-cells is not stationary in the sense that a given glucose concentration leads to a specific rate of insulin secretion. A number of time-dependent mechanisms appear to exist that modify insulin release both on a short and a longer time scale. Typically, two phases are described. The first phase, lasting up to 10 min, is a pulse of insulin release in response to fast changes in glucose concentration. The second phase is a more steady increase of insulin release over minutes to hours, if the elevated glucose concentration is sustained. The paper describes the glucose sensing mechanism via the complex dynamics of the key enzyme glucokinase, which controls the first step in glucose metabolism: phosphorylation of glucose to glucose-6-phosphate. Three time-dependent phenomena (mechanisms) are described. The fastest, corresponding to the first phase, is a delayed negative feedback regulating the glucokinase activity. Due to the delay, a rapid glucose increase will cause a burst of activity in the glucose sensing system, before the glucokinase is down-regulated. The second mechanism corresponds to the translocation of glucokinase from an inactive to an active form. As the translocation is controlled by the product(s) of the glucokinase reaction rather than by the substrate glucose, this mechanism gives a positive, but saturable, feedback. Finally, the release of the insulin granules is assumed to be enhanced by previous glucose exposure, giving a so-called glucose memory to the beta-cells. The effect depends on the insulin release of the cells, and this mechanism constitutes a second positive, saturable feedback system. Taken together, the three phenomena describe most of the glucose sensing behaviour of the beta-cells. The results indicate that the insulin release is not a precise function of the plasma glucose concentration. It rather looks as if the beta-cells just increase the insulin

  18. The biphasic effect of extracellular glucose concentration on carbachol-induced fluid secretion from mouse submandibular glands.

    PubMed

    Terachi, Momomi; Hirono, Chikara; Kitagawa, Michinori; Sugita, Makoto

    2018-06-01

    Cholinergic agonists evoke elevations of the cytoplasmic free-calcium concentration ([Ca 2+ ] i ) to stimulate fluid secretion in salivary glands. Salivary flow rates are significantly reduced in diabetic patients. However, it remains elusive how salivary secretion is impaired in diabetes. Here, we used an ex vivo submandibular gland perfusion technique to characterize the dependency of salivary flow rates on extracellular glucose concentration and activities of glucose transporters expressed in the glands. The cholinergic agonist carbachol (CCh) induced sustained fluid secretion, the rates of which were modulated by the extracellular glucose concentration in a biphasic manner. Both lowering the extracellular glucose concentration to less than 2.5 mM and elevating it to higher than 5 mM resulted in decreased CCh-induced fluid secretion. The CCh-induced salivary flow was suppressed by phlorizin, an inhibitor of the sodium-glucose cotransporter 1 (SGLT1) located basolaterally in submandibular acinar cells, which is altered at the protein expression level in diabetic animal models. Our data suggest that SGLT1-mediated glucose uptake in acinar cells is required to maintain the fluid secretion by sustaining Cl - secretion in real-time. High extracellular glucose levels may suppress the CCh-induced secretion of salivary fluid by altering the activities of ion channels and transporters downstream of [Ca 2+ ] i signals. © 2018 Eur J Oral Sci.

  19. Liver X receptor agonist alleviated high glucose-induced endothelial progenitor cell dysfunction via inhibition of reactive oxygen species and activation of AMP-activated protein kinase.

    PubMed

    Li, Xiaoxia; Song, Yimeng; Han, Yingying; Wang, Dawei; Zhu, Yi

    2012-08-01

    Liver X receptors (LXRs) are key regulators of cholesterol homeostasis. Synthetic LXR agonists are anti-atherogenic and anti-inflammatory. However, the effect of LXR agonists on endothelial progenitor cell (EPC) function is largely unknown. Here, we explored the effect of the LXR agonist TO901317 (TO) on EPC biology and the underlying mechanisms. Endothelial progenitor cells were cultured in mannitol or 30 mm glucose (high glucose) for 24 hours. For TO treatments, cells were pretreated with TO (10 μm) for 12 hours, then mannitol or high glucose was added for an additional 24 hours. EPCs function, reactive oxygen species (ROS) release, and phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) were analyzed. TO could restore the high glucose-impaired adhesion and migration capacity of EPCs. High glucose impaired EPC-mediated angiogenesis, and TO reversed the impairment. TO also alleviated ROS release induced by high glucose. Western blot analysis revealed that high glucose downregulated the phosphorylation of AMPK and endothelial nitric oxide synthase, which could be reversed with TO treatment. Furthermore, inhibiting AMPK activation by compound C could abolish the protective effects of TO on EPCs. TO had a protective effect on EPCs under high glucose by inhibiting ROS release and activating AMPK. © 2012 John Wiley & Sons Ltd.

  20. Dietary iron controls circadian hepatic glucose metabolism through heme synthesis.

    PubMed

    Simcox, Judith A; Mitchell, Thomas Creighton; Gao, Yan; Just, Steven F; Cooksey, Robert; Cox, James; Ajioka, Richard; Jones, Deborah; Lee, Soh-Hyun; King, Daniel; Huang, Jingyu; McClain, Donald A

    2015-04-01

    The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  1. Were Increased Closed Seclusions the Result of a Reinforcer-Abolishing Effect?

    PubMed

    Poling, Alan

    2013-01-01

    In recent years, the motivating operation (MO) concept and the terms associated with it, including "reinforcer-abolishing effect" (Laraway, Snycerski, Michael, & Poling, 2003), have been widely used in the behavior-analytic literature (Laraway, Snycerski, Olson, Becker, & Poling, in press) and elsewhere (Lotfizadeh, Edwards, & Poling, 2013). MOs are changes in the environment that alter the reinforcing effectiveness of designated classes of stimuli, such as food or water.

  2. Dexamethasone and perioperative blood glucose in patients undergoing total joint arthroplasty: A retrospective study.

    PubMed

    Nurok, Michael; Cheng, Jennifer; Romeo, Giulio R; Vecino, Stephanie M; Fields, Kara G; YaDeau, Jacques T

    2017-02-01

    Perioperative dexamethasone is commonly used to prevent nausea. It can also increase blood glucose levels, and recent concern about its blood glucose-elevating effect in humans has been raised. This study aimed to demonstrate relationships between dexamethasone administration and elevated perioperative blood glucose in patients undergoing total joint arthroplasty. Retrospective study. Academic, orthopedic hospital. A total of 625 patients (18-99years) who underwent total hip or total knee arthroplasty with an ASA ≤3 were included in the study. Patients who received dexamethasone perioperatively were compared to those who did not receive dexamethasone. The primary outcome, which was any postoperative glucose >200mg/dl, was compared between groups using multiple logistic regression. Demographic information, intraoperative information, incidence of postoperative nausea and vomiting, white blood cell count, medication use, and length of stay were also collected. Perioperative dexamethasone (median [1st quartile, 3rd quartile] dose=4 [4, 8] mg) was administered to 76% of patients. Only 5.6% (95% CI: 3.8-7.5) of patients had postoperative glucose levels >200mg/dl. After covariate adjustment, there was no evidence of a difference in odds of experiencing postoperative glucose levels >200mg/dl (odds ratio [95% CI]: 0.76 [0.28-2.07]; P=0.594) and maximum glucose levels (P=0.518) between groups. Dexamethasone-treated patients had greater changes in white blood cell count between baseline and postoperative days 0-1. There was no evidence of a difference in wound healing and length of stay between groups. There was no evidence of an association between perioperative dexamethasone administration and the odds of having postoperative glucose levels >200mg/dl or higher maximum glucose levels. However, these findings may not be generalizable to patients having different baseline characteristics or procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Low glucose availability stimulates progesterone production by mouse ovaries in vitro.

    PubMed

    Wilsterman, Kathryn; Pepper, Aimee; Bentley, George E

    2017-12-15

    Steroid production by the ovary is primarily stimulated by gonadotropins but can also be affected by biological cues that provide information about energy status and environmental stress. To further understand which metabolic cues the ovary can respond to, we exposed gonadotropin-stimulated mouse ovaries in vitro to glucose metabolism inhibitors and measured steroid accumulation in media. Gonadotropin-stimulated ovaries exposed to 2-deoxy-d-glucose increased progesterone production and steroidogenic acute regulatory protein mRNA levels. However, oocytes and granulosa cells in antral follicles do not independently mediate this response because targeted treatment of these cell types with a different inhibitor of glucose metabolism (bromopyruvic acid) did not affect progesterone production. Elevated progesterone production is consistent with the homeostatic role of progesterone in glucose regulation in mammals. It also may regulate follicle growth and/or atresia within the ovary. These results suggest that ovaries can regulate glucose homeostasis in addition to their primary role in reproductive activity. © 2017. Published by The Company of Biologists Ltd.

  4. Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

    PubMed Central

    Sun, Y; Wang, D; Ye, F; Hu, D-N; Liu, X; Zhang, L; Gao, L; Song, E; Zhang, D Y

    2013-01-01

    Purpose Müller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions. The objective of this study was to determine the potential mechanism of Müller cell proliferation and VEGF production due to high-glucose conditions. Methods Primary cultured rat Müller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h. The proliferation of Müller cells was assessed by the MTT assay. The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array. Results High concentrations of glucose-induced Müller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1α, NFκB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis. However, Müller cell alterations induced by high-glucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/phosphorylations (out of 47) were restored to their normal levels. Nine proteins, including NFκB p65, p-p38, tumor necrosis factor-α, urokinase-type plasminogen activator, CREB, IL-1β, HCAM, estrogen receptor-α, and p-Stat3, were involved in regulatory networks between XIAP and VEGF. Conclusions The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Müller cells. Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy. PMID:23928877

  5. Lysine acetyltransferase NuA4 and acetyl-CoA regulate glucose-deprived stress granule formation in Saccharomyces cerevisiae

    PubMed Central

    Huard, Sylvain; Morettin, Alan; Fullerton, Morgan D.; Côté, Jocelyn

    2017-01-01

    Eukaryotic cells form stress granules under a variety of stresses, however the signaling pathways regulating their formation remain largely unknown. We have determined that the Saccharomyces cerevisiae lysine acetyltransferase complex NuA4 is required for stress granule formation upon glucose deprivation but not heat stress. Further, the Tip60 complex, the human homolog of the NuA4 complex, is required for stress granule formation in cancer cell lines. Surprisingly, the impact of NuA4 on glucose-deprived stress granule formation is partially mediated through regulation of acetyl-CoA levels, which are elevated in NuA4 mutants. While elevated acetyl-CoA levels suppress the formation of glucose-deprived stress granules, decreased acetyl-CoA levels enhance stress granule formation upon glucose deprivation. Further our work suggests that NuA4 regulates acetyl-CoA levels through the Acetyl-CoA carboxylase Acc1. Altogether this work establishes both NuA4 and the metabolite acetyl-CoA as critical signaling pathways regulating the formation of glucose-deprived stress granules. PMID:28231279

  6. Alterations in gonadotropin secretion and ovarian function in prepubertal gilts by elevated environmental temperature.

    PubMed

    Flowers, B; Day, B N

    1990-03-01

    The effect of chronic exposure to elevated environmental temperature on gonadotropin secretion and ovarian function was studied in prepubertal gilts. Gilts were maintained under control (15.6 degrees C) or elevated temperature (33.3 degrees C) conditions from 150 to 180 days of age. Endocrine and ovarian responses to bilateral (BLO), unilateral (ULO), and sham ovariectomy were evaluated between 175 and 180 days of age. During the 96-h sampling period after BLO, plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were suppressed in heat-stressed females. Similarly, elevated temperatures abolished the transient rise in FSH and subsequent follicular growth normally associated with ULO. In contrast, environmental treatment had no effect on the secretion of FSH and LH after sham ovariectomy, yet the number of small follicles was lower in gilts exposed to elevated temperatures than in females maintained under control conditions. These results indicate that a chronic exposure to elevated environmental temperature during pubertal development diminished the ability of the hypothalamo-hypophyseal axis to secrete FSH and LH, which had physiological consequences on follicular growth. When provided an appropriate stimulus (ULO), an acute period of FSH secretion and subsequent development of follicles failed to occur in females exposed to elevated temperatures. Consequently, we propose that delayed puberty in gilts during periods of elevated environmental temperatures is due, in part, to a diminished capacity for gonadotropin secretion.

  7. Were Increased Closed Seclusions the Result of a Reinforcer-Abolishing Effect?

    PubMed Central

    Poling, Alan

    2013-01-01

    In recent years, the motivating operation (MO) concept and the terms associated with it, including “reinforcer-abolishing effect” (Laraway, Snycerski, Michael, & Poling, 2003), have been widely used in the behavior-analytic literature (Laraway, Snycerski, Olson, Becker, & Poling, in press) and elsewhere (Lotfizadeh, Edwards, & Poling, 2013). MOs are changes in the environment that alter the reinforcing effectiveness of designated classes of stimuli, such as food or water. PMID:27999634

  8. Elevated Medium-Chain Acylcarnitines Are Associated With Gestational Diabetes Mellitus and Early Progression to Type 2 Diabetes and Induce Pancreatic β-Cell Dysfunction.

    PubMed

    Batchuluun, Battsetseg; Al Rijjal, Dana; Prentice, Kacey J; Eversley, Judith A; Burdett, Elena; Mohan, Haneesha; Bhattacharjee, Alpana; Gunderson, Erica P; Liu, Ying; Wheeler, Michael B

    2018-05-01

    Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: 1 ) women with gestational diabetes mellitus (GDM) and 2 ) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function. © 2018 by the American Diabetes Association.

  9. Effects of glucose availability on expression of the key genes involved in synthesis of milk fat, lactose and glucose metabolism in bovine mammary epithelial cells.

    PubMed

    Liu, Hongyun; Zhao, Ke; Liu, Jianxin

    2013-01-01

    As the main precursor for lactose synthesis, large amounts of glucose are required by lactating dairy cows. Milk yield greatly depends on mammary lactose synthesis due to its osmoregulatory property for mammary uptake of water. Thus, glucose availability to the mammary gland could be a potential regulator of milk production. In the present study, the effect of glucose availability on expression of the key genes involved in synthesis of milk fat, lactose and glucose metabolism in vitro was investigated. Bovine mammary epithelial cells (BMEC) were treated for 12 h with various concentrations of glucose (2.5, 5, 10 or 20 mmol/L). The higher concentrations of glucose (10-20 mmol/L) did not affect the mRNA expression of acetyl-CoA carboxylase, diacyl glycerol acyl transferase, glycerol-3 phosphate acyl transferase and α-lactalbumin, whereas fatty acid synthase, sterol regulatory element binding protein-1 and beta-1, 4-galactosyl transferase mRNA expression increased at 10 mmol/L and then decreased at 20 mmol/L. The content of lactose synthase increased with increasing concentration of glucose, with addition of highest value at 20 mmol/L of glucose. Moreover, the increased glucose concentration stimulated the activities of pyruvate kinase and glucose-6-phosphate dehydrogenase, and elevated the energy status of the BMEC. Therefore, it was deduced that after increasing glucose availability, the extra absorbed glucose was partitioned to entering the synthesis of milk fat and lactose by the regulation of the mRNA expression of key genes, promoting glucose metabolism by glycolysis and pentose phosphate pathway as well as energy status. These results indicated that the sufficient availability of glucose in BMEC may promote glucose metabolism, and affect the synthesis of milk composition.

  10. Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase- dependent mechanism.

    PubMed

    Benomar, Yacir; Naour, Nadia; Aubourg, Alain; Bailleux, Virginie; Gertler, Arieh; Djiane, Jean; Guerre-Millo, Michèle; Taouis, Mohammed

    2006-05-01

    The insulin-sensitive glucose transporter Glut4 is expressed in brain areas that regulate energy homeostasis and body adiposity. In contrast with peripheral tissues, however, the impact of insulin on Glut4 plasma membrane (PM) translocation in neurons is not known. In this study, we examined the role of two anorexic hormones (leptin and insulin) on Glut4 translocation in a human neuronal cell line that express endogenous insulin and leptin receptors. We show that insulin and leptin both induce Glut4 translocation to the PM of neuronal cells and activate glucose uptake. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, totally abolished insulin- and leptin-dependent Glut4 translocation and stimulation of glucose uptake. Thus, Glut4 translocation is a phosphatidylinositol 3-kinase-dependent mechanism in neuronal cells. Next, we investigated the impact of chronic insulin and leptin treatments on Glut4 expression and translocation. Chronic exposure of neuronal cells to insulin or leptin down-regulates Glut4 proteins and mRNA levels and abolishes the acute stimulation of glucose uptake in response to acute insulin or leptin. In addition, chronic treatment with either insulin or leptin impaired Glut4 translocation. A cross-desensitization between insulin and leptin was apparent, where exposure to insulin affects leptin-dependent Glut4 translocation and vice versa. This cross-desensitization could be attributed to the increase in suppressor of cytokine signaling-3 expression, which was demonstrated in response to each hormone. These results provide evidence to suggest that Glut4 translocation to neuronal PM is regulated by both insulin and leptin signaling pathways. These pathways might contribute to an in vivo glucoregulatory reflex involving a neuronal network and to the anorectic effect of insulin and leptin.

  11. Abnormal Glucose Metabolism and High-Energy Expenditure in Idiopathic Pulmonary Arterial Hypertension

    PubMed Central

    Malin, Steven K.; Barnes, Jarrod W.; Tian, Liping; Kirwan, John P.; Dweik, Raed A.

    2017-01-01

    Rationale: Insulin resistance has emerged as a potential mechanism related to the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH). However, direct measurements of insulin and glucose metabolism have not been performed in patients with IPAH to date. Objectives: To perform comprehensive metabolic phenotyping of humans with IPAH. Methods: We assessed plasma insulin and glucose, using an oral glucose tolerance test and estimated insulin resistance, and β-cell function in 14 patients with IPAH and 14 control subjects matched for age, sex, blood pressure, and body mass index. Body composition (dual-energy X-ray absorptiometry), inflammation (CXC chemokine ligand 10, endothelin-1), physical fitness (6-min walk test), and energy expenditure (indirect calorimetry) were also assessed. Measurements and Main Results: Patients with IPAH had a higher rate of impaired glucose tolerance (57 vs. 14%; P < 0.05) and reduced glucose-stimulated insulin secretion compared with matched control subjects (IPAH: 1.31 ± 0.76 μU/ml⋅mg/dl vs. control subjects: 2.21 ± 1.27 μU/ml⋅mg/dl; P < 0.05). Pancreatic β-cell function was associated with circulating endothelin-1 (r = –0.71, P < 0.01) and CXC chemokine ligand 10 (r = –0.56, P < 0.05). Resting energy expenditure was elevated in IPAH (IPAH: 32 ± 3.4 vs. control subjects: 28.8 ± 2.9 kcal/d/kg fat-free mass; P < 0.05) and correlated with the plasma glucose response (r = 0.51, P < 0.01). Greater insulin resistance was associated with reduced 6-minute walk distance (r = 0.55, P < 0.05). Conclusions: Independent of age, sex, blood pressure, and body mass index, patients with IPAH have glucose intolerance, decreased insulin secretion in response to glucose, and elevated resting energy expenditure. These abnormalities are associated with circulating markers of inflammation and vascular dysfunction. PMID:27922752

  12. Paeoniflorin Suppressed High Glucose-Induced Retinal Microglia MMP-9 Expression and Inflammatory Response via Inhibition of TLR4/NF-κB Pathway Through Upregulation of SOCS3 in Diabetic Retinopathy.

    PubMed

    Zhu, Su-Hua; Liu, Bing-Qian; Hao, Mao-Juan; Fan, Yi-Xin; Qian, Cheng; Teng, Peng; Zhou, Xiao-Wei; Hu, Liang; Liu, Wen-Tao; Yuan, Zhi-Lan; Li, Qing-Ping

    2017-10-01

    Diabetic retinopathy (DR) is a serious-threatening complication of diabetes and urgently needed to be treated. Evidence has accumulated indicating that microglia inflammation within the retina plays a critical role in DR. Microglial matrix metalloproteinase 9 (MMP-9) has an important role in the destruction of the integrity of the blood-retinal barrier (BRB) associated with the development of DR. MMP-9 was also considered important for regulating inflammatory responses. Paeoniflorin, a monoterpene glucoside, has a potent immunomodulatory effect on microglia. We hypothesized that paeoniflorin could significantly suppress microglial MMP-9 activation induced by high glucose and further relieve DR. BV2 cells were used to investigate the effects and mechanism of paeoniflorin. The activation of MMP-9 was measured by gelatin zymography. Cell signaling was measured by western blot assay and immunofluorescence assay. High glucose increased the activation of MMP-9 in BV2 cells, which was abolished by HMGB1, TLR4, p38 MAPK, and NF-κB inhibition. Phosphorylation of p38 MAPK induced by high glucose was decreased by TLR4 inhibition in BV2 cells. Paeoniflorin induced suppressor of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells. The effect of paeoniflorin on SOCS3 was abolished by the TLR4 inhibitor. In streptozotocin (STZ)-induced diabetes mice, paeoniflorin induced SOCS3 expression and reduced MMP-9 activation. Paeoniflorin suppressed STZ-induced IBA-1 and IL-1β expression and decreased STZ-induced high blood glucose level. In conclusion, paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of the TLR4/NF-κB pathway through upregulation of SOCS3 in diabetic retinopathy.

  13. Chromium (D-phenylalanine)3 supplementation alters glucose disposal, insulin signaling, and glucose transporter-4 membrane translocation in insulin-resistant mice.

    PubMed

    Dong, Feng; Kandadi, Machender Reddy; Ren, Jun; Sreejayan, Nair

    2008-10-01

    Chromium has gained popularity as a nutritional supplement for diabetic and insulin-resistant subjects. This study was designed to evaluate the effect of chronic administration of a novel chromium complex of d-phenylalanine [Cr(D-phe)(3)] in insulin-resistant, sucrose-fed mice. Whole-body insulin resistance was generated in FVB mice by 9 wk of sucrose feeding, following which they were randomly assigned to be unsupplemented (S group) or to receive oral Cr(D-phe)(3) in drinking water (SCr group) at a dose of 45 mug.kg(-1).d(-1) ( approximately 3.8 mug of elemental chromium.kg(-1).d(-1)). A control group (C) did not consume sucrose and was not supplemented. Sucrose-fed mice had an elevated serum insulin concentration compared with controls and this was significantly lower in sucrose-fed mice that received Cr(D-phe)(3), which did not differ from controls. Impaired glucose tolerance in sucrose-fed mice, evidenced by the poor glucose disposal rate following an intraperitoneal glucose tolerance test, was significantly improved in mice receiving Cr(D-phe)(3). Chromium supplementation significantly enhanced insulin-stimulated Akt phosphorylation and membrane-associated glucose transporter-4 in skeletal muscles of sucrose-fed mice. In cultured adipocytes rendered insulin resistant by chronic exposure to high concentrations of glucose and insulin, Cr(D-phe)(3) augmented Akt phosphorylation and glucose uptake. These results indicate that dietary supplementation with Cr(D-phe)(3) may have potential beneficial effects in insulin-resistant, prediabetic conditions.

  14. Mapping glucose-mediated gut-to-brain signalling pathways in humans.

    PubMed

    Little, Tanya J; McKie, Shane; Jones, Richard B; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G; McLaughlin, John T

    2014-08-01

    Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250ml) of: 1M glucose+predosing with dexloxiglumide (CCK1 receptor antagonist), 1M glucose+placebo, or 0.9% saline (control)+placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose+dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. Copyright © 2014. Published by Elsevier Inc.

  15. Mapping glucose-mediated gut-to-brain signalling pathways in humans☆

    PubMed Central

    Little, Tanya J.; McKie, Shane; Jones, Richard B.; D'Amato, Massimo; Smith, Craig; Kiss, Orsolya; Thompson, David G.; McLaughlin, John T.

    2014-01-01

    Objectives Previous fMRI studies have demonstrated that glucose decreases the hypothalamic BOLD response in humans. However, the mechanisms underlying the CNS response to glucose have not been defined. We recently demonstrated that the slowing of gastric emptying by glucose is dependent on activation of the gut peptide cholecystokinin (CCK1) receptor. Using physiological functional magnetic resonance imaging this study aimed to determine the whole brain response to glucose, and whether CCK plays a central role. Experimental design Changes in blood oxygenation level-dependent (BOLD) signal were monitored using fMRI in 12 healthy subjects following intragastric infusion (250 ml) of: 1 M glucose + predosing with dexloxiglumide (CCK1 receptor antagonist), 1 M glucose + placebo, or 0.9% saline (control) + placebo, in a single-blind, randomised fashion. Gallbladder volume, blood glucose, insulin, and GLP-1 and CCK concentrations were determined. Hunger, fullness and nausea scores were also recorded. Principal observations Intragastric glucose elevated plasma glucose, insulin, and GLP-1, and reduced gall bladder volume (an in vivo assay for CCK secretion). Glucose decreased BOLD signal, relative to saline, in the brainstem and hypothalamus as well as the cerebellum, right occipital cortex, putamen and thalamus. The timing of the BOLD signal decrease was negatively correlated with the rise in blood glucose and insulin levels. The glucose + dex arm highlighted a CCK1-receptor dependent increase in BOLD signal only in the motor cortex. Conclusions Glucose induces site-specific differences in BOLD response in the human brain; the brainstem and hypothalamus show a CCK1 receptor-independent reduction which is likely to be mediated by a circulatory effect of glucose and insulin, whereas the motor cortex shows an early dexloxiglumide-reversible increase in signal, suggesting a CCK1 receptor-dependent neural pathway. PMID:24685436

  16. Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.

    PubMed

    Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

    2018-04-15

    Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis. The enhanced hepatic glycolysis is reflected by increased lactate accumulation, increased expression of many glycolytic enzymes, and elevated expression of c-Myc that stimulates glycolysis. The increased HMS is reflected by increased glucose-6-phosphate dehydrogenase activity and elevated production of NADPH and the reduced glutathione. We have previously shown that restoration of hepatic G6Pase-α expression in G6Pase-α-deficient liver corrects metabolic abnormalities, normalizes autophagy, and prevents HCA/HCC development in GSD-Ia. We now show that restoration of hepatic G6Pase-α expression normalizes both glycolysis and HMS in GSD-Ia. Moreover, the HCA/HCC lesions in L-G6pc-/- mice exhibit elevated levels of hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) which play an important role in aerobic glycolysis and cancer cell proliferation. Taken together, hepatic G6Pase-α deficiency causes metabolic reprogramming, leading to enhanced glycolysis and elevated HMS that along with impaired autophagy can contribute to HCA/HCC development in GSD-Ia. Published by Elsevier Inc.

  17. Proprioceptive input patterns elevator activity in the locust flight system.

    PubMed

    Wolf, H; Pearson, K G

    1988-06-01

    1. In the locust, Locusta migratoria, the roles of two groups of wing sense organs, hind wing tegulae and wing-hinge stretch receptors, in the generation of the flight motor pattern were investigated. A preparation was employed that allowed the intracellular recording of neural activity in almost intact tethered flying locusts or after selective manipulations of sensory input. The functions of the two sets of receptors were assessed 1) by studying the phases of their discharges in the wingbeat cycle (Fig. 3), 2) by the selective ablation of input from the receptors (Figs. 4-7), and 3) by the selective stimulation of the receptor afferents (Figs. 8-12). 2. Input from the tegulae was found to be responsible for the initiation of elevator activity (Figs. 9 and 10) and for the generation of a distinct initial rapid depolarization (Figs. 4, 5, and 8) characteristic of elevator motor neuron activity in intact locusts (Figs. 1 and 16). 3. Input from the wing-hinge stretch receptors was found to control the duration of elevator depolarizations by the graded suppression of a second late component of the elevator depolarizations as wingbeat frequency increased (Figs. 6, 7, 11, and 12). The characteristics of this late component of elevator activity suggested that it is generated by the same (central nervous) mechanism that produces the elevator depolarizations recorded in deafferented animals (Fig. 2). Apparently this late component contributes to the intact pattern of elevator depolarizations only at lower wingbeat frequencies and is abolished by the action of stretch-receptor input at frequencies above approximately 15 Hz (Figs. 1, 2, and 4). At these high wingbeat frequencies elevator activity is dominated by the rapid depolarizations generated as a result of tegula input. 4. The present study demonstrates 1) that the timing of elevator motor neuron activity is determined by phasic afferent input from tegulae and stretch receptors and 2) that input from the stretch

  18. Association of Biomarkers of Inflammation and Endothelial Dysfunction with Fasting and Postload Glucose Metabolism: A Population-Based Prospective Cohort Study Among Inner Mongolians in China.

    PubMed

    Wu, Jiahui; Liang, Zhu; Zhou, Jingwen; Zhong, Chongke; Jiang, Wei; Zhang, Yonghong; Zhang, Shaoyan

    2016-12-01

    To examine the associations between elevated levels of C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) with fasting and 2-hour postload glucometabolic status among Inner Mongolians in China. Based on a cross-sectional survey of patients during 2003, 2260 participants were reinvestigated between 2013 and 2014. We categorized the participants into 3 subgroups according to fasting and postload glucose levels, respectively. The associations between biomarkers of inflammation and endothelial dysfunction and deterioration of fasting and postload glucometabolic status were examined by ordinal logistic regression analysis. We found 142 and 49 persons who had impaired fasting glucose (IFG) levels and type 2 diabetes in the fasting state and 335 and 50 persons who had impaired glucose tolerance (IGT) and type 2 diabetes in the postload state. After multivariable adjustment, elevated CRP and sICAM-1 levels were associated with deterioration of fasting glucometabolic status from normal fasting glucose to IFG and type 2 diabetes (odds ratio [OR] 1.73 [95% CI 1.18 to 2.54] for elevated CRP levels, OR 1.86 [95% CI 1.30 to 2.66] for elevated sICAM-1 levels). Elevated sE-selectin levels were associated with deterioration of postload glucometabolic status from normal glucose tolerance to IGT and type 2 diabetes (OR 1.34 [95% CI 1.01 to 1.77]) in the multivariable-adjusted model. Biomarkers of inflammation and endothelial dysfunction were separately associated with fasting and postload glucose metabolism among Inner Mongolians. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  19. Contribution of partial pancreatectomy, systemic hormone delivery, and duct obliteration to glucose regulation in canine pancreas. Importance in pancreas transplantation.

    PubMed

    van der Burg, M P; Gooszen, H G; Guicherit, O R; Jansen, J B; Frölich, M; van Haastert, F A; Lamers, C B

    1989-09-01

    Our aim was to isolate and determine the contribution of partial pancreatectomy, systemic delivery of pancreatic hormones, and duct obliteration to glucose regulation after segmental pancreas transplantation in dogs. Fasting, postprandial, and intravenous glucose-stimulated glucose, insulin, glucagon, pancreatic polypeptide (PP), and cholecystokinin (CCK) and intravenous bombesin-stimulated PP levels were studied in beagles at three successive intervals in a crossover design. The first was 6 wk after partial (approximately 70%) pancreatectomy with intact regular enteric exocrine drainage from the duodenal pancreatic remnant, the next was 2 wk after venous transposition with systemic delivery of pancreatic hormones, and the third was 6 wk after in situ duct obliteration of the remnant. With partial pancreatectomy, K values were modestly diminished (30%), and a concomitant reduction of second-phase intravenous glucose-stimulated insulin release was observed. Other parameters were not significantly affected. Venous transposition doubled peripheral plasma levels of insulin under all conditions. Fasting glucose, PP, and CCK levels decreased slightly. Other parameters were not affected. Duct obliteration of the systemic draining pancreatic remnants seriously impaired glucose sensitivity, resulting in a 50% reduction of K values and fasting and sustained postprandial hyperglycemia (approximately 8 mM) and a 70-50% reduction (acute and overall responses, respectively) of intravenous glucose-stimulated insulin. Fasting hormone and postprandial insulin, glucagon, and CCK levels were not affected. The postprandial PP response was severely reduced, and bombesin-stimulated PP release was abolished by duct obliteration. We conclude that histological changes associated with duct obliteration are the major determinants of glucose regulation in segmental pancreas transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Glucose deprivation elicits phenotypic plasticity via ZEB1-mediated expression of NNMT

    PubMed Central

    Kanska, Justyna; Aspuria, Paul-Joseph P.; Taylor-Harding, Barbie; Spurka, Lindsay; Funari, Vincent; Orsulic, Sandra; Karlan, Beth Y.; Wiedemeyer, W. Ruprecht

    2017-01-01

    Glucose is considered the primary energy source for all cells, and some cancers are addicted to glucose. Here, we investigated the functional consequences of chronic glucose deprivation in serous ovarian cancer cells. We found that cells resistant to glucose starvation (glucose-restricted cells) demonstrated increased metabolic plasticity that was dependent on NNMT (Nicotinamide N-methyltransferase) expression. We further show that ZEB1 induced NNMT, rendered cells resistant to glucose deprivation and recapitulated metabolic adaptations and mesenchymal gene expression observed in glucose-restricted cells. NNMT depletion reversed metabolic plasticity in glucose-restricted cells and prevented de novo formation of glucose-restricted colonies. In addition to its role in glucose independence, we found that NNMT was required for other ZEB1-induced phenotypes, such as increased migration. NNMT protein levels were also elevated in metastatic and recurrent tumors compared to matched primary carcinomas, while normal ovary and fallopian tube tissue had no detectable NNMT expression. Our studies define a novel ZEB1/NNMT signaling axis, which elicits mesenchymal gene expression, as well as phenotypic and metabolic plasticity in ovarian cancer cells upon chronic glucose starvation. Understanding the causes of cancer cell plasticity is crucial for the development of therapeutic strategies to counter intratumoral heterogeneity, acquired drug resistance and recurrence in high-grade serous ovarian cancer (HGSC). PMID:28412735

  1. Chromium dinicocysteinate supplementation can lower blood glucose, CRP, MCP-1, ICAM-1, creatinine, apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 in livers of Zucker diabetic fatty rats

    PubMed Central

    Jain, Sushil K.; Croad, Jennifer L.; Velusamy, Thirunavukkarasu; Rains, Justin L.; Bull, Rebeca

    2011-01-01

    Aim Chromium and cysteine supplementation can improve glucose metabolism in animal studies. This study examined the hypothesis that a cysteinate complex of chromium is significantly beneficial than either of them in lowering blood glucose and vascular inflammation markers in ZDF rats. Methods Starting at the age of 6 wks, ZDF rats were supplemented orally (daily gavages for 8 more wks) with saline-placebo (D) or chromium (400µg Cr/KgBW) as chromium-dinicocysteinate (CDNC), chromium-dinicotinate (CDN), or chromium-picolinate (CP) or equimolar L-cysteine (LC, img/Kg BW), and fed Purina 5008 diet for 8 wks. ZDF rats of 6 wks age before any supplementations and onset of diabetes were considered as baseline (BL). Results D rats showed elevated levels of fasting blood glucose, HbA1, CRP, MCP-1, ICAM-1 and oxidative stress (LP) and lower adiponectin and vitamin C, when compared to BL rats. In comparison to D group, CDNC group had significantly lower blood glucose, HbA1, CRP, MCP-1, ICAM-1 and LP and increased vitamin C and adiponectin levels. CDN, CP or LC showed significantly less or no effect on these biomarkers. Only CDNC lowered blood creatinine levels in comparison to D. While CDN and CP had no effect, activation of NFkB, Akt and GLUT-2 levels were decreased, IRS-1 activation increased in livers of CDNC-rats. CDNC effect on glycemia, NFkB, Akt and IRS-1 in liver was significantly greater compared with LC. Blood chromium levels did not differ between Cr-groups. Exogenous vitamin C supplementation significantly inhibited MCP-1 secretion in U937 monocytes cultured in high-glucose-medium. Conclusions CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkB, Akt, and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats. PMID:20306473

  2. Transient elevation of glycolysis confers radio-resistance by facilitating DNA repair in cells.

    PubMed

    Bhatt, Anant Narayan; Chauhan, Ankit; Khanna, Suchit; Rai, Yogesh; Singh, Saurabh; Soni, Ravi; Kalra, Namita; Dwarakanath, Bilikere S

    2015-05-01

    Cancer cells exhibit increased glycolysis for ATP production (the Warburg effect) and macromolecular biosynthesis; it is also linked with therapeutic resistance that is generally associated with compromised respiratory metabolism. Molecular mechanisms underlying radio-resistance linked to elevated glycolysis remain incompletely understood. We stimulated glycolysis using mitochondrial respiratory modifiers (MRMs viz. di-nitro phenol, DNP; Photosan-3, PS3; Methylene blue, MB) in established human cell lines (HEK293, BMG-1 and OCT-1). Glucose utilization and lactate production, levels of glucose transporters and glycolytic enzymes were investigated as indices of glycolysis. Clonogenic survival, DNA repair and cytogenetic damage were studied as parameters of radiation response. MRMs induced the glycolysis by enhancing the levels of two important regulators of glucose metabolism GLUT-1 and HK-II and resulted in 2 fold increase in glucose consumption and lactate production. This increase in glycolysis resulted in resistance against radiation-induced cell death (clonogenic survival) in different cell lines at an absorbed dose of 5 Gy. Inhibition of glucose uptake and glycolysis (using fasentin, 2-deoxy-D-glucose and 3-bromopyruvate) in DNP treated cells failed to increase the clonogenic survival of irradiated cells, suggesting that radio-resistance linked to inhibition of mitochondrial respiration is glycolysis dependent. Elevated glycolysis also facilitated rejoining of radiation-induced DNA strand breaks by activating both non-homologous end joining (NHEJ) and homologous recombination (HR) pathways of DNA double strand break repair leading to a reduction in radiation-induced cytogenetic damage (micronuclei formation) in these cells. These findings suggest that enhanced glycolysis generally observed in cancer cells may be responsible for the radio-resistance, partly by enhancing the repair of DNA damage.

  3. Impact of L-FABP and glucose on polyunsaturated fatty acid induction of PPARα-regulated β-oxidative enzymes

    PubMed Central

    Petrescu, Anca D.; Huang, Huan; Martin, Gregory G.; McIntosh, Avery L.; Storey, Stephen M.; Landrock, Danilo; Kier, Ann B.

    2013-01-01

    Liver fatty acid binding protein (L-FABP) is the major soluble protein that binds very-long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) in hepatocytes. However, nothing is known about L-FABP's role in n-3 PUFA-mediated peroxisome proliferator activated receptor-α (PPARα) transcription of proteins involved in long-chain fatty acid (LCFA) β-oxidation. This issue was addressed in cultured primary hepatocytes from wild-type, L-FABP-null, and PPARα-null mice with these major findings: 1) PUFA-mediated increase in the expression of PPARα-regulated LCFA β-oxidative enzymes, LCFA/LCFA-CoA binding proteins (L-FABP, ACBP), and PPARα itself was L-FABP dependent; 2) PPARα transcription, robustly potentiated by high glucose but not maltose, a sugar not taken up, correlated with higher protein levels of these LCFA β-oxidative enzymes and with increased LCFA β-oxidation; and 3) high glucose altered the potency of n-3 relative to n-6 PUFA. This was not due to a direct effect of glucose on PPARα transcriptional activity nor indirectly through de novo fatty acid synthesis from glucose. Synergism was also not due to glucose impacting other signaling pathways, since it was observed only in hepatocytes expressing both L-FABP and PPARα. Ablation of L-FABP or PPARα as well as treatment with MK886 (PPARα inhibitor) abolished/reduced PUFA-mediated PPARα transcription of these genes, especially at high glucose. Finally, the PUFA-enhanced L-FABP distribution into nuclei with high glucose augmentation of the L-FABP/PPARα interaction reveals not only the importance of L-FABP for PUFA induction of PPARα target genes in fatty acid β-oxidation but also the significance of a high glucose enhancement effect in diabetes. PMID:23238934

  4. Pleocytosis is not fully responsible for low CSF glucose in meningitis.

    PubMed

    Baud, Maxime O; Vitt, Jeffrey R; Robbins, Nathaniel M; Wabl, Rafael; Wilson, Michael R; Chow, Felicia C; Gelfand, Jeffrey M; Josephson, S Andrew; Miller, Steve

    2018-01-01

    The mechanism of hypoglycorrhachia-low CSF glucose-in meningitis remains unknown. We sought to evaluate the relative contribution of CSF inflammation vs microorganisms (bacteria and fungi) in lowering CSF glucose levels. We retrospectively categorized CSF profiles into microbial and aseptic meningitis and analyzed CSF leukocyte count, glucose, and protein concentrations. We assessed the relationship between these markers using multivariate and stratified linear regression analysis for initial and repeated CSF sampling. We also calculated the receiver operating characteristics of CSF glucose and CSF-to-serum glucose ratios to presumptively diagnose microbial meningitis. We found that increasing levels of CSF inflammation were associated with decreased CSF glucose levels in the microbial but not aseptic category. Moreover, elevated CSF protein levels correlated more strongly than the leukocyte count with low CSF glucose levels on initial ( R 2 = 36%, p < 0.001) and repeated CSF sampling ( R 2 = 46%, p < 0.001). Hypoglycorrhachia (<40 mg/dL) was observed in 50.1% of microbial cases, but only 9.6% of aseptic cases, most of which were neurosarcoidosis. Absolute CSF glucose and CSF-to-serum glucose ratios had similar low sensitivity and moderate-to-high specificity in diagnosing microbial meningitis at thresholds commonly used. The main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation and proteins, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis. A major notable exception is neurosarcoidosis. Low CSF glucose and CSF-to-serum glucose ratios are useful markers for the diagnosis of microbial meningitis.

  5. Blood glucose, diet-based glycemic load and cognitive aging among dementia-free older adults.

    PubMed

    Seetharaman, Shyam; Andel, Ross; McEvoy, Cathy; Dahl Aslan, Anna K; Finkel, Deborah; Pedersen, Nancy L

    2015-04-01

    Although evidence indicates that Type II Diabetes is related to abnormal brain aging, the influence of elevated blood glucose on long-term cognitive change is unclear. In addition, the relationship between diet-based glycemic load and cognitive aging has not been extensively studied. The focus of this study was to investigate the influence of diet-based glycemic load and blood glucose on cognitive aging in older adults followed for up to 16 years. Eight-hundred and thirty-eight cognitively healthy adults aged ≥50 years (M = 63.1, SD = 8.3) from the Swedish Adoption/Twin Study of Aging were studied. Mixed effects growth models were utilized to assess overall performance and change in general cognitive functioning, perceptual speed, memory, verbal ability, and spatial ability as a function of baseline blood glucose and diet-based glycemic load. High blood glucose was related to poorer overall performance on perceptual speed as well as greater rates of decline in general cognitive ability, perceptual speed, verbal ability, and spatial ability. Diet-based glycemic load was related to poorer overall performance in perceptual speed and spatial ability. Diet-based glycemic load and, in particular, elevated blood glucose appear important for cognitive performance/cognitive aging. Blood glucose control (perhaps through low glycemic load diets) may be an important target in the detection and prevention of age-related cognitive decline. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  6. Testosterone abolishes implicit subordination in social anxiety.

    PubMed

    Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah J; Stein, Dan J; Honk, Jack van

    2016-10-01

    Neuro-evolutionary theories describe social anxiety as habitual subordinate tendencies acquired through a recursive cycle of social defeat and submissive reactions. If so, the steroid hormone testosterone might be of therapeutic value, as testosterone is a main force behind implicit dominance drive in many species including humans. We combined these two theories to investigate whether the tendency to submit to the dominance of others is an implicit mechanism in social anxiety (Study-1), and whether this can be relieved through testosterone administration (Study-2). Using interactive eye-tracking we demonstrate that socially anxious humans more rapidly avert gaze from subliminal angry eye contact (Study-1). We replicate this effect of implicit subordination in social anxiety in an independent sample, which is subsequently completely abolished after a single placebo-controlled sublingual testosterone administration (Study-2). These findings provide crucial evidence for hormonal and behavioral treatment strategies that specifically target mechanisms of dominance and subordination in social anxiety. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Glucose Induces Protein Targeting to Glycogen in Hepatocytes by Fructose 2,6-Bisphosphate-Mediated Recruitment of MondoA to the Promoter

    PubMed Central

    Petrie, John L.; Al-Oanzi, Ziad H.; Arden, Catherine; Tudhope, Susan J.; Mann, Jelena; Kieswich, Julius; Yaqoob, Muhammad M.; Towle, Howard C.

    2013-01-01

    In the liver, a high glucose concentration activates transcription of genes encoding glucose 6-phosphatase and enzymes for glycolysis and lipogenesis by elevation in phosphorylated intermediates and recruitment of the transcription factor ChREBP (carbohydrate response element binding protein) and its partner, Mlx, to gene promoters. A proposed function for this mechanism is intracellular phosphate homeostasis. In extrahepatic tissues, MondoA, the paralog of ChREBP, partners with Mlx in transcriptional induction by glucose. We tested for glucose induction of regulatory proteins of the glycogenic pathway in hepatocytes and identified the glycogen-targeting proteins, GL and PTG (protein targeting to glycogen), as being encoded by Mlx-dependent glucose-inducible genes. PTG induction by glucose was MondoA dependent but ChREBP independent and was enhanced by forced elevation of fructose 2,6-bisphosphate and by additional xylitol-derived metabolites. It was counteracted by selective depletion of fructose 2,6-bisphosphate with a bisphosphatase-active kinase-deficient variant of phosphofructokinase 2/fructosebisphosphatase 2, which prevented translocation of MondoA to the nucleus and recruitment to the PTG promoter. We identify a novel role for MondoA in the liver and demonstrate that elevated fructose 2,6-bisphosphate is essential for recruitment of MondoA to the PTG promoter. Phosphometabolite activation of MondoA and ChREBP and their recruitment to target genes is consistent with a mechanism for gene regulation to maintain intracellular phosphate homeostasis. PMID:23207906

  8. Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter.

    PubMed

    Grès, Sandra; Bour, Sandy; Valet, Philippe; Carpéné, Christian

    2012-12-01

    Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized. To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO-substrate benzylamine, already reported in mice. Therefore, we crossed SSAO-deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes. Although the aP2-hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of benzylamine.

  9. Novel single skeletal muscle fiber analysis reveals a fiber type-selective effect of acute exercise on glucose uptake.

    PubMed

    Cartee, Gregory D; Arias, Edward B; Yu, Carmen S; Pataky, Mark W

    2016-11-01

    One exercise session can induce subsequently elevated insulin sensitivity that is largely attributable to greater insulin-stimulated glucose uptake by skeletal muscle. Because skeletal muscle is a heterogeneous tissue comprised of diverse fiber types, our primary aim was to determine exercise effects on insulin-independent and insulin-dependent glucose uptake by single fibers of different fiber types. We hypothesized that each fiber type featuring elevated insulin-independent glucose uptake immediately postexercise (IPEX) would be characterized by increased insulin-dependent glucose uptake at 3.5 h postexercise (3.5hPEX). Rat epitrochlearis muscles were isolated and incubated with 2-[ 3 H]deoxyglucose. Muscles from IPEX and sedentary (SED) controls were incubated without insulin. Muscles from 3.5hPEX and SED controls were incubated ± insulin. Glucose uptake (2-[ 3 H]deoxyglucose accumulation) and fiber type (myosin heavy chain isoform expression) were determined for single fibers dissected from the muscles. Major new findings included the following: 1) insulin-independent glucose uptake was increased IPEX in single fibers of each fiber type (types I, IIA, IIB, IIBX, and IIX), 2) glucose uptake values from insulin-stimulated type I and IIA fibers exceeded the values for the other fiber types, 3) insulin-stimulated glucose uptake for type IIX exceeded IIB fibers, and 4) the 3.5hPEX group vs. SED had greater insulin-stimulated glucose uptake in type I, IIA, IIB, and IIBX but not type IIX fibers. Insulin-dependent glucose uptake was increased at 3.5hPEX in each fiber type except for IIX fibers, although insulin-independent glucose uptake was increased IPEX in all fiber types (including type IIX). Single fiber analysis enabled the discovery of this fiber type-related difference for postexercise, insulin-stimulated glucose uptake. Copyright © 2016 the American Physiological Society.

  10. The Encoding of Sound Source Elevation in the Human Auditory Cortex.

    PubMed

    Trapeau, Régis; Schönwiesner, Marc

    2018-03-28

    Spatial hearing is a crucial capacity of the auditory system. While the encoding of horizontal sound direction has been extensively studied, very little is known about the representation of vertical sound direction in the auditory cortex. Using high-resolution fMRI, we measured voxelwise sound elevation tuning curves in human auditory cortex and show that sound elevation is represented by broad tuning functions preferring lower elevations as well as secondary narrow tuning functions preferring individual elevation directions. We changed the ear shape of participants (male and female) with silicone molds for several days. This manipulation reduced or abolished the ability to discriminate sound elevation and flattened cortical tuning curves. Tuning curves recovered their original shape as participants adapted to the modified ears and regained elevation perception over time. These findings suggest that the elevation tuning observed in low-level auditory cortex did not arise from the physical features of the stimuli but is contingent on experience with spectral cues and covaries with the change in perception. One explanation for this observation may be that the tuning in low-level auditory cortex underlies the subjective perception of sound elevation. SIGNIFICANCE STATEMENT This study addresses two fundamental questions about the brain representation of sensory stimuli: how the vertical spatial axis of auditory space is represented in the auditory cortex and whether low-level sensory cortex represents physical stimulus features or subjective perceptual attributes. Using high-resolution fMRI, we show that vertical sound direction is represented by broad tuning functions preferring lower elevations as well as secondary narrow tuning functions preferring individual elevation directions. In addition, we demonstrate that the shape of these tuning functions is contingent on experience with spectral cues and covaries with the change in perception, which may indicate that the

  11. In vitro glucose uptake activity of Aegles marmelos and Syzygium cumini by activation of Glut-4, PI3 kinase and PPARgamma in L6 myotubes.

    PubMed

    Anandharajan, R; Jaiganesh, S; Shankernarayanan, N P; Viswakarma, R A; Balakrishnan, A

    2006-06-01

    The purpose of the present study is to investigate the effect of methanolic extracts of Aegles marmelos and Syzygium cumini on a battery of targets glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPARgamma) and phosphatidylinositol 3' kinase (PI3 kinase) involved in glucose transport. A. marmelos and S. cumini are anti-diabetic medicinal plants being used in Indian traditional medicine. Different solvent extracts extracted sequentially were analysed for glucose uptake activity at each step and methanol extracts were found to be significantly active at 100ng/ml dose comparable with insulin and rosiglitazone. Elevation of Glut-4, PPARgamma and PI3 kinase by A. marmelos and S. cumini in association with glucose transport supported the up-regulation of glucose uptake. The inhibitory effect of cycloheximide on A. marmelos- and S. cumini-mediated glucose uptake suggested that new protein synthesis is required for the elevated glucose transport. Current observation concludes that methanolic extracts of A. marmelos and S. cumini activate glucose transport in a PI3 kinase-dependent fashion.

  12. Altered glucose kinetics in diabetic rats during Gram-negative infection

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lang, C.H.; Dobrescu, C.; Bagby, G.J.

    The present study examined the purported exacerbating effect of sepsis on glucose metabolism in diabetes. Diabetes was induced in rats by an intravenous injection of 70 or 45 mg/kg streptozotocin. The higher dose produced severe diabetes, whereas the lower dose of streptozotocin produced a miler, latent diabetes. After a chronic diabetic state had developed for 4 wk, rats had catheters implanted and sepsis induced by intraperitoneal injections of live Escherichia coli. After 24 h of sepsis the blood glucose concentration was unchanged in nondiabetics and latent diabetics, but glucose decreased from 15 to 8 mM in the septic severe diabeticmore » group. This decrease in blood glucose was not accompanied by alterations in the plasma insulin concentration. Glucose turnover, assessed by the constant intravenous infusion of (6-{sup 3}H)- and (U-{sup 14}C)glucose, was elevated in the severe diabetic group, compared with either latent diabetics or nondiabetics. Sepsis increased the rate of glucose disappearance in nondiabetic rats but had no effect in either group of diabetic animals. Sepsis also failed to alter the insulinogenic index, used to estimate the insulin secretory capacity, in diabetic rats. Thus the present study suggests that the imposition of nonlethal Gram-negative sepsis on severe diabetic animals does not further impair glucose homeostasis and that the milder latent diabetes was not converted to a more severe diabetic state by the septic challenge.« less

  13. Neuregulin-1β promotes glucose uptake via PI3K/Akt in neonatal rat cardiomyocytes.

    PubMed

    Pentassuglia, Laura; Heim, Philippe; Lebboukh, Sonia; Morandi, Christian; Xu, Lifen; Brink, Marijke

    2016-05-01

    Nrg1β is critically involved in cardiac development and also maintains function of the adult heart. Studies conducted in animal models showed that it improves cardiac performance under a range of pathological conditions, which led to its introduction in clinical trials to treat heart failure. Recent work also implicated Nrg1β in the regenerative potential of neonatal and adult hearts. The molecular mechanisms whereby Nrg1β acts in cardiac cells are still poorly understood. In the present study, we analyzed the effects of Nrg1β on glucose uptake in neonatal rat ventricular myocytes and investigated to what extent mTOR/Akt signaling pathways are implicated. We show that Nrg1β enhances glucose uptake in cardiomyocytes as efficiently as IGF-I and insulin. Nrg1β causes phosphorylation of ErbB2 and ErbB4 and rapidly induces the phosphorylation of FAK (Tyr(861)), Akt (Thr(308) and Ser(473)), and its effector AS160 (Thr(642)). Knockdown of ErbB2 or ErbB4 reduces Akt phosphorylation and blocks the glucose uptake. The Akt inhibitor VIII and the PI3K inhibitors LY-294002 and Byl-719 abolish Nrg1β-induced phosphorylation and glucose uptake. Finally, specific mTORC2 inactivation after knockdown of rictor blocks the Nrg1β-induced increases in Akt-p-Ser(473) but does not modify AS160-p-Thr(642) or the glucose uptake responses to Nrg1β. In conclusion, our study demonstrates that Nrg1β enhances glucose uptake in cardiomyocytes via ErbB2/ErbB4 heterodimers, PI3Kα, and Akt. Furthermore, although Nrg1β activates mTORC2, the resulting Akt-Ser(473) phosphorylation is not essential for glucose uptake induction. These new insights into pathways whereby Nrg1β regulates glucose uptake in cardiomyocytes may contribute to the understanding of its regenerative capacity and protective function in heart failure. Copyright © 2016 the American Physiological Society.

  14. CRISPR Epigenome Editing of AKAP150 in DRG Neurons Abolishes Degenerative IVD-Induced Neuronal Activation.

    PubMed

    Stover, Joshua D; Farhang, Niloofar; Berrett, Kristofer C; Gertz, Jason; Lawrence, Brandon; Bowles, Robby D

    2017-09-06

    Back pain is a major contributor to disability and has significant socioeconomic impacts worldwide. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to back pain, but a better understanding of the interactions between the degenerative IVD and nociceptive neurons innervating the disc and treatment strategies that directly target these interactions is needed to improve our understanding and treatment of back pain. We investigated degenerative IVD-induced changes to dorsal root ganglion (DRG) neuron activity and utilized CRISPR epigenome editing as a neuromodulation strategy. By exposing DRG neurons to degenerative IVD-conditioned media under both normal and pathological IVD pH levels, we demonstrate that degenerative IVDs trigger interleukin (IL)-6-induced increases in neuron activity to thermal stimuli, which is directly mediated by AKAP and enhanced by acidic pH. Utilizing this novel information on AKAP-mediated increases in nociceptive neuron activity, we developed lentiviral CRISPR epigenome editing vectors that modulate endogenous expression of AKAP150 by targeted promoter histone methylation. When delivered to DRG neurons, these epigenome-modifying vectors abolished degenerative IVD-induced DRG-elevated neuron activity while preserving non-pathologic neuron activity. This work elucidates the potential for CRISPR epigenome editing as a targeted gene-based pain neuromodulation strategy. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  15. Uptake of a fluorescent L-glucose derivative 2-NBDLG into three-dimensionally accumulating insulinoma cells in a phloretin-sensitive manner.

    PubMed

    Sasaki, Ayako; Nagatomo, Katsuhiro; Ono, Koki; Yamamoto, Toshihiro; Otsuka, Yuji; Teshima, Tadashi; Yamada, Katsuya

    2016-01-01

    Of two stereoisomers of glucose, only D- and not L-glucose is abundantly found in nature, being utilized as an essential fuel by most organisms. The uptake of D-glucose into mammalian cells occurs through glucose transporters such as GLUTs, and this process has been effectively monitored by a fluorescent D-glucose derivative 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) at the single cell level. However, since fluorescence is an arbitrary measure, we have developed a fluorescent analog of L-glucose 2-[N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-L-glucose (2-NBDLG), as a negative control substrate for more accurately identifying the stereoselectivity of the uptake. Interestingly, a small portion of mouse insulinoma cells MIN6 abundantly took up 2-NBDLG at a late culture stage (≳ 10 days in vitro, DIV) when multi-cellular spheroids exhibiting heterogeneous nuclei were formed, whereas no such uptake was detected at an early culture stage (≲ 6 DIV). The 2-NBDLG uptake was persistently observed in the presence of a GLUT inhibitor cytochalasin B. Neither D- nor L-glucose in 50 mM abolished the uptake. No significant inhibition was detected by inactivating sodium/glucose cotransporters (SGLTs) with Na(+)-free condition. To our surprise, the 2-NBDLG uptake was totally inhibited by phloretin, a broad spectrum inhibitor against transporters/channels including GLUTs and aquaporins. From these, a question might be raised if non-GLUT/non-SGLT pathways participate in the 2-NBDLG uptake into spheroid-forming MIN6 insulinoma. It might also be worthwhile investigating whether 2-NBDLG can be used as a functional probe for detecting cancer, since the nuclear heterogeneity is among critical features of malignancy.

  16. Genetically elevated fetuin-A levels, fasting glucose levels, and risk of type 2 diabetes: the cardiovascular health study.

    PubMed

    Jensen, Majken K; Bartz, Traci M; Djoussé, Luc; Kizer, Jorge R; Zieman, Susan J; Rimm, Eric B; Siscovick, David S; Psaty, Bruce M; Ix, Joachim H; Mukamal, Kenneth J

    2013-10-01

    Fetuin-A levels are associated with higher risk of type 2 diabetes, but it is unknown if the association is causal. We investigated common (>5%) genetic variants in the fetuin-A gene (AHSG) fetuin-A levels, fasting glucose, and risk of type 2 diabetes. Genetic variation, fetuin-A levels, and fasting glucose were assessed in 2,893 Caucasian and 542 African American community-living individuals 65 years of age or older in 1992-1993. Common AHSG variants (rs4917 and rs2248690) were strongly associated with fetuin-A concentrations (P<0.0001). In analyses of 259 incident cases of type 2 diabetes, the single nucleotide polymorphisms (SNPs) were not associated with diabetes risk during follow-up and similar null associations were observed when 579 prevalent cases were included. As expected, higher fetuin-A levels were associated with higher fasting glucose concentrations (1.9 mg/dL [95% CI, 1.2-2.7] higher per SD in Caucasians), but Mendelian randomization analyses using both SNPs as unbiased proxies for measured fetuin-A did not support an association between genetically predicted fetuin-A levels and fasting glucose (-0.3 mg/dL [95% CI, -1.9 to 1.3] lower per SD in Caucasians). The difference between the associations of fasting glucose with actual and genetically predicted fetuin-A level was statistically significant (P=0.001). Results among the smaller sample of African Americans trended in similar directions but were statistically insignificant. Common variants in the AHSG gene are strongly associated with plasma fetuin-A concentrations, but not with risk of type 2 diabetes or glucose concentrations, raising the possibility that the association between fetuin-A and type 2 diabetes may not be causal.

  17. Nitric oxide protects murine embryonic liver cells (BNL CL.2) from cytotoxicity induced by glucose deprivation.

    PubMed

    Pae, H O; Kim, H G; Paik, Y S; Paik, S G; Kim, Y M; Oh, G S; Chung, H T

    2000-03-01

    We investigated the protective effects of nitric oxide on cell death of murine embryonic liver cells (BNL CL.2) after glucose deprivation. Endogenous nitric oxide production by BNL CL.2 cells was induced by 6 hr pretreatment with interferon-gamma and lipopolysaccharide. We used sodium nitroprusside and S-nitroso-L-glutathione as exogenous nitric oxide-generating compounds. All agents were used at doses that did not show direct cytotoxicity as measured by crystal violet staining assay. In the BNL CL.2 cells, the viability dropped very steeply after 24 hr incubation with glucose-free media. Endogenous nitric oxide produced by treatment of the cells with interferon-gamma and lipopolysaccharide protected the cells from glucose deprivation-induced cytotoxicity, but did not protect them in the presence of the nitric oxide synthesis inhibitor, N(G)-monomethyl-L-arginine. Exogenous nitric oxide protected the cells from glucose deprivation-induced cytotoxicity in a concentration-dependent manner. Cytoprotection by nitric oxide donors was abolished by the use of nitric oxide scavenger, 2-phenyl-4,4,5,5,-tetramethylimidazole, but not by the soluble guanosine cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. In addition, cytoprotective effects comparable to endogenous or exogenous nitric oxide were not observed when the cells were incubated with dibutyl guanosine 3',5'-cyclic monophosphate. Based upon these results, we suggest that nitric oxide may enhance the cell survival of BNL CL.2 cells after glucose deprivation via a guanosine 3',5'-cyclic monophosphate-independent pathway.

  18. 77 FR 63205 - Prevailing Rate Systems; Abolishment of Montgomery, Pennsylvania, as a Nonappropriated Fund...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-16

    ... Montgomery, Pennsylvania, as a Nonappropriated Fund Federal Wage System Wage Area AGENCY: U.S. Office of... final rule to abolish the Montgomery, Pennsylvania, nonappropriated fund (NAF) Federal Wage System (FWS) wage area and redefine Chester, Montgomery, and Philadelphia Counties, PA, to the Burlington, NJ, NAF...

  19. The glucose oxidase-peroxidase assay for glucose

    USDA-ARS?s Scientific Manuscript database

    The glucose oxidase-peroxidase assay for glucose has served as a very specific, sensitive, and repeatable assay for detection of glucose in biological samples. It has been used successfully for analysis of glucose in samples from blood and urine, to analysis of glucose released from starch or glycog...

  20. Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis

    PubMed Central

    Martin, Neil A.; McArthur, David L.; Hovda, David A.; Vespa, Paul; Johnson, Matthew L.; Horning, Michael A.; Brooks, George A.

    2015-01-01

    Abstract We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-2H2]glucose, i.e., D2-glucose, and [3-13C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2–10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain. PMID:25279664

  1. Endogenous Nutritive Support after Traumatic Brain Injury: Peripheral Lactate Production for Glucose Supply via Gluconeogenesis.

    PubMed

    Glenn, Thomas C; Martin, Neil A; McArthur, David L; Hovda, David A; Vespa, Paul; Johnson, Matthew L; Horning, Michael A; Brooks, George A

    2015-06-01

    We evaluated the hypothesis that nutritive needs of injured brains are supported by large and coordinated increases in lactate shuttling throughout the body. To that end, we used dual isotope tracer ([6,6-(2)H2]glucose, i.e., D2-glucose, and [3-(13)C]lactate) techniques involving central venous tracer infusion along with cerebral (arterial [art] and jugular bulb [JB]) blood sampling. Patients with traumatic brain injury (TBI) who had nonpenetrating head injuries (n=12, all male) were entered into the study after consent of patients' legal representatives. Written and informed consent was obtained from healthy controls (n=6, including one female). As in previous investigations, the cerebral metabolic rate (CMR) for glucose was suppressed after TBI. Near normal arterial glucose and lactate levels in patients studied 5.7±2.2 days (range of days 2-10) post-injury, however, belied a 71% increase in systemic lactate production, compared with control, that was largely cleared by greater (hepatic+renal) glucose production. After TBI, gluconeogenesis from lactate clearance accounted for 67.1% of glucose rate of appearance (Ra), which was compared with 15.2% in healthy controls. We conclude that elevations in blood glucose concentration after TBI result from a massive mobilization of lactate from corporeal glycogen reserves. This previously unrecognized mobilization of lactate subserves hepatic and renal gluconeogenesis. As such, a lactate shuttle mechanism indirectly makes substrate available for the body and its essential organs, including the brain, after trauma. In addition, when elevations in arterial lactate concentration occur after TBI, lactate shuttling may provide substrate directly to vital organs of the body, including the injured brain.

  2. IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells

    PubMed Central

    Krolopp, James E.; Thornton, Shantaé M.; Abbott, Marcia J.

    2016-01-01

    Myokines are specialized cytokines that are secreted from skeletal muscle (SKM) in response to metabolic stimuli, such as exercise. Interleukin-15 (IL-15) is a myokine with potential to reduce obesity and increase lean mass through induction of metabolic processes. It has been previously shown that IL-15 acts to increase glucose uptake in SKM cells. However, the downstream signals orchestrating the link between IL-15 signaling and glucose uptake have not been fully explored. Here we employed the mouse SKM C2C12 cell line to examine potential downstream targets of IL-15-induced alterations in glucose uptake. Following differentiation, C2C12 cells were treated overnight with 100 ng/ml of IL-15. Activation of factors associated with glucose metabolism (Akt and AMPK) and known downstream targets of IL-15 (Jak1, Jak3, STAT3, and STAT5) were assessed with IL-15 stimulation. IL-15 stimulated glucose uptake and GLUT4 translocation to the plasma membrane. IL-15 treatment had no effect on phospho-Akt, phospho-Akt substrates, phospho-AMPK, phospho-Jak1, or phospho-STAT5. However, with IL-15, phospho-Jak3 and phospho-STAT3 levels were increased along with increased interaction of Jak3 and STAT3. Additionally, IL-15 induced a translocation of phospho-STAT3 from the cytoplasm to the nucleus. We have evidence that a mediator of glucose uptake, HIF1α, expression was dependent on IL-15 induced STAT3 activation. Finally, upon inhibition of STAT3 the positive effects of IL-15 on glucose uptake and GLUT4 translocation were abolished. Taken together, we provide evidence for a novel signaling pathway for IL-15 acting through Jak3/STAT3 to regulate glucose metabolism. PMID:28066259

  3. Increased SHP-1 Protein Expression by High Glucose Levels Reduces Nephrin Phosphorylation in Podocytes*

    PubMed Central

    Denhez, Benoit; Lizotte, Farah; Guimond, Marie-Odile; Jones, Nina; Takano, Tomoko; Geraldes, Pedro

    2015-01-01

    Nephrin, a critical podocyte membrane component that is reduced in diabetic nephropathy, has been shown to activate phosphotyrosine signaling pathways in human podocytes. Nephrin signaling is important to reduce cell death induced by apoptotic stimuli. We have shown previously that high glucose level exposure and diabetes increased the expression of SHP-1, causing podocyte apoptosis. SHP-1 possesses two Src homology 2 domains that serve as docking elements to dephosphorylate tyrosine residues of target proteins. However, it remains unknown whether SHP-1 interacts with nephrin and whether its elevated expression affects the nephrin phosphorylation state in diabetes. Here we show that human podocytes exposed to high glucose levels exhibited elevated expression of SHP-1, which was associated with nephrin. Coexpression of nephrin-CD16 and SHP-1 reduced nephrin tyrosine phosphorylation in transfected human embryonic kidney 293 cells. A single tyrosine-to-phenylalanine mutation revealed that rat nephrin Tyr1127 and Tyr1152 are required to allow SHP-1 interaction with nephrin. Overexpression of dominant negative SHP-1 in human podocytes prevented high glucose-induced reduction of nephrin phosphorylation. In vivo, immunoblot analysis demonstrated that nephrin expression and phosphorylation were decreased in glomeruli of type 1 diabetic Akita mice (Ins2+/C96Y) compared with control littermate mice (Ins2+/+), and this was associated with elevated SHP-1 and cleaved caspase-3 expression. Furthermore, immunofluorescence analysis indicated increased colocalization of SHP-1 with nephrin in diabetic mice compared with control littermates. In conclusion, our results demonstrate that high glucose exposure increases SHP-1 interaction with nephrin, causing decreased nephrin phosphorylation, which may, in turn, contribute to diabetic nephropathy. PMID:25404734

  4. Loss of CTRP1 disrupts glucose and lipid homeostasis

    PubMed Central

    Rodriguez, Susana; Lei, Xia; Petersen, Pia S.; Tan, Stefanie Y.; Little, Hannah C.

    2016-01-01

    C1q/TNF-related protein 1 (CTRP1) is a conserved plasma protein of the C1q family with notable metabolic and cardiovascular functions. We have previously shown that CTRP1 infusion lowers blood glucose and that transgenic mice with elevated circulating CTRP1 are protected from diet-induced obesity and insulin resistance. Here, we used a genetic loss-of-function mouse model to address the requirement of CTRP1 for metabolic homeostasis. Despite similar body weight, food intake, and energy expenditure, Ctrp1 knockout (KO) mice fed a low-fat diet developed insulin resistance and hepatic steatosis. Impaired glucose metabolism in Ctrp1 KO mice was associated with increased hepatic gluconeogenic gene expression and decreased skeletal muscle glucose transporter glucose transporter 4 levels and AMP-activated protein kinase activation. Loss of CTRP1 enhanced the clearance of orally administered lipids but did not affect intestinal lipid absorption, hepatic VLDL-triglyceride export, or lipoprotein lipase activity. In contrast to triglycerides, hepatic cholesterol levels were reduced in Ctrp1 KO mice, paralleling the reduced expression of cholesterol synthesis genes. Contrary to expectations, when challenged with a high-fat diet to induce obesity, Ctrp1 KO mice had increased physical activity and reduced body weight, adiposity, and expression of lipid synthesis and fibrotic genes in adipose tissue; these phenotypes were linked to elevated FGF-21 levels. Due in part to increased hepatic AMP-activated protein kinase activation and reduced expression of lipid synthesis genes, Ctrp1 KO mice fed a high-fat diet also had reduced liver and serum triglyceride and cholesterol levels. Taken together, these results provide genetic evidence to establish the significance of CTRP1 to systemic energy metabolism in different metabolic and dietary contexts. PMID:27555298

  5. Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells.

    PubMed

    del Nogal, Maria; Troyano, Nuria; Calleros, Laura; Griera, Mercedes; Rodriguez-Puyol, Manuel; Rodriguez-Puyol, Diego; Ruiz-Torres, María P

    2014-09-01

    Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated β-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Predictors of stroke in patients with impaired glucose tolerance: results from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research trial.

    PubMed

    Preiss, David; Giles, Thomas D; Thomas, Laine E; Sun, Jie-Lena; Haffner, Steven M; Holman, Rury R; Standl, Eberhard; Mazzone, Theodore; Rutten, Guy E; Tognoni, Gianni; Chiang, Fu-Tien; McMurray, John J V; Califf, Robert M

    2013-09-01

    Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance. We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide. Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline. The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.

  7. Elevated [CO2] magnifies isoprene emissions under heat and improves thermal resistance in hybrid aspen.

    PubMed

    Sun, Zhihong; Hüve, Katja; Vislap, Vivian; Niinemets, Ülo

    2013-12-01

    Isoprene emissions importantly protect plants from heat stress, but the emissions become inhibited by instantaneous increase of [CO2], and it is currently unclear how isoprene-emitting plants cope with future more frequent and severe heat episodes under high [CO2]. Hybrid aspen (Populus tremula x Populus tremuloides) saplings grown under ambient [CO2] of 380 μmol mol(-1) and elevated [CO2] of 780 μmol mol(-1) were used to test the hypothesis that acclimation to elevated [CO2] reduces the inhibitory effect of high [CO2] on emissions. Elevated-[CO2]-grown plants had greater isoprene emission capacity and a stronger increase of isoprene emissions with increasing temperature. High temperatures abolished the instantaneous [CO2] sensitivity of isoprene emission, possibly due to removing the substrate limitation resulting from curbed cycling of inorganic phosphate. As a result, isoprene emissions were highest in elevated-[CO2]-grown plants under high measurement [CO2]. Overall, elevated growth [CO2] improved heat resistance of photosynthesis, in particular, when assessed under high ambient [CO2] and the improved heat resistance was associated with greater cellular sugar and isoprene concentrations. Thus, contrary to expectations, these results suggest that isoprene emissions might increase in the future.

  8. Elevated [CO2] magnifies isoprene emissions under heat and improves thermal resistance in hybrid aspen

    PubMed Central

    Niinemets, Ülo

    2013-01-01

    Isoprene emissions importantly protect plants from heat stress, but the emissions become inhibited by instantaneous increase of [CO2], and it is currently unclear how isoprene-emitting plants cope with future more frequent and severe heat episodes under high [CO2]. Hybrid aspen (Populus tremula x Populus tremuloides) saplings grown under ambient [CO2] of 380 μmol mol−1 and elevated [CO2] of 780 μmol mol−1 were used to test the hypothesis that acclimation to elevated [CO2] reduces the inhibitory effect of high [CO2] on emissions. Elevated-[CO2]-grown plants had greater isoprene emission capacity and a stronger increase of isoprene emissions with increasing temperature. High temperatures abolished the instantaneous [CO2] sensitivity of isoprene emission, possibly due to removing the substrate limitation resulting from curbed cycling of inorganic phosphate. As a result, isoprene emissions were highest in elevated-[CO2]-grown plants under high measurement [CO2]. Overall, elevated growth [CO2] improved heat resistance of photosynthesis, in particular, when assessed under high ambient [CO2] and the improved heat resistance was associated with greater cellular sugar and isoprene concentrations. Thus, contrary to expectations, these results suggest that isoprene emissions might increase in the future. PMID:24153419

  9. Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese BL/6J mice[S

    PubMed Central

    Tripathy, Sasmita; Torres-Gonzalez, Moises; Jump, Donald B.

    2010-01-01

    Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity by a recombinant adenoviral approach restored blood glucose and insulin, HOMA-IR, and glucose tolerance to normal values in obese mice. Elevated Elovl5 activity increased hepatic content of Elovl5 products (20:3,n-6, 22:4,n-6) and suppressed levels of enzymes (Pck1, G6Pc) and transcription factors (FoxO1 and PGC1α, but not CRTC2) involved in gluconeogenesis. Effects of Elovl5 on FoxO1 nuclear abundance correlated with increased phosphorylation of FoxO1, Akt, and the catalytic unit of PP2A, as well as a decline in cellular abundance of TRB3. Such changes are mechanistically linked to the regulation of FoxO1 nuclear abundance and gluconeogenesis. These results show that Elovl5 activity impacts the hepatic abundance and phosphorylation status of multiple proteins involved in gluconeogenesis. Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia. PMID:20488798

  10. Caffeic acid as active principle from the fruit of Xanthium strumarium to lower plasma glucose in diabetic rats.

    PubMed

    Hsu, F L; Chen, Y C; Cheng, J T

    2000-04-01

    The antihyperglycemic effect of caffeic acid, one of the phenolic compounds contained in the fruit of Xanthium strumarium, was investigated. After an intravenous injection of caffeic acid into diabetic rats of both streptozotocin-induced and insulin-resistant models, a dose-dependent decrease of plasma glucose was observed. However, a similar effect was not produced in normal rats. An insulin-independent action of caffeic acid can thus be considered. Otherwise, this compound reduced the elevation of plasma glucose level in insulin-resistant rats receiving a glucose challenge test. Also, glucose uptake into the isolated adipocytes was raised by caffeic acid in a concentration-dependent manner. Increase of glucose utilization by caffeic acid seems to be responsible for the lowering of plasma glucose.

  11. Modification of beta-cell response to different postprandial blood glucose concentrations by prandial repaglinide and combined acarbose/repaglinide application.

    PubMed

    Rosak, C; Hofmann, U; Paulwitz, O

    2004-06-01

    This study was designed to compare the effects of repaglinide plus acarbose combination treatment to repaglinide alone on postprandial glucose, serum insulin, C-peptide and proinsulin concentrations. A total of 40 patients with Type 2 diabetes (T2DM) (fasting blood glucose: 120-180 mg/dl; postprandial blood glucose: 140-240 mg/dl) were included in this single-centre, controlled, randomised, single-dose, cross-over study. On two consecutive days, patients either received 2 mg repaglinide 15 min before breakfast followed by 100 mg acarbose with breakfast or repaglinide alone. Two fasting (7.30 h, 8.00 h) and five postprandial blood samples (from 8.30 h to 12.00 h) were taken for blood glucose, serum insulin, C-peptide and proinsulin determination. Repaglinide plus acarbose treatment significantly reduced the mean increase in postprandial blood glucose levels (24.2+/-18.2 mg/dl) compared to repaglinide alone (51.1+/-29.0 mg/dl; p<0.001). Serum insulin, C-peptide and proinsulin levels [mean area under the curve (AUC7.30-12.00h)] were significantly lower than those observed with repaglinide monotherapy (e.g. insulin: 1089.2+/-604.5 hr x pmol/l and 1596.8+/-1080.6 hr x pmol/l, resp., p<0.001), suggesting that acarbose modifies the rapid insulin release induced by repaglinide. Prandial treatment with a combination of acarbose and repaglinide results in an additive glucose lowering effect and modified insulin secretion compared to repaglinide alone. Postprandial hyperglycaemia is not abolished by rapid stimulation of insulin release induced by repaglinide. Additional reduction of postprandial blood glucose by acarbose modifies the stimulation of insulin release.

  12. [Influence and mechanism of a tight control of blood glucose by intensive insulin therapy on human sepsis].

    PubMed

    Yu, Wen-kui; Li, Wei-qin; Wang, Xiao-dong; Yan, Xiao-wen; Qi, Xiao-ping; Li, Ning; Li, Jie-shou

    2005-01-01

    To investigate the effect of a tight control of blood glucose by intensive insulin therapy on human sepsis, and to explore the potential mechanism of the intensive insulin therapy. Eligible patients were randomized by a blinded pharmacist to receive tight control of blood glucose by intensive insulin therapy (maintenance of blood glucose at a level between 4.4 and 6.1 mmol/L) or to receive conventional treatment (maintenance of glucose at a level between 10.0 and 11.1 mmol/L). The expression of HLA-DR on peripheral monocytes was measured in 54 patients by flow cytometry on 24 h, 3 d, 5 d, 7 d, 10 d and 14 d of intensive care in parallel with serum c-reactive protein (CRP), severity of the disease (APACHE II score, SOFA score) and clinical data collection. Patients receiving intensive insulin therapy were less likely to require prolonged mechanical ventilation. Tight control of blood glucose significantly reduced the number of days during which leukopenia or leukocytosis and the days with hypo- or hyperthermia (P < 0.05). Hypoglycemia occurred in 3 patients (10.7%) in the tight control of blood glucose group. There were no instance of hemodynamic deterioration or convulsions. Compared with the conventional treatment, tight control of blood glucose also increased the HLA-DR expression of peripheral monocytes, and there were significantly difference on 3 d, 5 d and 7 d (P < 0.05). Whereas it suppressed the elevated serum CRP concentrations, there was significantly difference on 7 d (P < 0.05). Tight control of blood glucose by intensive insulin therapy expedited healing of human sepsis, and increased the HLA-DR expression of peripheral and suppressed the elevated serum CRP. So, it is necessary to use insulin to strict control the glucose levels in human sepsis.

  13. Fluoride Alteration of [3H]Glucose Uptake in Wistar Rat Brain and Peripheral Tissues.

    PubMed

    Rogalska, Anna; Kuter, Katarzyna; Żelazko, Aleksandra; Głogowska-Gruszka, Anna; Świętochowska, Elżbieta; Nowak, Przemysław

    2017-04-01

    The present study was designed to investigate the role of postnatal fluoride intake on [3H]glucose uptake and transport in rat brain and peripheral tissues. Sodium fluoride (NaF) in a concentration of 10 or 50 ppm was added to the drinking water of adult Wistar rats. The control group received distilled water. After 4 weeks, respective plasma fluoride levels were 0.0541 ± 0.0135 μg/ml (control), 0.0596 ± 0.0202 μg/ml (10 ppm), and 0.0823 ± 0.0199 μg/ml (50 ppm). Although plasma glucose levels were not altered in any group, the plasma insulin level in the fluoride (50 ppm) group was elevated (0.72 ± 0.13 μg/ml) versus the control group (0.48 ± 0.24 μg/ml) and fluoride (10 ppm) group. In rats receiving fluoride for 4 weeks at 10 ppm in drinking water, [3H]glucose uptake was unaltered in all tested parts of the brain. However, in rats receiving fluoride at 50 ppm, [3H]glucose uptake in cerebral cortex, hippocampus, and thalamus with hypothalamus was elevated, versus the saline group. Fluoride intake had a negligible effect on [3H]glucose uptake by peripheral tissues (liver, pancreas, stomach, small intestine, atrium, aorta, kidney, visceral tissue, lung, skin, oral mucosa, tongue, salivary gland, incisor, molars, and jawbone). In neither fluoride group was glucose transporter proteins 1 (GLUT 1) or 3 (GLUT 3) altered in frontal cortex and striatum versus control. On the assumption that increased glucose uptake (by neural tissue) reasonably reflects neuronal activity, it appears that fluoride damage to the brain results in a compensatory increase in glucose uptake and utilization without changes in GLUT 1 and GLUT 3 expression.

  14. Glyceollin-containing fermented soybeans improve glucose homeostasis in diabetic mice.

    PubMed

    Park, Sunmin; Kim, Da Sol; Kim, Jeong Hwan; Kim, Jong Sang; Kim, Hyo Jung

    2012-02-01

    Our previous in vitro study demonstrated that glyceollins help normalize glucose homeostasis by potentiating β-cell function and survival in insulinoma cells as well as improving glucose utilization in adipocytes. Here, we investigated whether fermented soybeans containing glyceollins had an antidiabetic action in type 2 diabetic animals. The diabetic mice, their diabetes induced by intraperitoneal injections of streptozotocin (20 mg/kg bw), were administered a high fat diet with no soybeans (control), 10% unfermented soybeans and 10% fermented soybeans containing glyceollins, respectively, (FSG) for 8 weeks. As positive controls, rosiglitazone (20 mg/kg/bw) was given to diabetic mice fed a no soybean diet and non-diabetic mice were also placed on the same diet. Among the diabetic mice, FSG-treated mice exhibited the lowest peak for blood glucose levels with an elevation of serum insulin levels during the first part of oral glucose tolerance testing. FSG also made blood glucose levels drop quickly after the peak and it decreased blood glucose levels more than the control during insulin tolerance testing. This improvement was associated with increased hepatic glycogen accumulation and decreased triglyceride storage. The phosphorylation of Akt, AMP-kinase, and acetyl-CoA carboxylase in the liver was potentiated by FSG, whereas phosphoenolpyruvate carboxykinase expression decreased. The enhancement of glucose homeostasis was comparable to the effect induced by rosiglitazone, a commercial peroxisome proliferator-activated receptor-γ agonist, but it did not match the level of glucose homeostasis in the non-diabetic mice. Glyceollin-containing FSG improves glucose homeostasis, partly by enhancing hepatic insulin sensitivity in type 2 diabetic mice. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.

    PubMed

    Tajima, Naoko; Kurata, Hideaki; Nakaya, Noriaki; Mizuno, Kyoichi; Ohashi, Yasuo; Kushiro, Toshio; Teramoto, Tamio; Uchiyama, Shinichiro; Nakamura, Haruo

    2008-08-01

    Diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD) in patients with no history of CVD. Evidence for the effect of statins on CVD in the diabetic population in low-risk populations (e.g., Japanese) is limited. We evaluated the effect of pravastatin on risk reduction of CVD related to baseline glucose status in a primary prevention setting. The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, in patients with mild-to-moderate hypercholesterolemia (220-270 mg/dL), showed that low-dose pravastatin significantly reduced the risk for CVD by 26%. This exploratory subanalyses examined the efficacy of diet plus pravastatin on CVD in 2210 patients with abnormal fasting glucose (AFG, including 1746 patients with DM and 464 patients with impaired fasting glucose (IFG) at 5 years in the MEGA Study. CVD was threefold higher in AFG patients (threefold higher in DM, and twofold higher in IFG) compared with normal fasting glucose (NFG) patients in the diet group. Diet plus pravastatin treatment significantly reduced the risk of CVD by 32% (hazard ratio 0.68, 95% CI 0.48-0.96, number needed to treat, 42) in the AFG group compared with the diet alone group, and no significant interaction between AFG and NFG (interaction P=0.85) was found. Safety problems were not observed during long-term treatment with pravastatin. In conclusion, pravastatin reduces the risk of CVD in subjects with hypercholesterolemia and abnormal fasting glucose in the primary prevention setting in Japan.

  16. Somatostatin promotes glucose generation of Ca2+oscillations in pancreatic islets both in the absence and presence of tolbutamide.

    PubMed

    Hellman, Bo; Dansk, Heléne; Grapengiesser, Eva

    2018-06-01

    Many cellular processes, including pulsatile release of insulin, are triggered by increase of cytoplasmic Ca 2+ . This study examines how somatostatin affects glucose generation of cytoplasmic Ca 2+ oscillations in mouse islets in absence and presence of tolbutamide blockade of the K ATP channels. Ca 2+ was measured with dual wavelength microflurometry in isolated islets loaded with the indicator Fura-2. Rise of glucose from 3 to 20 mM evoked introductory lowering of Ca 2+ prolonged by activation of somatostatin receptors. During continued superfusion exposure to somatostatin triggered oscillations mediated by periodic increase from the basal level (absence of tolbutamide) or by periodic interruption of an elevated level (presence of tolbutamide). In the latter situation the oscillations were transformed into sustained elevation by activation of muscarinic receptors (acetylcholine) or increase of cyclic AMP (IBMX, 8-bromo-cyclic AMP, forskolin). The observed effect of cyclic AMP raises the question whether high proportions of the glucagon-producing α-cells promote steady-state elevation of Ca 2+ . In support for this idea somatostatin was found to trigger glucose-induced Ca 2+ oscillations essentially in small islets that contain very few α-cells. The results indicate that somatostatin promotes glucose generation of Ca 2+ oscillations with similar characteristics both in the absence and presence of functional K ATP channels. Copyright © 2018. Published by Elsevier Ltd.

  17. Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway.

    PubMed

    Leem, Kang-Hyun; Kim, Myung-Gyou; Hahm, Young-Tae; Kim, Hye Kyung

    2016-12-09

    Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited α-glucosidase activity and intestinal glucose absorption assessed by Na⁺-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C ) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased β-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway.

  18. Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway

    PubMed Central

    Leem, Kang-Hyun; Kim, Myung-Gyou; Hahm, Young-Tae; Kim, Hye Kyung

    2016-01-01

    Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited α-glucosidase activity and intestinal glucose absorption assessed by Na+-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased β-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway. PMID:27941667

  19. Abolishing coinsurance for oral antihyperglycemic agents: effects on social insurance budgets.

    PubMed

    Athanasakis, Kostas; Skroumpelos, Anastasis G; Tsiantou, Vassiliki; Milona, Katerina; Kyriopoulos, John

    2011-02-01

    To assess the effects of abolishing coinsurance for oral antihyperglycemic agents (OAAs) on the social insurance fund budget in Greece. A mathematical model estimating the effect of a decrease in patient coinsurance rate on demand for and adherence to OAAs and the subsequent clinical and economic outcomes. Price elasticity of demand for antidiabetic agents was used to estimate quantity demand change as a result of a coinsurance rate decrease and consequent increased adherence to OAAs. Given the inverse relationship between OAA adherence and glycated hemoglobin (A1C) level, the model calculated the mean decrease in A1C level and associated cost savings based on the cost difference between patients with controlled versus uncontrolled A1C levels. A decrease in patient coinsurance rate from 25% to 0% led to an incremental increase in OAA adherence of 30.5% and a mean decrease in A1C level of 0.6%. The A1C level decrease contributed to an 18.5% "shift" of uncontrolled patients to controlled A1C levels (<7%), which in economic terms translated into savings of 324 euro per patient over a 3-year period and an investment return rate of 122.8%. A series of 1-way and 2-way sensitivity analyses were conducted to verify the robustness and validity of the outcomes. The introduction of policies aimed at abolishing coinsurance for OAAs can result in improved patient outcomes and cost savings for the healthcare system.

  20. Effects of prenatal caffeine exposure on glucose homeostasis of adult offspring rats

    NASA Astrophysics Data System (ADS)

    Kou, Hao; Wang, Gui-hua; Pei, Lin-guo; Zhang, Li; Shi, Chai; Guo, Yu; Wu, Dong-fang; Wang, Hui

    2017-12-01

    Epidemiological evidences show that prenatal caffeine exposure (PCE) could induce intrauterine growth retardation (IUGR). The IUGR offspring also present glucose intolerance and type 2 diabetes mellitus after maturity. We have previously demonstrated that PCE induced IUGR and increased susceptibility to adult metabolic syndrome in rats. This study aimed to further investigate the effects of PCE on glucose homeostasis in adult offspring rats. Pregnant rats were administered caffeine (120 mg/kg/day, intragastrically) from gestational days 11 to 20. PCE offspring presented partial catch-up growth pattern after birth, characterizing by the increased body weight gain rates. Meanwhile, PCE had no significant influences on the basal blood glucose and insulin phenotypes of adult offspring but increased the glucose tolerance, glucose-stimulated insulin section and β cell sensitivity to glucose in female progeny. The insulin sensitivity of both male and female PCE offspring were enhanced accompanied with reduced β cell fraction and mass. Western blotting results revealed that significant augmentation in protein expression of hepatic insulin signaling elements of PCE females, including insulin receptor (INSR), insulin receptor substrate 1 (IRS-1) and the phosphorylation of serine-threonine protein kinase (Akt), was also potentiated. In conclusion, we demonstrated that PCE reduced the pancreatic β mass but increased the glucose tolerance in adult offspring rats, especially for females. The adaptive compensatory enhancement of β cell responsiveness to glucose and elevated insulin sensitivity mainly mediated by upregulated hepatic insulin signaling might coordinately contribute to the increased glucose tolerance.

  1. Involvement of α(2)-adrenergic receptor in the regulation of the blood glucose level induced by immobilization stress.

    PubMed

    Kang, Yu-Jung; Sim, Yun-Beom; Park, Soo-Hyun; Sharma, Naveen; Suh, Hong-Won

    2015-01-01

    The blood glucose profiles were characterized after mice were forced into immobilization stress with various exposure durations. The blood glucose level was significantly enhanced by immobilization stress for 30 min or 1 h, respectively. On the other hand, the blood glucose level was not affected in the groups which were forced into immobilization stress for 2 or 4 h. We further examined the effect of yohimbine (an α2-adrenergic receptor antagonist) administered systemically or centrally in the immobilization stress model. Mice were pretreated intraperitoneally (i.p.; from 0.5 to 5 mg/kg), intracerebroventricularly (i.c.v.; from 1 to 10 µg/5 µl), or intrathecally (i.t.; from 1 to 10 µg/5 µl) with yohimbine for 10 min and then, forced into immobilization stress for 30 min. The blood glucose level was measured right after immobilization stress. We found that up-regulation of the blood glucose level induced by immobilization stress was abolished by i.p. pretreatment with yohimbine. And the immobilization stress-induced blood glucose level was not inhibited by i.c.v. or i.t. pretreatment with yohimbine at a lower dose (1 µg/5 µl). However, immobilization stress-induced blood glucose level was significantly inhibited by i.c.v. or i.t. pretreatment with yohimbine at higher doses (5 and 10 µg/5 µl). In addition, the i.p. (5 mg/kg), i.c.v. (10 µg/5 µl), or i.t. (10 µg/5 µl) pretreatment with yohimbine reduced hypothalamic glucose transporter 4 expression. The involvement of α2-adrenergic receptor in regulation of immobilization stress- induced blood glucose level was further confirmed by the i.p, i.c.v, or i.t pretreatment with idazoxan, another specific α2-adrenergic receptor antagonist. Finally, i.p., i.c.v., or i.t. pretreatment with yohimbine attenuated the blood glucose level in D-glucose-fed model. We suggest that α2-adrenergic receptors located at the peripheral, the brain and the spinal cord play important roles in the up

  2. Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia

    PubMed Central

    Meek, Thomas H.; Dorfman, Mauricio D.; Matsen, Miles E.; Fischer, Jonathan D.; Cubelo, Alexis; Kumar, Monica R.; Taborsky, Gerald J.

    2015-01-01

    Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia. PMID:25633417

  3. Evidence for dual control mechanism regulating hepatic glucose output in nondiabetic men

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Clore, J.N.; Glickman, P.S.; Helm, S.T.

    1991-08-01

    The authors previously reported a fall in hepatic glucose output (HGO) during sleep accompanied by reductions in glucose utilization (Rd) and free fatty acids (FFAs). This study was undertaken to determine the potential role of changes in Rd and FFA on HGO in nondiabetic men. To determine if the fall in HGO during sleep could be reversed by FFA elevation, seven nondiabetic men underwent (3-3H)glucose infusions from 2200 to 0800, with heparin (90 mU.kg-1.min-1) added at 0200. Glucose appearance (Ra) fell from 11.7 {plus minus} 1.1 at 2430 to 8.9 {plus minus} 0.8 mumol.kg-1.min-1 (P less than 0.05) at 0200.more » The fall in Ra was associated with decreases in FFA (0.57 {plus minus} 0.10 to 0.48 {plus minus} 0.07 mM) and glycerol (0.08 {plus minus} 0.01 to 0.06 {plus minus} 0.01 mM). Infusion of heparin significantly increased FFA and glycerol (1.09 {plus minus} 0.21 and 0.11 {plus minus} 0.01 mM, respectively, P less than 0.01) and resulted in a significant fall in plasma alanine, suggesting that gluconeogenesis had been increased. However, rates of glucose turnover were indistinguishable from overnight studies without heparin. In additional studies (n = 6), intralipid and heparin-induced FFA elevation (from 0.61 {plus minus} 0.07 to 0.95 {plus minus} 0.05 mM, P less than 0.01) stimulated gluconeogenesis ((U-14C)alanine to glucose) twofold (188 {plus minus} 22% increase compared to 114 {plus minus} 6% in saline control studies, P less than 0.01). However, despite increasing gluconeogenesis, overall HGO did not change (10.6 {plus minus} 0.5 vs. 10.7 {plus minus} 0.6 mumol.kg-1.min-1) during lipid infusion.« less

  4. CD14 Deficiency Impacts Glucose Homeostasis in Mice through Altered Adrenal Tone

    PubMed Central

    Young, James L.; Mora, Alfonso; Cerny, Anna; Czech, Michael P.; Woda, Bruce; Kurt-Jones, Evelyn A.; Finberg, Robert W.; Corvera, Silvia

    2012-01-01

    The toll-like receptors comprise one of the most conserved components of the innate immune system, signaling the presence of molecules of microbial origin. It has been proposed that signaling through TLR4, which requires CD14 to recognize bacterial lipopolysaccharide (LPS), may generate low-grade inflammation and thereby affect insulin sensitivity and glucose metabolism. To examine the long-term influence of partial innate immune signaling disruption on glucose homeostasis, we analyzed knockout mice deficient in CD14 backcrossed into the diabetes-prone C57BL6 background at 6 or 12 months of age. CD14-ko mice, fed either normal or high-fat diets, displayed significant glucose intolerance compared to wild type controls. They also displayed elevated norepinephrine urinary excretion and increased adrenal medullary volume, as well as an enhanced norepinephrine secretory response to insulin-induced hypoglycemia. These results point out a previously unappreciated crosstalk between innate immune- and sympathoadrenal- systems, which exerts a major long-term effect on glucose homeostasis. PMID:22253759

  5. Thymoquinone, a bioactive component of Nigella sativa, normalizes insulin secretion from pancreatic β-cells under glucose overload via regulation of malonyl-CoA

    PubMed Central

    Gray, Joshua P.; Zayasbazan Burgos, Delaine; Yuan, Tao; Seeram, Navindra; Rebar, Rebecca; Follmer, Rebecca

    2015-01-01

    Thymoquinone (2-isopropyl-5-methylbenzo-1,4-quinone) is a major bioactive component of Nigella sativa, a plant used in traditional medicine to treat a variety of symptoms, including elevated blood glucose levels in type 2 diabetic patients. Normalization of elevated blood glucose depends on both glucose disposal by peripheral tissues and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. We employed clonal β-cells and rodent islets to investigate the effects of thymoquinone (TQ) and Nigella sativa extracts (NSEs) on GSIS and cataplerotic metabolic pathways implicated in the regulation of GSIS. TQ and NSE regulated NAD(P)H/NAD(P)+ ratios via a quinone-dependent redox cycling mechanism. TQ content was positively correlated with the degree of redox cycling activity of NSE extracts, suggesting that TQ is a major component engaged in mediating NSE-dependent redox cycling. Both acute and chronic exposure to TQ and NSE enhanced GSIS and were associated with the ability of TQ and NSE to increase the ATP/ADP ratio. Furthermore, TQ ameliorated the impairment of GSIS following chronic exposure of β-cells to glucose overload. This protective action was associated with the TQ-dependent normalization of chronic accumulation of malonyl-CoA, elevation of acetyl-CoA carboxylase (ACC), fatty acid synthase, and fatty acid-binding proteins following chronic glucose overload. Together, these data suggest that TQ modulates the β-cell redox circuitry and enhances the sensitivity of β-cell metabolic pathways to glucose and GSIS under normal conditions as well as under hyperglycemia. This action is associated with the ability of TQ to regulate carbohydrate-to-lipid flux via downregulation of ACC and malonyl-CoA. PMID:26786775

  6. Long-term exposure to high glucose induces changes in the content and distribution of some exocytotic proteins in cultured hippocampal neurons.

    PubMed

    Gaspar, J M; Castilho, Á; Baptista, F I; Liberal, J; Ambrósio, A F

    2010-12-29

    A few studies have reported the existence of depletion of synaptic vesicles, and changes in neurotransmitter release and in the content of exocytotic proteins in the hippocampus of diabetic rats. Recently, we found that diabetes alters the levels of synaptic proteins in hippocampal nerve terminals. Hyperglycemia is considered the main trigger of diabetic complications, although other factors, such as low insulin levels, also contribute to diabetes-induced changes. Thus, the aim of this work was to evaluate whether long-term elevated glucose per se, which mimics prolonged hyperglycemia, induces significant changes in the content and localization of synaptic proteins involved in exocytosis in hippocampal neurons. Hippocampal cell cultures were cultured for 14 days and were exposed to high glucose (50 mM) or mannitol (osmotic control; 25 mM plus 25 mM glucose), for 7 days. Cell viability and nuclear morphology were evaluated by MTT and Hoechst assays, respectively. The protein levels of vesicle-associated membrane protein-2 (VAMP-2), synaptosomal-associated protein-25 (SNAP-25), syntaxin-1, synapsin-1, synaptophysin, synaptotagmin-1, rabphilin 3a, and also of vesicular glutamate and GABA transporters (VGluT-1 and VGAT), were evaluated by immunoblotting, and its localization was analyzed by immunocytochemistry. The majority of the proteins were not affected. However, elevated glucose decreased the content of SNAP-25 and increased the content of synaptotagmin-1 and VGluT-1. Moreover, there was an accumulation of syntaxin-1, synaptotagmin-1 and VGluT-1 in the cell body of some hippocampal neurons exposed to high glucose. No changes were detected in mannitol-treated cells. In conclusion, elevated glucose per se did not induce significant changes in the content of the majority of the synaptic proteins studied in hippocampal cultures, with the exception of SNAP-25, synaptotagmin-1 and VGluT-1. However, there was an accumulation of some proteins in cell bodies of hippocampal

  7. Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Deusing, Dorothé Jenni, E-mail: Dorothe.J.Deusing@ernaehrung.uni-giessen.de; Beyrer, Melanie, E-mail: m.beyrer@web.de; Fitzenberger, Elena, E-mail: Elena.Fitzenberger@ernaehrung.uni-giessen.de

    Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effectsmore » of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation.« less

  8. Elevation of Glucose 6-Phosphate Dehydrogenase Activity Induced by Amplified Insulin Response in Low Glutathione Levels in Rat Liver

    PubMed Central

    Taniguchi, Misako; Mori, Nobuko; Iramina, Chizuru

    2016-01-01

    Weanling male Wistar rats were fed on a 10% soybean protein isolate (SPI) diet for 3 weeks with or without supplementing 0.3% sulfur-containing amino acids (SAA; methionine or cystine) to examine relationship between glutathione (GSH) levels and activities of NADPH-producing enzymes, glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), in the liver. Of rats on the 10% SPI diet, GSH levels were lower and the enzyme activities were higher than of those fed on an SAA-supplemented diet. Despite the lower GSH level, γ-glutamylcysteine synthetase (γ-GCS) activity was higher in the 10% SPI group than other groups. Examination of mRNAs of G6PD and ME suggested that the GSH-suppressing effect on enzyme induction occurred prior to and/or at transcriptional levels. Gel electrophoresis of G6PD indicated that low GSH status caused a decrease in reduced form and an increase in oxidized form of the enzyme, suggesting an accelerated turnover rate of the enzyme. In primary cultured hepatocytes, insulin response to induce G6PD activity was augmented in low GSH levels manipulated in the presence of buthionine sulfoximine. These findings indicated that elevation of the G6PD activity in low GSH levels was caused by amplified insulin response for expression of the enzyme and accelerated turnover rate of the enzyme molecule. PMID:27597985

  9. MLR-1023 is a potent and selective allosteric activator of Lyn kinase in vitro that improves glucose tolerance in vivo.

    PubMed

    Saporito, Michael S; Ochman, Alexander R; Lipinski, Christopher A; Handler, Jeffrey A; Reaume, Andrew G

    2012-07-01

    2(1H)-pyrimidinone,5-(3-methylphenoxy) (MLR-1023) is a candidate for the treatment of type 2 diabetes. The current studies were aimed at determining the mechanism by which MLR-1023 mediates glycemic control. In these studies, we showed that MLR-1023 reduced blood glucose levels without increasing insulin secretion in vivo. We have further determined that MLR-1023 did not activate peroxisome proliferator-activated α, δ, and γ receptors or glucagon-like peptide-1 receptors or inhibit dipeptidyl peptidase-4 or α-glucosidase enzyme activity. However, in an in vitro broad kinase screen MLR-1023 activated the nonreceptor-linked Src-related tyrosine kinase Lyn. MLR-1023 increased the V(max) of Lyn with an EC(50) of 63 nM. This Lyn kinase activation was ATP binding site independent, indicating that MLR-1023 regulated the kinase through an allosteric mechanism. We have established a link between Lyn activation and blood glucose lowering with studies showing that the glucose-lowering effects of MLR-1023 were abolished in Lyn knockout mice, consistent with existing literature linking Lyn kinase and the insulin-signaling pathway. In summary, these studies describe MLR-1023 as a unique blood glucose-lowering agent and show that MLR-1023-mediated blood glucose lowering depends on Lyn kinase activity. These results, coupled with other results (J Pharmacol Exp Ther 342:23-32, 2012), suggest that MLR-1023 and Lyn kinase activation may be a new treatment modality for type 2 diabetes.

  10. MondoA Is an Essential Glucose-Responsive Transcription Factor in Human Pancreatic β-Cells.

    PubMed

    Richards, Paul; Rachdi, Latif; Oshima, Masaya; Marchetti, Piero; Bugliani, Marco; Armanet, Mathieu; Postic, Catherine; Guilmeau, Sandra; Scharfmann, Raphael

    2018-03-01

    Although the mechanisms by which glucose regulates insulin secretion from pancreatic β-cells are now well described, the way glucose modulates gene expression in such cells needs more understanding. Here, we demonstrate that MondoA, but not its paralog carbohydrate-responsive element-binding protein, is the predominant glucose-responsive transcription factor in human pancreatic β-EndoC-βH1 cells and in human islets. In high-glucose conditions, MondoA shuttles to the nucleus where it is required for the induction of the glucose-responsive genes arrestin domain-containing protein 4 (ARRDC4) and thioredoxin interacting protein (TXNIP), the latter being a protein strongly linked to β-cell dysfunction and diabetes. Importantly, increasing cAMP signaling in human β-cells, using forskolin or the glucagon-like peptide 1 mimetic Exendin-4, inhibits the shuttling of MondoA and potently inhibits TXNIP and ARRDC4 expression. Furthermore, we demonstrate that silencing MondoA expression improves glucose uptake in EndoC-βH1 cells. These results highlight MondoA as a novel target in β-cells that coordinates transcriptional response to elevated glucose levels. © 2017 by the American Diabetes Association.

  11. Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction

    PubMed Central

    Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T.; Dufour, Eric

    2012-01-01

    Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an “emergency shutdown” system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. PMID:23007390

  12. Whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats.

    PubMed

    Preuss, Harry G; Echard, Bobby; Polansky, Marilyn M; Anderson, Richard

    2006-04-01

    Many agents (nutrients, nutraceuticals, and drugs) that enhance insulin sensitivity and/or reduce circulating insulin concentrations lower blood pressure (BP). Recently, it was reported that cinnamon has the potential to favorably influence the glucose/insulin system. Accordingly, the purpose of the present study was to examine the effects of dietary cinnamon on systolic BP (SBP), and various glucose- and insulin-related parameters in spontaneously hypertensive rats (SHR). In a series of three experiments, treated SHR eating sucrose and non sucrose containing diets were given various amounts of cinnamon, cinnamon extracts, or chromium. Then various parameters such as: body weight, systolic blood pressure, hematology and blood chemistries were followed for three to four weeks. Diets high in sucrose content are associated with insulin resistance and the elevation of SBP. Addition to diets of cinnamon (8% w/w) reduced the SBP of rats eating sucrose containing diets to virtually the same levels as SHR consuming non sucrose containing (only starch) diets. The presence of cinnamon in the diet also decreased the SBP of SHR consuming a non sucrose-containing diet, suggesting that cinnamon reduces more than just sucrose-induced SBP elevations--perhaps a genetic component(s) of the elevated BP as well. The effects of cinnamon on SBP tended to be dose-dependent. Cinnamon did not decrease the levels of blood glucose, but did lower circulating insulin concentrations. Aqueous extracts of cinnamon also decreased SBP and lowered the circulating levels of fructosamine. Cinnamon is used for flavor and taste in food preparation, but cinnamon may have additional roles in glucose metabolism and BP regulation. Therefore, BP regulation may not only be influenced favorably by limiting the amounts of dietary substances that have negative effects on BP and insulin function but also by the addition of beneficial ones, such as cinnamon, that have positive effects.

  13. Secrets of the lac operon. Glucose hysteresis as a mechanism in dietary restriction, aging and disease.

    PubMed

    Mobbs, Charles V; Mastaitis, Jason W; Zhang, Minhua; Isoda, Fumiko; Cheng, Hui; Yen, Kelvin

    2007-01-01

    Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

  14. Long-term feeding of red algae (Gelidium amansii) ameliorates glucose and lipid metabolism in a high fructose diet-impaired glucose tolerance rat model.

    PubMed

    Liu, Hshuan-Chen; Chang, Chun-Ju; Yang, Tsung-Han; Chiang, Meng-Tsan

    2017-07-01

    This study was designed to investigate the effect of Gelidium amansii (GA) on carbohydrate and lipid metabolism in rats with high fructose (HF) diet (57.1% w/w). Five-week-old male Sprague-Dawley rats were fed a HF diet to induce glucose intolerance and hyperlipidemia. The experiment was divided into three groups: (1) control diet group (Con); (2) HF diet group (HF); and (3) HF with GA diet group (HF + 5% GA). The rats were fed the experimental diets and drinking water ad libitum for 23 weeks. The results showed that GA significantly decreased retroperitoneal fat mass weight of HF diet-fed rats. Supplementation of GA caused a decrease in plasma glucose, insulin, tumor necrosis factor-α, and leptin. HF diet increased hepatic lipid content. However, intake of GA reduced the accumulation of hepatic lipids including total cholesterol (TC) and triglyceride contents. GA elevated the excretion of fecal lipids and bile acid in HF diet-fed rats. Furthermore, GA significantly decreased plasma TC, triglyceride, low density lipoprotein plus very low density lipoprotein cholesterol, and TC/high density lipoprotein cholesterol ratio in HF diet-fed rats. HF diet induced an in plasma glucose and an impaired glucose tolerance, but GA supplementation decreased homeostasis model assessment equation-insulin resistance and improved impairment of glucose tolerance. Taken together, these results indicate that supplementation of GA can improve the impairment of glucose and lipid metabolism in an HF diet-fed rat model. Copyright © 2016. Published by Elsevier B.V.

  15. Decrease of Plasma Glucose by Hibiscus taiwanensis in Type-1-Like Diabetic Rats

    PubMed Central

    Wang, Lin-Yu; Chung, Hsien-Hui

    2013-01-01

    Hibiscus taiwanensis (Malvaceae) is widely used as an alternative herb to treat disorders in Taiwan. In the present study, it is used to screen the effect on diabetic hyperglycemia in streptozotocin-induced diabetic rats (STZ-diabetic rats). The extract of Hibiscus taiwanensis showed a significant plasma glucose-lowering action in STZ-diabetic rats. Stems of Hibiscus taiwanensis are more effective than other parts to decrease the plasma glucose in a dose-dependent manner. Oral administration of Hibiscus taiwanensis three times daily for 3 days into STZ-diabetic rats increased the sensitivity to exogenous insulin showing an increase in insulin sensitivity. Moreover, similar repeated administration of Hibiscus taiwanensis for 3 days in STZ-diabetic rats produced a marked reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression in liver and an increased expression of glucose transporter subtype 4 (GLUT 4) in skeletal muscle. Taken together, our results suggest that Hibiscus taiwanensis has the ability to lower plasma glucose through an increase in glucose utilization via elevation of skeletal GLUT 4 and decrease of hepatic PEPCK in STZ-diabetic rats. PMID:23690841

  16. Effects of Smoking Versus Nonsmoking on Postprandial Glucose Metabolism in Heavy Smokers Compared With Nonsmokers.

    PubMed

    Grøndahl, Magnus F; Bagger, Jonatan I; Lund, Asger; Faurschou, Annesofie; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2018-06-01

    Epidemiological studies suggest that smoking increases the risk of type 2 diabetes. We hypothesized that smoking-derived nicotine and ensuing activation of nicotinic cholinergic receptors in the gastrointestinal tract and the autonomic nervous system would have a detrimental effect on postprandial glucose metabolism and, thus, potentially constitute a link between smoking and the development of type 2 diabetes. We subjected 11 male heavy smokers to two identical 4-h liquid mixed-meal tests: one with concomitant cigarette smoking (immediately before and after meal intake) and one without smoking. Twelve age-, sex-, and BMI-matched nonsmokers underwent an identical meal test without smoking. The smokers were characterized by higher fasting plasma concentrations of glucagon compared with the nonsmokers. Among smokers, cigarette smoking before and after the meal significantly reduced postprandial plasma glucose excursions. There were no differences in gut or pancreatic hormone concentrations between the test days in the smoking group, and the responses were similar to those in the control group. Our results suggest that smoking in association with meal intake decreases the postprandial plasma glucose concentrations, possibly through decreased gastric emptying, and that elevated fasting glucagon concentrations rather than smoking-induced alterations in postprandial glucose and hormone responses may be associated with the elevated risk of type 2 diabetes in chronic smokers. © 2018 by the American Diabetes Association.

  17. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis.

    PubMed

    Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

    2014-07-18

    14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen-glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Emotionally arousing pictures increase blood glucose levels and enhance recall.

    PubMed

    Blake, T M; Varnhagen, C K; Parent, M B

    2001-05-01

    Arousal enhances memory in human participants and this enhancing effect is likely due to the release of peripheral epinephrine. As epinephrine does not readily enter the brain, one way that peripheral epinephrine may enhance memory is by increasing circulating blood glucose levels. The present study investigated the possibility that emotionally arousing color pictures would improve memory and elevate blood glucose levels in human participants. Blood glucose levels were measured before, 15 min, and 30 min after male university students viewed 60 emotionally arousing or relatively neutral pictures. Participants viewed each picture for 6 s and then had 10 s to rate the arousal (emotional intensity) and valence (pleasantness) of each picture. A free-recall memory test was given 30 min after the last picture was viewed. Although the emotionally arousing and neutral picture sets were given comparable valence ratings, participants who viewed the emotionally arousing pictures rated the pictures as being more arousing, recalled more pictures, and had higher blood glucose levels after viewing the pictures than did participants who viewed the neutral pictures. These findings indicate that emotionally arousing pictures increase blood glucose levels and enhance memory, and that this effect is not due to differences in the degree of pleasantness of the stimuli. These findings support the possibility that increases in circulating blood glucose levels in response to emotional arousal may be part of the biological mechanism that allows emotional arousal to enhance memory. Copyright 2001 Academic Press.

  19. The Effects of an Abolishing Operation Intervention Component on Play Skills, Challenging Behavior, and Stereotypy

    ERIC Educational Resources Information Center

    Lang, Russell; O'Reilly, Mark; Sigafoos, Jeff; Machalicek, Wendy; Rispoli, Mandy; Lancioni, Giulio E.; Aguilar, Jeannie; Fragale, Christina

    2010-01-01

    The purpose of this study was to reduce stereotypy and challenging behavior during play skills instruction by adding an abolishing operation component (AOC) to the intervention strategy. An alternating treatments design compared one condition in which participants were allowed to engage in stereotypy freely before beginning the play skills…

  20. A Central Catecholaminergic Circuit Controls Blood Glucose Levels during Stress.

    PubMed

    Zhao, Zhe; Wang, Liang; Gao, Wenling; Hu, Fei; Zhang, Juen; Ren, Yuqi; Lin, Rui; Feng, Qiru; Cheng, Mingxiu; Ju, Dapeng; Chi, Qingsheng; Wang, Dehua; Song, Sen; Luo, Minmin; Zhan, Cheng

    2017-07-05

    Stress-induced hyperglycemia is a fundamental adaptive response that mobilizes energy stores in response to threats. Here, our examination of the contributions of the central catecholaminergic (CA) neuronal system to this adaptive response revealed that CA neurons in the ventrolateral medulla (VLM) control stress-induced hyperglycemia. Ablation of VLM CA neurons abolished the hyperglycemic response to both physical and psychological stress, whereas chemogenetic activation of these neurons was sufficient to induce hyperglycemia. We further found that CA neurons in the rostral VLM, but not those in the caudal VLM, cause hyperglycemia via descending projections to the spinal cord. Monosynaptic tracing experiments showed that VLM CA neurons receive direct inputs from multiple stress-responsive brain areas. Optogenetic studies identified an excitatory PVN-VLM circuit that induces hyperglycemia. This study establishes the central role of VLM CA neurons in stress-induced hyperglycemia and substantially expands our understanding of the central mechanism that controls glucose metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Modification of glucose import capacity in Escherichia coli: physiologic consequences and utility for improving DNA vaccine production

    PubMed Central

    2013-01-01

    Background The bacterium Escherichia coli can be grown employing various carbohydrates as sole carbon and energy source. Among them, glucose affords the highest growth rate. This sugar is nowadays widely employed as raw material in industrial fermentations. When E. coli grows in a medium containing non-limiting concentrations of glucose, a metabolic imbalance occurs whose main consequence is acetate secretion. The production of this toxic organic acid reduces strain productivity and viability. Solutions to this problem include reducing glucose concentration by substrate feeding strategies or the generation of mutant strains with impaired glucose import capacity. In this work, a collection of E. coli strains with inactive genes encoding proteins involved in glucose transport where generated to determine the effects of reduced glucose import capacity on growth rate, biomass yield, acetate and production of an experimental plasmid DNA vaccine (pHN). Results A group of 15 isogenic derivatives of E. coli W3110 were generated with single and multiple deletions of genes encoding glucose, mannose, beta-glucoside, maltose and N-acetylglucosamine components of the phosphoenolpyruvate:sugar phosphotransferase system (PTS), as well as the galactose symporter and the Mgl galactose/glucose ABC transporter. These strains were characterized by growing them in mineral salts medium supplemented with 2.5 g/L glucose. Maximum specific rates of glucose consumption (qs) spanning from 1.33 to 0.32 g/g h were displayed by the group of mutants and W3110, which resulted in specific growth rates ranging from 0.65-0.18 h-1. Acetate accumulation was reduced or abolished in cultures with all mutant strains. W3110 and five selected mutant derivatives were transformed with pHN. A 3.2-fold increase in pHN yield on biomass was observed in cultures of a mutant strain with deletion of genes encoding the glucose and mannose PTS components, as well as Mgl. Conclusions The group of E. coli mutants

  2. Leptin receptor-deficient obese Zucker rats reduce their food intake in response to a systemic supply of calories from glucose.

    PubMed

    Gilbert, Marc; Magnan, Christophe; Turban, Sophie; André, Jocelyne; Guerre-Millo, Michèle

    2003-02-01

    It has been established that leptin exerts a negative control on food intake, allowing one to maintain stable caloric intake over time. The aim of the present study was to investigate whether leptin regulates food intake when a supply of calories is provided by the systemic route. Experiments were carried out in leptin receptor-deficient obese fa/fa rats and lean Fa/fa controls. In both groups, 48 h of glucose infusion reduced food intake in proportion to caloric supply, resulting in virtually no change in total caloric intake as compared to before the infusion. This hypophagic response was reproduced without adding systemic calories, but by increasing glucose and insulin concentrations specifically in the brain through carotid artery infusion. Concomitant intracerebroventricular administration of 5-(tetradecyloxy)-2-furoic acid, an acetyl CoA carboxylase inhibitor that precludes malonyl-CoA synthesis, abolished the restriction of feeding in carotid-infused lean and obese rats. These data indicate that a supply of calories via glucose infusion induces a hypophagic response independent of leptin signaling in the rat, and support the hypothesis that a rise in central malonyl-CoA, triggered by increased glucose and insulin concentrations, participates in this adaptation. This process could contribute to the limiting of hyperphagia, primarily when leptin signaling is altered, as in the obese state.

  3. AMPK-Dependent Phosphorylation of GAPDH Triggers Sirt1 Activation and Is Necessary for Autophagy upon Glucose Starvation.

    PubMed

    Chang, Chunmei; Su, Hua; Zhang, Danhong; Wang, Yusha; Shen, Qiuhong; Liu, Bo; Huang, Rui; Zhou, Tianhua; Peng, Chao; Wong, Catherine C L; Shen, Han-Ming; Lippincott-Schwartz, Jennifer; Liu, Wei

    2015-12-17

    Eukaryotes initiate autophagy to cope with the lack of external nutrients, which requires the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase Sirtuin 1 (Sirt1). However, the mechanisms underlying the starvation-induced Sirt1 activation for autophagy initiation remain unclear. Here, we demonstrate that glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a conventional glycolytic enzyme, is a critical mediator of AMP-activated protein kinase (AMPK)-driven Sirt1 activation. Under glucose starvation, but not amino acid starvation, cytoplasmic GAPDH is phosphorylated on Ser122 by activated AMPK. This causes GAPDH to redistribute into the nucleus. Inside the nucleus, GAPDH interacts directly with Sirt1, displacing Sirt1's repressor and causing Sirt1 to become activated. Preventing this shift of GAPDH abolishes Sirt1 activation and autophagy, while enhancing it, through overexpression of nuclear-localized GAPDH, increases Sirt1 activation and autophagy. GAPDH is thus a pivotal and central regulator of autophagy under glucose deficiency, undergoing AMPK-dependent phosphorylation and nuclear translocation to activate Sirt1 deacetylase activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Dynamin-mediated Nephrin Phosphorylation Regulates Glucose-stimulated Insulin Release in Pancreatic Beta Cells*

    PubMed Central

    Jeon, Jongmin; Leibiger, Ingo; Moede, Tilo; Walter, Britta; Faul, Christian; Maiguel, Dony; Villarreal, Rodrigo; Guzman, Johanna; Berggren, Per-Olof; Mundel, Peter; Ricordi, Camillo; Merscher-Gomez, Sandra; Fornoni, Alessia

    2012-01-01

    We have previously demonstrated a role for Nephrin in glucose stimulated insulin release (GSIR). We now hypothesize that Nephrin phosphorylation is required for GSIR and that Dynamin influences Nephrin phosphorylation and function. MIN6-C3 Nephrin-deficient pancreatic beta cells and human islets were transfected with WT-Nephrin or with a mutant Nephrin in which the tyrosine residues responsible for SH2 domain binding were substituted with phenylalanine (3YF-Nephrin). GSIR and live images of Nephrin and vesicle trafficking were studied. Immunoprecipitation experiments and overexpression of WT-Dynamin or dominant negative Dynamin mutant (K44A-Dynamin) in WT-Nephrin, 3YF-Nephrin, or Nephrin siRNA-transfected cells were utilized to study Nephrin-Dynamin interaction. In contrast to WT-Nephrin or to single tyrosine mutants, 3YF-Nephrin did not positively affect GSIR and led to impaired cell-cell contacts and vesicle trafficking. K44A-Dynamin prevented the effect of Nephrin on GSIR in the absence of protein-protein interaction between Nephrin and Dynamin. Nephrin gene silencing abolished the positive effects of WT-Dynamin on GSIR. The effects of protamine sulfate and vanadate on Nephrin phosphorylation and GSIR were studied in MIN6 cells and human islets. WT-Nephrin phosphorylation after glucose occurred at Tyr-1176/1193 and resulted in improved GSIR. On the contrary, protamine sulfate-induced phosphorylation at Tyr-1176/1193/1217 was associated with Nephrin degradation and impaired GSIR. Vanadate, which prevented Nephrin dephosphorylation after glucose stimulation, improved GSIR in human islets and MIN6 cells. In conclusion, Dynamin-dependent Nephrin phosphorylation occurs in response to glucose and is necessary for Nephrin-mediated augmentation of GSIR. Pharmacological modulation of Nephrin phosphorylation may thus facilitate pancreatic beta cell function. PMID:22718751

  5. Calibration in dogs of a subcutaneous miniaturized glucose sensor using a glucose meter for blood glucose determination.

    PubMed

    Poitout, V; Moatti-Sirat, D; Reach, G

    1992-01-01

    The feasibility of calibrating a glucose sensor by using a wearable glucose meter for blood glucose determination and moderate variations of blood glucose concentration was assessed. Six miniaturized glucose sensors were implanted in the subcutaneous tissue of conscious dogs, and the parameters used for the in vivo calibration of the sensor (sensitivity coefficient and extrapolated current in the absence of glucose) were determined from values of blood glucose and sensor response obtained during glucose infusion. (1) Venous plasma glucose level and venous total blood glucose level were measured simultaneously on the same sample, using a Beckman analyser and a Glucometer II, respectively. The regression between plasma glucose (x) and whole blood glucose (y) was y = 1.12x-0.08 mM (n = 114 values, r = 0.96, p = 0.0001). The error grid analysis indicated that the use of a Glucometer II for blood glucose determination was appropriate in dogs. (2) The in vivo sensitivity coefficients were 0.57 +/- 0.11 nA mM-1 when determined from plasma glucose, and 0.51 +/- 0.07 nA mM-1 when determined from whole blood glucose (t = 1.53, p = 0.18, n.s.). The background currents were 0.88 +/- 0.57 nA when determined from plasma glucose, and 0.63 +/- 0.77 nA when determined from whole blood glucose (t = 0.82, p = 0.45, n.s.). (3) The regression equation of the estimation of the subcutaneous glucose level obtained from the two methods was y = 1.04x + 0.56 mM (n = 171 values, r = 0.98, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Acute Low-Dose Endotoxin Treatment Results in Improved Whole-Body Glucose Homeostasis in Mice

    PubMed Central

    Stevens, Joseph R.; McMillan, Ryan P.; Resendes, Justin T.; Lloyd, Shannon K.; Ali, Mostafa M.; Frisard, Madlyn I.; Hargett, Stefan; Keller, Susanna R.; Hulver, Matthew W.

    2017-01-01

    Background Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. Purpose/Procedures The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Main Findings Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. Conclusions This

  7. Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.

    PubMed

    Stevens, Joseph R; McMillan, Ryan P; Resendes, Justin T; Lloyd, Shannon K; Ali, Mostafa M; Frisard, Madlyn I; Hargett, Stefan; Keller, Susanna R; Hulver, Matthew W

    2017-03-01

    Obese individuals present with an increased inflammatory tone as compared to healthy, normal-weight individuals, which is associated with insulin resistance. One factor hypothesized to contribute to increased inflammation in obese and diabetic states is elevated blood endotoxin levels, a condition known as metabolic endotoxemia. In non-obese and insulin sensitive individuals, circulating endotoxin concentrations fluctuate over the course of the day with elevations in the post-prandial state that return to baseline levels in the post-absorptive state. Evidence suggests that high-fat feeding alters these fluctuations causing endotoxin levels to remain high throughout the day. The effects of alterations in endotoxin levels on glucose metabolism are not clearly understood. The goal of this study was to determine the effects of both short-term and long-term increases in endotoxin (lipopolysaccharide, LPS) of a low magnitude on the glucose tolerance and insulin signaling in a human primary cell line as well as the effects of short-term endotoxin treatments on glucose homeostasis in a C57/Bl6 mouse model. First, we tested the hypothesis that short-term low-dose endotoxin treatments would augment insulin signaling and glycogen synthesis while long-term treatments would be disruptive in the cell culture model. Second, we examined if these short-term low dose treatments of endotoxin would contribute to similar improvements in whole-body glucose homeostasis in a mouse model. Contrary to our initial hypothesis, short-term endotoxin treatment had no effect on insulin signaling or glycogen synthesis, however long-term treatment indeed decreased glycogen synthesis (P<.05). Interestingly, short-term endotoxin treatment resulted in significant improvements in glucose homeostasis in the mouse model (P<.01); which is believed to be at least partly attributed to an inhibitory action of LPS on liver glucose production. This research shows that low-magnitude, short-term changes in LPS

  8. Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells.

    PubMed

    Lee, Hak Joo; Lee, Doug Yoon; Mariappan, Meenalakshmi M; Feliers, Denis; Ghosh-Choudhury, Goutam; Abboud, Hanna E; Gorin, Yves; Kasinath, Balakuntalam S

    2017-04-07

    High-glucose increases NADPH oxidase 4 (NOX4) expression, reactive oxygen species generation, and matrix protein synthesis by inhibiting AMP-activated protein kinase (AMPK) in renal cells. Because hydrogen sulfide (H 2 S) inhibits high glucose-induced matrix protein increase by activating AMPK in renal cells, we examined whether H 2 S inhibits high glucose-induced expression of NOX4 and matrix protein and whether H 2 S and NO pathways are integrated. High glucose increased NOX4 expression and activity at 24 h in renal proximal tubular epithelial cells, which was inhibited by sodium hydrosulfide (NaHS), a source of H 2 S. High glucose decreased AMPK phosphorylation and activity, which was restored by NaHS. Compound C, an AMPK inhibitor, prevented NaHS inhibition of high glucose-induced NOX4 expression. NaHS inhibition of high glucose-induced NOX4 expression was abrogated by N (ω)-nitro-l-arginine methyl ester, an inhibitor of NOS. NaHS unexpectedly augmented the expression of inducible NOS (iNOS) but not endothelial NOS. iNOS siRNA and 1400W, a selective iNOS inhibitor, abolished the ameliorative effects of NaHS on high glucose-induced NOX4 expression, reactive oxygen species generation, and, matrix laminin expression. Thus, H 2 S recruits iNOS to generate NO to inhibit high glucose-induced NOX4 expression, oxidative stress, and matrix protein accumulation in renal epithelial cells; the two gasotransmitters H 2 S and NO and their interaction may serve as therapeutic targets in diabetic kidney disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. Why control blood glucose levels?

    PubMed

    Rossini, A A

    1976-03-01

    The controversy as to the relationship between the degree of control of diabetes and the progression of the complications of the disease has not been solved. However, in this review, various studies suggesting a relationship between the metabolic abnormality and the diabetic complications are examined. The disadvantages of the uncontrolled diabetes mellitus can be divided into two major categories-short-term and long-term. The short-term disadvantages of controlled diabetes mellitus include the following: (1) ketoacidosis and hyperosmolar coma; (2) intracellular dehydration; (3) electrolyte imbalance; (4) decreased phagocytosis; (5) immunologic and lymphocyte activity; (6) impairment of wound healing; and (7) abnormality of lipids. The long-term disadvantages of uncontrolled diabetes melitus include the following: (1) nephropathy; (2) neuropathy; (3) retinopathy; (4) cataract formation; (5) effect on perinatal mortality; (6) complications of vascular disease; and (7) the evaluation of various clinical studies suggesting the relationship of elevated blood glucose levels and complications of diabetes mellitus. It is suggested that until the question of control can absolutely be resolved, the recommendation is that the blood glucose levels should be controlled as close to the normal as possible.

  10. Elevation of branched-chain amino acid levels in diabetes and NAFL and changes with antidiabetic drug treatment.

    PubMed

    Iwasa, Motoh; Ishihara, Tomoaki; Mifuji-Moroka, Rumi; Fujita, Naoki; Kobayashi, Yoshinao; Hasegawa, Hiroshi; Iwata, Kazuko; Kaito, Masahiko; Takei, Yoshiyuki

    2015-01-01

    Diabetes mellitus (DM), non-alcoholic fatty liver (NAFL), and obesity are associated with elevated branched-chain amino acid (BCAA) levels, but the mechanism and significance of this has not been elucidated. Eighty-four subjects were enrolled including 43 with DM. Serum BCAA levels were positively correlated with waist-hip ratio and ALT. Serum BCAA levels in subjects with DM were higher than non-DM and those in subjects with NAFL were also higher than non-NAFL. Treatment with pioglitazone and alogliptin (19 of 43 DM subjects) improved serum haemoglobin A1c and decreased BCAA levels. The decrease in BCAAs with improved glucose metabolism suggests that abnormal glucose metabolism is also a factor in elevated BCAA levels. Copyright © 2015 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  11. Maternal diabetes and high glucose in vitro trigger Sca1+ cardiac progenitor cell apoptosis through FoxO3a.

    PubMed

    Yang, Penghua; Yang, Wendy W; Chen, Xi; Kaushal, Sunjay; Dong, Daoyin; Shen, Wei-Bin

    2017-01-22

    Recent controversies surrounding the authenticity of c-kit + cardiac progenitor cells significantly push back the advance in regenerative therapies for cardiovascular diseases. There is an urgent need for research in characterizing alternative types of cardiac progenitor cells. Towards this goal, in the present study, we determined the effect of maternal diabetes on Sca1 + cardiac progenitor cells. Maternal diabetes induced caspase 3-dependent apoptosis in Sca1 + cardiac progenitor cells derived from embryonic day 17.5 (E17.5). Similarly, high glucose in vitro but not the glucose osmotic control mannitol triggered Sca1 + cardiac progenitor cell apoptosis in a dose- and time-dependent manner. Both maternal diabetes and high glucose in vitro activated the pro-apoptotic transcription factor, Forkhead O 3a (FoxO3a) via dephosphorylation at threonine 32 (Thr-32) residue. foxo3a gene deletion abolished maternal diabetes-induced Sca1 + cardiac progenitor cell apoptosis. The dominant negative FoxO3a mutant without the transactivation domain from the C terminus blocked high glucose-induced Sca1 + cardiac progenitor cell apoptosis, whereas the constitutively active FoxO3a mutant with the three phosphorylation sites, Thr-32, Ser-253, and Ser-315, being replaced by alanine residues mimicked the pro-apoptotic effect of high glucose. Thus, maternal diabetes and high glucose in vitro may limit the regenerative potential of Sca1 + cardiac progenitor cells by inducing apoptosis through FoxO3a activation. These findings will serve as the guide in optimizing the autologous therapy using Sca1 + cardiac progenitor cells in cardiac defect babies born exposed to maternal diabetes. Copyright © 2016. Published by Elsevier Inc.

  12. Increased energy expenditure and glucose oxidation during acute nontraumatic skin pain in humans.

    PubMed

    Holland-Fischer, Peter; Greisen, Jacob; Grøfte, Thorbjørn; Jensen, Troels S; Hansen, Peter O; Vilstrup, Hendrik

    2009-04-01

    Tissue injury is accompanied by pain and results in increased energy expenditure, which may promote catabolism. The extent to which pain contributes to this sequence of events is not known. In a cross-over design, 10 healthy volunteers were examined on three occasions; first, during self-controlled nontraumatic electrical painful stimulus to the abdominal skin, maintaining an intensity of 8 on the visual analogue scale (0-10). Next, the electrical stimulus was reproduced during local analgesia and, finally, there was a control session without stimulus. Indirect calorimetry and blood and urine sampling was done in order to calculate energy expenditure and substrate utilization. During pain stimulus, energy expenditure increased acutely and reversibly by 62% (95% confidence interval, 43-83), which was abolished by local analgesia. Energy expenditure paralleled both heart rate and blood catecholamine levels. The energy expenditure increase was fuelled by all energy sources, with the largest increase in glucose utilization. The pain-related increase in energy expenditure was possibly mediated by adrenergic activity and was probably to a large extent due to increased muscle tone. These effects may be enhanced by cortical events related to the pain. The increase in glucose consumption favours catabolism. Our findings emphasize the clinical importance of pain management.

  13. Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

    PubMed

    Currie, Craig J; Holden, Sarah E; Jenkins-Jones, Sara; Morgan, Christopher Ll; Voss, Bernd; Rajpathak, Swapnil N; Alemayehu, Berhanu; Peters, John R; Engel, Samuel S

    2018-04-01

    To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk. © 2017 The Authors. Diabetes

  14. Circulating catecholamine and glucose concentrations in Japanese toads (Bufo japonicus) during the breeding season.

    PubMed

    Wilson, J X; Sawai, H; Kikuchi, M; Kubokawa, K; Ishii, S

    1995-06-01

    We investigated the relationship between catecholamine neurohormones and glucose during seasonal reproductive activity in Japanese toads (Bufo japonicus). Field studies found that plasma epinephrine concentration increased as toads migrated to their breeding ponds, where amplexus most frequently took place. Blood glucose concentration also increased as toads arrived at the ponds, even though these animals did not eat during the breeding season, and there was a positive correlation between epinephrine and glucose levels. Blood glucose concentration was higher in amplectic than in solitary males, whereas this relationship did not occur in females. For both males and females, plasma epinephrine concentration was elevated during amplexus. The plasma concentration of norepinephrine was lower than that of epinephrine and did not correlate with either the proximity of the animal to the breeding ponds or the blood glucose concentration. Laboratory experiments showed that systemic injection of [Trp7,Leu8]gonadotropin-releasing hormone (sGnRH) increased plasma epinephrine to levels characteristic of amplectic feral toads. These results suggest that a physiological role of GnRH-like peptides may be to stimulate epinephrine secretion and consequently to increase glucose production in toads under the starvation conditions associated with the breeding migration.

  15. Ibrolipim attenuates high glucose-induced endothelial dysfunction in cultured human umbilical vein endothelial cells via PI3K/Akt pathway.

    PubMed

    Xiao, Guohua; Wang, Zongbao; Zeng, Huaicai; Yu, Jian; Yin, Weidong; Zhang, Sujun; Wang, Yueting; Zhang, Yali

    2011-10-01

    Endothelial dysfunction is a key event in the onset and progression of atherosclerosis associated with diabetes. Increasing cell apoptosis may lead to endothelial dysfunction and contribute to vascular complications. Therefore, we aimed to elucidate the possible role and mechanism of ibrolipim in preventing endothelial dysfunction induced by high glucose. Human umbilical vein endothelial cells (HUVECs) were cultured respectively under normal glucose level (5.5mM), high glucose level (33mM), and high glucose level with ibrolipim treatment. Endothelial dysfunction was identified by the expression of ET-1 and vWF through reverse transcription PCR (RT-PCR). HUVECs apoptosis was assessed by fluorescent staining with Hoechst 33258. Akt activity was analyzed by western blot. High glucose condition significantly increased the rate of apoptotic cells, weakened cell viability, and decreased the expression of ET-1 and vWF. Ibrolipim treatment significantly attenuated these alterations of endothelial dysfunction. The lower concentrations (2, 4, 8 microM) of ibrolipim inhibited apoptosis of cultured HUVECs, improved cell viability, down-regulated the mRNA levels of ET-1, vWF, and attenuated the cytotoxicity; however, higher concentration (16, 32 microM) of ibrolipim aggravated the damage of HUVECs cultured under high glucose level. Meanwhile, high glucose induced a decrease of Akt activity which led to apoptosis, and ibrolipim prevented the decrease and attenuated apoptotic effect induced by high glucose. Furthermore, the PI3K inhibitor LY294002 significantly abolished the anti-apoptotic effect of ibrolipim, and decreased Akt phosphorylation. Although, the expression of Akt mRNA and total protein were not altered in cultured HUVECs. Ibrolipim at lower concentrations can inhibit high glucose-induced apoptosis in cultured HUVECs, which might be related to the alternation of Akt activity. Ibrolipim has the potential to attenuate endothelial dysfunction and lower the risk of

  16. Glucose Enhances Basal or Melanocortin-Induced cAMP-Response Element Activity in Hypothalamic Cells

    PubMed Central

    Wicht, Kristina; Boekhoff, Ingrid; Glas, Evi; Lauffer, Lisa; Mückter, Harald; Gudermann, Thomas

    2016-01-01

    Melanocyte-stimulating hormone (MSH)-induced activation of the cAMP-response element (CRE) via the CRE-binding protein in hypothalamic cells promotes expression of TRH and thereby restricts food intake and increases energy expenditure. Glucose also induces central anorexigenic effects by acting on hypothalamic neurons, but the underlying mechanisms are not completely understood. It has been proposed that glucose activates the CRE-binding protein-regulated transcriptional coactivator 2 (CRTC-2) in hypothalamic neurons by inhibition of AMP-activated protein kinases (AMPKs), but whether glucose directly affects hypothalamic CRE activity has not yet been shown. Hence, we dissected effects of glucose on basal and MSH-induced CRE activation in terms of kinetics, affinity, and desensitization in murine, hypothalamic mHypoA-2/10-CRE cells that stably express a CRE-dependent reporter gene construct. Physiologically relevant increases in extracellular glucose enhanced basal or MSH-induced CRE-dependent gene transcription, whereas prolonged elevated glucose concentrations reduced the sensitivity of mHypoA-2/10-CRE cells towards glucose. Glucose also induced CRCT-2 translocation into the nucleus and the AMPK activator metformin decreased basal and glucose-induced CRE activity, suggesting a role for AMPK/CRTC-2 in glucose-induced CRE activation. Accordingly, small interfering RNA-induced down-regulation of CRTC-2 expression decreased glucose-induced CRE-dependent reporter activation. Of note, glucose also induced expression of TRH, suggesting that glucose might affect the hypothalamic-pituitary-thyroid axis via the regulation of hypothalamic CRE activity. These findings significantly advance our knowledge about the impact of glucose on hypothalamic signaling and suggest that TRH release might account for the central anorexigenic effects of glucose and could represent a new molecular link between hyperglycaemia and thyroid dysfunction. PMID:27144291

  17. Improved Properties of Baker's Yeast Mutants Resistant to 2-Deoxy-d-Glucose

    PubMed Central

    Rincón, Ana M.; Codón, Antonio C.; Castrejón, Francisco; Benítez, Tahía

    2001-01-01

    We isolated spontaneous mutants from Saccharomyces cerevisiae (baker's yeast V1) that were resistant to 2-deoxy-d-glucose and had improved fermentative capacity on sweet doughs. Three mutants could grow at the same rate as the wild type in minimal SD medium (0.17% Difco yeast nitrogen base without amino acids and ammonium sulfate, 0.5% ammonium sulfate, 2% glucose) and had stable elevated levels of maltase and/or invertase under repression conditions but lower levels in maltose-supplemented media. Two of the mutants also had high levels of phosphatase active on 2-deoxy-d-glucose-6-phosphate. Dough fermentation (CO2 liberation) by two of the mutants was faster and/or produced higher final volumes than that by the wild type, both under laboratory and industrial conditions, when the doughs were supplemented with glucose or sucrose. However, the three mutants were slower when fermenting plain doughs. Fermented sweet bakery products obtained with these mutants were of better quality than those produced by the wild type, with regard to their texture and their organoleptic properties. PMID:11526034

  18. Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis.

    PubMed

    Gautam, D; Han, S-J; Duttaroy, A; Mears, D; Hamdan, F F; Li, J H; Cui, Y; Jeon, J; Wess, J

    2007-11-01

    The release of insufficient amounts of insulin in the presence of elevated blood glucose levels is one of the key features of type 2 diabetes. Various lines of evidence indicate that acetylcholine (ACh), the major neurotransmitter of the parasympathetic nervous system, can enhance glucose-stimulated insulin secretion from pancreatic beta-cells. Studies with isolated islets prepared from whole body M(3) muscarinic ACh receptor knockout mice showed that cholinergic amplification of glucose-dependent insulin secretion is exclusively mediated by the M(3) muscarinic receptor subtype. To investigate the physiological relevance of this muscarinic pathway, we used Cre/loxP technology to generate mutant mice that lack M(3) receptors only in pancreatic beta-cells. These mutant mice displayed impaired glucose tolerance and significantly reduced insulin secretion. In contrast, transgenic mice overexpressing M(3) receptors in pancreatic beta-cells showed a pronounced increase in glucose tolerance and insulin secretion and were resistant to diet-induced glucose intolerance and hyperglycaemia. These findings indicate that beta-cell M(3) muscarinic receptors are essential for maintaining proper insulin secretion and glucose homeostasis. Moreover, our data suggest that enhancing signalling through beta-cell M(3) muscarinic receptors may represent a new avenue in the treatment of glucose intolerance and type 2 diabetes.

  19. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

    PubMed

    Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

    2018-02-15

    The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. [Valsartan inhibits angiotensin II-Notch signaling of mesangial cells induced by high glucose].

    PubMed

    Yuan, Qin; Lyu, Chuan; Wu, Can; Lei, Sha; Shao, Ying; Wang, Qiuyue

    2016-01-01

    To explore the role of angiotensin II (Ang II)-Notch signaling in high glucose-induced secretion of extracellular matrix of rat mesangial cells (RMCs) and to further investigate the protective effect of valsartan (one of Ang II receptor blockers) on kidney. Subcultured RMCs were divided into groups as follows: normal glucose group (5.5 mmol/L glucose); high glucose group (30 mmol/L glucose); high concentration of mannitol as osmotic control group (5.5 mmol/L glucose and 24.5 mmol/L mannitol); normal glucose plus 1 μmol/L N-[N-(3, 5-difluorophenacetyl)-L-alanyl ]-S-phenylglycine t-butyl ester (DAPT) group; normal glucose plus (1, 5, 10) μmol/L valsartan group; high glucose plus 1 μmol/L DAPT group; high glucose plus (1, 5, 10) μmol/L valsartan group. Cells and supernatants were harvested after 12, 24 and 48 hours. Notch1 expression was examined by Western blotting. Secretion of transforming growth factor (TGF-β) and fibronectin (FN) were detected by ELISA. Compared to the normal glucose group, Notch1 expression was elevated in the high glucose group after 12 hours, and peaked at 24 hours. Besides, secretion of TGF-β and FN were much higher in the high glucose group than in the normal glucose group in a time-dependent manner. Compared to the untreated group, Notch1 expression decreased in a dose-dependent manner in the valsartan or DAPT treated group under high glucose after 24 hours. After pre-treatment by either valsartan or DAPT in the high glucose group, secretion of TGF-β and FN obviously decreased as compared to the untreated group. Hyperglycemia could stimulate activation of Notch signaling in cultured RMCs, which may increase secretion of downstream fibrotic factors such as TGF-β and FN. Valsartan may decrease the secretion of downstream FN in a dose-dependent manner via inhibiting AngII-Notch signaling.

  1. Specific Glucose-Induced Control of Insulin Receptor Substrate-2 Expression Is Mediated via Ca2+-Dependent Calcineurin/NFAT Signaling in Primary Pancreatic Islet β-Cells

    PubMed Central

    Demozay, Damien; Tsunekawa, Shin; Briaud, Isabelle; Shah, Ramila; Rhodes, Christopher J.

    2011-01-01

    OBJECTIVE Insulin receptor substrate-2 (IRS-2) plays an essential role in pancreatic islet β-cells by promoting growth and survival. IRS-2 turnover is rapid in primary β-cells, but its expression is highly regulated at the transcriptional level, especially by glucose. The aim was to investigate the molecular mechanism on how glucose regulates IRS-2 gene expression in β-cells. RESEARCH DESIGN AND METHODS Rat islets were exposed to inhibitors or subjected to adenoviral vector–mediated gene manipulations and then to glucose-induced IRS-2 expression analyzed by real-time PCR and immunoblotting. Transcription factor nuclear factor of activated T cells (NFAT) interaction with IRS-2 promoter was analyzed by chromatin immunoprecipitation assay and glucose-induced NFAT translocation by immunohistochemistry. RESULTS Glucose-induced IRS-2 expression occurred in pancreatic islet β-cells in vivo but not in liver. Modulating rat islet β-cell Ca2+ influx with nifedipine or depolarization demonstrated that glucose-induced IRS-2 gene expression was dependent on a rise in intracellular calcium concentration derived from extracellular sources. Calcineurin inhibitors (FK506, cyclosporin A, and a peptide calcineurin inhibitor [CAIN]) abolished glucose-induced IRS-2 mRNA and protein levels, whereas expression of a constitutively active calcineurin increased them. Specific inhibition of NFAT with the peptide inhibitor VIVIT prevented a glucose-induced IRS-2 transcription. NFATc1 translocation to the nucleus in response to glucose and association of NFATc1 to conserved NFAT binding sites in the IRS-2 promoter were demonstrated. CONCLUSIONS The mechanism behind glucose-induced transcriptional control of IRS-2 gene expression specific to the islet β-cell is mediated by the Ca2+/calcineurin/NFAT pathway. This insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass. PMID:21940781

  2. Effects of hydrogen sulfide on high glucose-induced glomerular podocyte injury in mice

    PubMed Central

    Liu, Ye; Zhao, Huichen; Qiang, Ye; Qian, Guanfang; Lu, Shengxia; Chen, Jicui; Wang, Xiangdong; Guan, Qingbo; Liu, Yuantao; Fu, Yuqin

    2015-01-01

    The aim of this study was to assess the effects of hydrogen sulfide on high glucose-induced mouse podocyte (MPC) injury and the underlying mechanisms. Mouse podocytes were randomly divided into 4 groups, including high glucose (HG), normal glucose (NG), normal glucose + DL-propargylglycine (PPG), and high glucose + NaHS (HG + NaHS) groups for treatment. Then, ZO-2, nephrin, β-catenin, and cystathionine γ-lyase (CSE) protein expression levels were determined by western blot. We found that high glucose significantly reduced nephrin, ZO-2, and CSE expression levels (P<0.05), and overtly elevated β-catenin amounts (P<0.05), in a time-dependent manner. Likewise, PPG at different concentrations in normal glucose resulted in significantly lower CSE, ZO-2, and nephrin levels (P<0.05), and increased β-catenin amounts (P<0.05). Interestingly, significantly increased ZO-2 and nephrin levels, and overtly reduced β-catenin amounts were observed in the HG + NaHS group compared with HG treated cells (P<0.01). Compared with NG treated cells, decreased ZO-2 and nephrin levels and higher β-catenin amounts were obtained in the HG + NaHS group. In conclusion,CSE downregulation contributes to hyperglycemia induced podocyte injury, which is alleviated by exogenous H2S possibly through ZO-2 upregulation and the subsequent suppression of Wnt/β-catenin pathway. PMID:26261567

  3. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation.

    PubMed

    Goji, Takeo; Takahara, Kazuhiko; Negishi, Manabu; Katoh, Hironori

    2017-12-01

    Oncogenic signaling in cancer cells alters glucose uptake and utilization to supply sufficient energy and biosynthetic intermediates for survival and sustained proliferation. Oncogenic signaling also prevents oxidative stress and cell death caused by increased production of reactive oxygen species. However, elevated glucose metabolism in cancer cells, especially in glioblastoma, results in the cells becoming sensitive to glucose deprivation ( i.e. in high glucose dependence), which rapidly induces cell death. However, the precise mechanism of this type of cell death remains unknown. Here, we report that glucose deprivation alone does not trigger glioblastoma cell death. We found that, for cell death to occur in glucose-deprived glioblastoma cells, cystine and glutamine also need to be present in culture media. We observed that cystine uptake through the cystine/glutamate antiporter xCT under glucose deprivation rapidly induces NADPH depletion, reactive oxygen species accumulation, and cell death. We conclude that although cystine uptake is crucial for production of antioxidant glutathione in cancer cells its transport through xCT also induces oxidative stress and cell death in glucose-deprived glioblastoma cells. Combining inhibitors targeting cancer-specific glucose metabolism with cystine and glutamine treatment may offer a therapeutic approach for glioblastoma tumors exhibiting high xCT expression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. The effect of PCSK1 variants on waist, waist-hip ratio and glucose metabolism is modified by sex and glucose tolerance status.

    PubMed

    Gjesing, Anette P; Vestmar, Marie A; Jørgensen, Torben; Heni, Martin; Holst, Jens J; Witte, Daniel R; Hansen, Torben; Pedersen, Oluf

    2011-01-01

    We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2-1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005-0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1-1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (-0.7-9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating plasma glucose and hormone levels may be influenced by glucose tolerance

  5. Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake.

    PubMed

    Renguet, Edith; Ginion, Audrey; Gélinas, Roselle; Bultot, Laurent; Auquier, Julien; Robillard Frayne, Isabelle; Daneault, Caroline; Vanoverschelde, Jean-Louis; Des Rosiers, Christine; Hue, Louis; Horman, Sandrine; Beauloye, Christophe; Bertrand, Luc

    2017-08-01

    High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells have suggested that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts. Although leucine activated mTOR/p70S6K, the mTOR inhibitor rapamycin did not prevent leucine's inhibitory action on glucose uptake, ruling out the contribution of the insulin-negative feedback loop. α-Ketoisocaproate, the first metabolite of leucine catabolism, mimicked leucine's effect on glucose uptake. Incubation of cardiomyocytes with [ 13 C]leucine ascertained its metabolism to ketone bodies (KBs), which had a similar negative impact on insulin-stimulated glucose transport. Both leucine and KBs reduced glucose uptake by affecting translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Finally, we found that leucine elevated the global protein acetylation level. Pharmacological inhibition of lysine acetyltransferases counteracted this increase in protein acetylation and prevented leucine's inhibitory action on both glucose uptake and GLUT4 translocation. Taken together, these results indicate that leucine metabolism into KBs contributes to inhibition of cardiac glucose uptake by hampering the translocation of GLUT4-containing vesicles via acetylation. They offer new insights into the establishment of insulin resistance in the heart. NEW & NOTEWORTHY Catabolism of the branched-chain amino acid leucine into ketone bodies efficiently inhibits cardiac glucose uptake through decreased translocation of glucose transporter 4 to the plasma membrane. Leucine increases protein acetylation. Pharmacological inhibition of acetylation

  6. Compartmentalized acyl-CoA metabolism in skeletal muscle regulates systemic glucose homeostasis.

    PubMed

    Li, Lei O; Grevengoed, Trisha J; Paul, David S; Ilkayeva, Olga; Koves, Timothy R; Pascual, Florencia; Newgard, Christopher B; Muoio, Deborah M; Coleman, Rosalind A

    2015-01-01

    The impaired capacity of skeletal muscle to switch between the oxidation of fatty acid (FA) and glucose is linked to disordered metabolic homeostasis. To understand how muscle FA oxidation affects systemic glucose, we studied mice with a skeletal muscle-specific deficiency of long-chain acyl-CoA synthetase (ACSL)1. ACSL1 deficiency caused a 91% loss of ACSL-specific activity and a 60-85% decrease in muscle FA oxidation. Acsl1(M-/-) mice were more insulin sensitive, and, during an overnight fast, their respiratory exchange ratio was higher, indicating greater glucose use. During endurance exercise, Acsl1(M-/-) mice ran only 48% as far as controls. At the time that Acsl1(M-/-) mice were exhausted but control mice continued to run, liver and muscle glycogen and triacylglycerol stores were similar in both genotypes; however, plasma glucose concentrations in Acsl1(M-/-) mice were ∼40 mg/dL, whereas glucose concentrations in controls were ∼90 mg/dL. Excess use of glucose and the likely use of amino acids for fuel within muscle depleted glucose reserves and diminished substrate availability for hepatic gluconeogenesis. Surprisingly, the content of muscle acyl-CoA at exhaustion was markedly elevated, indicating that acyl-CoAs synthesized by other ACSL isoforms were not available for β-oxidation. This compartmentalization of acyl-CoAs resulted in both an excessive glucose requirement and severely compromised systemic glucose homeostasis. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  7. Medial PFC Damage Abolishes the Self-reference Effect

    PubMed Central

    Philippi, Carissa L.; Duff, Melissa C.; Denburg, Natalie L.; Tranel, Daniel; Rudrauf, David

    2012-01-01

    Functional neuroimaging studies suggest that the medial PFC (mPFC) is a key component of a large-scale neural system supporting a variety of self-related processes. However, it remains unknown whether the mPFC is critical for such processes. In this study, we used a human lesion approach to examine this question. We administered a standard trait judgment paradigm [Kelley, W. M., Macrae, C. N., Wyland, C. L., Caglar, S., Inati, S., & Heatherton, T. F. Finding the self? An event-related fMRI study. Journal of Cognitive Neuroscience, 14, 785–794, 2002] to patients with focal brain damage to the mPFC. The self-reference effect (SRE), a memory advantage conferred by self-related processing, served as a measure of intact self-processing ability. We found that damage to the mPFC abolished the SRE. The results demonstrate that the mPFC is necessary for the SRE and suggest that this structure is important for self-referential processing and the neural representation of self. PMID:21942762

  8. Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression.

    PubMed

    Heilig, C W; Kreisberg, J I; Freytag, S; Murakami, T; Ebina, Y; Guo, L; Heilig, K; Loberg, R; Qu, X; Jin, Y; Henry, D; Brosius, F C

    2001-04-01

    A stable clone of rat mesangial cells expressing antisense GLUT-1 (i.e., MCGT1AS cells) was developed to protect them from high glucose exposure. GLUT-1 protein was reduced 50%, and the 2-deoxy-[(3)H]glucose uptake rate was reduced 33% in MCGT1AS. MCLacZ control cells and MCGT1 GLUT-1-overexpressing cells were used for comparisons. In MCLacZ, 20 mM D-glucose increased GLUT-1 transcription 90% vs. no increase in MCGT1AS. Glucose (8 mM) and 12 mM xylitol [a hexose monophosphate (HMP) shunt substrate] did not stimulate GLUT-1 transcription. An 87% replacement of the standard 8 mM D-glucose with 3-O-methylglucose reduced GLUT-1 transcription 80%. D-Glucose (20 mM) increased fibronectin mRNA and protein by 47 and 100%, respectively, in MCLacZ vs. no increases in MCGT1AS. Fibronectin synthesis was elevated 48% in MCGT1 and reduced 44% in MCGT1AS. We conclude that 1) transcription of GLUT-1 in response to D-glucose depends on glucose metabolism, although not through the HMP shunt, and 2) antisense GLUT-1 treatment of mesangial cells blocks D-glucose-induced GLUT-1 and fibronectin expression, thereby demonstrating a protective effect that could be beneficial in the setting of diabetes.

  9. FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics.

    PubMed

    Fuller, Miles; Li, Xiaoran; Fisch, Robert; Bughara, Moneb; Wicksteed, Barton; Kovatcheva-Datchary, Petia; Layden, Brian T

    2016-01-01

    During the insulin resistant phase of pregnancy, the mRNA expression of free fatty acid 2 receptor (Ffar2) is upregulated and as we recently reported, this receptor contributes to insulin secretion and pancreatic beta cell mass expansion in order to maintain normal glucose homeostasis during pregnancy. As impaired gestational glucose levels can affect metabolic health of offspring, we aimed to explore the role of maternal Ffar2 expression during pregnancy on the metabolic health of offspring and also the effects of antibiotics, which have been shown to disrupt gut microbiota fermentative activity (the source of the FFA2 ligands) on gestational glucose homeostasis. We found that maternal Ffar2 expression and impaired glucose tolerance during pregnancy had no effect on the growth rates, ad lib glucose and glucose tolerance in the offspring between 3 and 6 weeks of age. To disrupt short chain fatty acid production, we chronically treated WT mice and Ffar2-/- mice with broad range antibiotics and further compared their glucose tolerance prior to pregnancy and at gestational day 15, and also quantified cecum and plasma SCFAs. We found that during pregnancy antibiotic treatment reduced the levels of SCFAs in the cecum of the mice, but resulted in elevated levels of plasma SCFAs and altered concentrations of individual SCFAs. Along with these changes, gestational glucose tolerance in WT mice, but not Ffar2-/- mice improved while on antibiotics. Additional data showed that gestational glucose tolerance worsened in Ffar2-/- mice during a second pregnancy. Together, these results indicate that antibiotic treatment alone is inadequate to deplete plasma SCFA concentrations, and that modulation of gut microbiota by antibiotics does not disrupt the contribution of FFA2 to gestational glucose tolerance.

  10. Blood glucose regulation mechanism in depressive disorder animal model during hyperglycemic states.

    PubMed

    Lim, Su-Min; Park, Soo-Hyun; Sharma, Naveen; Kim, Sung-Su; Lee, Jae-Ryeong; Jung, Jun-Sub; Suh, Hong-Won

    2016-06-01

    Depression is more common among diabetes people than in the general population. In the present study, blood glucose change in depression animal model was characterized by various types of hyperglycemia models such as d-glucose-fed-, immobilization stress-, and drug-induced hyperglycemia models. First, the ICR mice were enforced into chronic restraint stress for 2h daily for 2 weeks to produce depression animal model. The animals were fed with d-glucose (2g/kg), forced into restraint stress for 30min, or administered with clonidine (5μg/5μl) supraspinally or spinally to produce hyperglycemia. The blood glucose level in depression group was down-regulated compared to that observed in the normal group in d-glucose-fed-, restraint stress-, and clonidine-induced hyperglycemia models. The up-regulated corticosterone level induced by d-glucose feeding or restraint stress was reduced in the depression group while the up-regulation of plasma corticosterone level is further elevated after i.t. or i.c.v. clonidine administration in the depression group. The up-regulated insulin level induced by d-glucose feeding or restraint stress was reduced in the depression group. On the other hand, blood corticosterone level in depression group was up-regulated compared to the normal group after i.t. or i.c.v. clonidine administration. Whereas the insulin level in depression group was not altered when mice were administered clonidine i.t. or i.c.v. Our results suggest that the blood glucose level in depression group is down-regulated compared to the normal group during d-glucose-fed-, immobilization stress-, and clonidine-induced hyperglycemia in mice. The down-regulation of the blood glucose level might be one of the important pathophysiologic changes in depression. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. 76 FR 70321 - Prevailing Rate Systems; Abolishment of Cumberland, ME, as a Nonappropriated Fund Federal Wage...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ... abolish the Cumberland, Maine, nonappropriated fund (NAF) Federal Wage System (FWS) wage area and redefine... closure of the Naval Air Station Brunswick left the Cumberland wage area without an activity having the... Cumberland, Maine, nonappropriated fund (NAF) Federal Wage System (FWS) wage area and redefine Cumberland...

  12. Elevated Carbon Dioxide Alleviates Aluminum Toxicity by Decreasing Cell Wall Hemicellulose in Rice (Oryza sativa)

    PubMed Central

    Zhu, Xiao Fang; Zhao, Xu Sheng; Wang, Bin; Wu, Qi; Shen, Ren Fang

    2017-01-01

    Carbon dioxide (CO2) is involved in plant growth as well as plant responses to abiotic stresses; however, it remains unclear whether CO2 is involved in the response of rice (Oryza sativa) to aluminum (Al) toxicity. In the current study, we discovered that elevated CO2 (600 μL·L−1) significantly alleviated Al-induced inhibition of root elongation that occurred in ambient CO2 (400 μL·L−1). This protective effect was accompanied by a reduced Al accumulation in root apex. Al significantly induced citrate efflux and the expression of OsALS1, but elevated CO2 had no further effect. By contrast, elevated CO2 significantly decreased Al-induced accumulation of hemicellulose, as well as its Al retention. As a result, the amount of Al fixed in the cell wall was reduced, indicating an alleviation of Al-induced damage to cell wall function. Furthermore, elevated CO2 decreased the Al-induced root nitric oxide (NO) accumulation, and the addition of the NO scavenger c-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) abolished this alleviation effect, indicating that NO maybe involved in the CO2-alleviated Al toxicity. Taken together, these results demonstrate that the alleviation of Al toxicity in rice by elevated CO2 is mediated by decreasing hemicellulose content and the Al fixation in the cell wall, possibly via the NO pathway. PMID:28769823

  13. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.

    PubMed Central

    Boden, G; Chen, X

    1995-01-01

    It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus. PMID:7657800

  14. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.

    PubMed

    Boden, G; Chen, X

    1995-09-01

    It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.

  15. Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats

    PubMed Central

    Swithers, Susan E.; Laboy, Alycia F.; Clark, Kiely; Cooper, Stephanie; Davidson, T.L.

    2012-01-01

    Previous work from our lab has demonstrated that experience with high-intensity sweeteners in rats leads to increased food intake, body weight gain and adiposity, along with diminished caloric compensation and decreased thermic effect of food. These changes may occur as a result of interfering with learned relations between the sweet taste of food and the caloric or nutritive consequences of consuming those foods. The present experiments determined whether experience with the high-intensity sweetener saccharin versus the caloric sweetener glucose affected blood glucose homeostasis. The results demonstrated that during oral glucose tolerance tests, blood glucose levels were more elevated in animals that had previously consumed the saccharin-sweetened supplements. In contrast, during glucose tolerance tests when a glucose solution was delivered directly into the stomach, no differences in blood glucose levels between the groups were observed. Differences in oral glucose tolerance responses were not accompanied by differences in insulin release; insulin release was similar in animals previously exposed to saccharin and those previously exposed to glucose. However, release of GLP-1 in response to an oral glucose tolerance test, but not to glucose tolerance tests delivered by gavage, was significantly lower in saccharin-exposed animals compared to glucose-exposed animals. Differences in both blood glucose and GLP-1 release in saccharin animals were rapid and transient, and suggest that one mechanism by which exposure to high-intensity sweeteners that interfere with a predictive relation between sweet tastes and calories may impair energy balance is by suppressing GLP-1 release, which could alter glucose homeostasis and reduce satiety. PMID:22561130

  16. CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress.

    PubMed

    Petersen, Pia S; Lei, Xia; Wolf, Risa M; Rodriguez, Susana; Tan, Stefanie Y; Little, Hannah C; Schweitzer, Michael A; Magnuson, Thomas H; Steele, Kimberley E; Wong, G William

    2017-04-01

    Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes. Copyright © 2017 the American Physiological Society.

  17. CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

    PubMed Central

    Petersen, Pia S.; Lei, Xia; Wolf, Risa M.; Rodriguez, Susana; Tan, Stefanie Y.; Little, Hannah C.; Schweitzer, Michael A.; Magnuson, Thomas H.; Steele, Kimberley E.

    2017-01-01

    Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes. PMID:28223291

  18. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

    PubMed

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

  19. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose

    PubMed Central

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P.

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes. PMID:29474476

  20. Possible involvement of 12-lipoxygenase activation in glucose-deprivation/reload-treated neurons.

    PubMed

    Nagasawa, Kazuki; Kakuda, Taichi; Higashi, Youichirou; Fujimoto, Sadaki

    2007-12-18

    The aim of this study was to clarify whether 12-lipoxygenase (12-LOX) activation was involved in reactive oxygen species (ROS) generation, extensive poly(ADP-ribose) polymerase (PARP) activation and neuronal death induced by glucose-deprivation, followed by glucose-reload (GD/R). The decrease of neuronal viability and accumulation of poly(ADP-ribose) induced by GD/R were prevented 3-aminobenzamide, a representative PARP inhibitor, demonstrating this treatment protocol caused the same oxidative stress with the previously reported one. The PARP activation, ROS generation and decrease of neuron viability induced by GD/R treatment were almost completely abolished by an extracellular zinc chelator, CaEDTA. p47(phox), a cytosolic component of NADPH oxidase was translocated the membrane fraction by GD/R, indicating its activation, but it did not generate detectable ROS. Surprisingly, pharmacological inhibition of NADPH oxidase with apocynin and AEBSF further decreased the decreased neuron viability induced by GD/R. On the other hand, AA861, a 12-LOX inhibitor, prevented ROS generation and decrease of neuron viability caused by GD/R. Interestingly, an antioxidant, N-acetyl-l-cysteine rescued the neurons from GD/R-induced oxidative stress, implying effectiveness of antioxidant administration. These findings suggested that activation of 12-LOX, but not NADPH oxidase, following to zinc release might play an important role in ROS generation and decrease of viability in GD/R-treated neurons.

  1. Histidine augments the suppression of hepatic glucose production by central insulin action.

    PubMed

    Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-Ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

    2013-07-01

    Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes.

  2. Histidine Augments the Suppression of Hepatic Glucose Production by Central Insulin Action

    PubMed Central

    Kimura, Kumi; Nakamura, Yusuke; Inaba, Yuka; Matsumoto, Michihiro; Kido, Yoshiaki; Asahara, Shun-ichiro; Matsuda, Tomokazu; Watanabe, Hiroshi; Maeda, Akifumi; Inagaki, Fuyuhiko; Mukai, Chisato; Takeda, Kiyoshi; Akira, Shizuo; Ota, Tsuguhito; Nakabayashi, Hajime; Kaneko, Shuichi; Kasuga, Masato; Inoue, Hiroshi

    2013-01-01

    Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes. PMID:23474485

  3. Featured Article: Inhibition of diabetic cataract by glucose tolerance factor extracted from yeast

    PubMed Central

    Cohen, Revital; Eliaz, Anat; Dovrat, Ahuva

    2016-01-01

    Diabetes leads to many complications; among them is the development of cataract. Hyperglycemia brings to increased polyol concentration in the lens, to glycation of lens proteins, and to elevated level of ROS (Reactive Oxygen Species) causing oxidative stress. The glucose tolerance factor (GTF) was found by several groups to decrease hyperglycemia and oxidative stress both in diabetic animals and humans. The aim of our study was to explore the damages induced by high glucose to the eye lens and to assess the protective effects of GTF both in vivo and in vitro. The in vivo study included control healthy rats, streptozotocin (STZ) diabetic untreated rats, and STZ diabetic rats orally treated with 15 doses of GTF. The diabetic untreated rats developed cataracts, whereas the development of cataract was totally or partially prevented in GTF treated animals. In vitro studies were done on bovine lenses incubated for 14 days. Half of the lenses were incubated in normal glucose conditions, and half in high glucose conditions (450 mg%). To one group of the normal or high glucose condition GTF was added. The optical quality of all the lenses was measured daily by an automated scanning laser system. The control lenses, whether with or without GTF addition, did not show any reduction in their quality. High glucose conditions induced optical damage to the lenses. Addition of GTF to high glucose conditions prevented this damage. High glucose conditions affected the activity of aldose reductase and sodium potassium ATPase in lens epithelial cell. Addition of GTF decreased the destructive changes induced by high glucose conditions. The amount of soluble cortical lens proteins was decreased and structural changes were detected in lenses incubated in high glucose medium. These changes could be prevented when GTF was added to high glucose medium. Our findings demonstrate the anticataractogenic potential of GTF. PMID:26825353

  4. Carbohydrate Ingestion Before and During Soccer Match Play and Blood Glucose and Lactate Concentrations

    PubMed Central

    Russell, Mark; Benton, David; Kingsley, Michael

    2014-01-01

    Context: The ingestion of carbohydrate (CHO) before and during exercise and at halftime is commonly recommended to soccer players for maintaining blood glucose concentrations throughout match play. However, an exercise-induced rebound glycemic response has been observed in the early stages of the second half of simulated soccer-specific exercise when CHO-electrolyte beverages were consumed regularly. Therefore, the metabolic effects of CHO beverage consumption throughout soccer match play remain unclear. Objective: To investigate the blood glucose and blood lactate responses to CHOs ingested before and during soccer match play. Design: Crossover study. Setting: Applied research study. Patients or Other Participants: Ten male outfield academy soccer players (age = 15.6 ± 0.2 years, height = 1.74 ± 0.02 m, mass = 65.3 ± 1.9 kg, estimated maximal oxygen consumption = 58.4 ± 0.8 mL·kg−1·min−1). Intervention(s): Players received a 6% CHO-electrolyte solution or an electrolyte (placebo) solution 2 hours before kickoff, before each half (within 10 minutes), and every 15 minutes throughout exercise. Blood samples were obtained at rest, every 15 minutes during the match (first half: 0–15, 15–30, and 30–45 minutes; second half: 45–60, 60–75, and 75–90 minutes) and 10 minutes into the halftime break. Main Outcome Measure(s): Metabolic responses (blood glucose and blood lactate concentrations) and markers of exercise intensity (heart rate) were recorded. Results: Supplementation influenced the blood glucose response to exercise (time × treatment interaction effect: P ≤ .05), such that glucose concentrations were higher at 30 to 45 minutes in the CHO than in the placebo condition. However, in the second half, blood glucose concentrations were similar between conditions because of transient reductions from peak values occurring in both trials at halftime. Blood lactate concentrations were elevated above those at rest in the first 15 minutes of exercise

  5. Carbohydrate ingestion before and during soccer match play and blood glucose and lactate concentrations.

    PubMed

    Russell, Mark; Benton, David; Kingsley, Michael

    2014-01-01

    The ingestion of carbohydrate (CHO) before and during exercise and at halftime is commonly recommended to soccer players for maintaining blood glucose concentrations throughout match play. However, an exercise-induced rebound glycemic response has been observed in the early stages of the second half of simulated soccer-specific exercise when CHO-electrolyte beverages were consumed regularly. Therefore, the metabolic effects of CHO beverage consumption throughout soccer match play remain unclear. To investigate the blood glucose and blood lactate responses to CHOs ingested before and during soccer match play. Crossover study. Applied research study. Ten male outfield academy soccer players (age = 15.6 ± 0.2 years, height = 1.74 ± 0.02 m, mass = 65.3 ± 1.9 kg, estimated maximal oxygen consumption = 58.4 ± 0.8 mL·kg(-1)·min(-1)). Players received a 6% CHO-electrolyte solution or an electrolyte (placebo) solution 2 hours before kickoff, before each half (within 10 minutes), and every 15 minutes throughout exercise. Blood samples were obtained at rest, every 15 minutes during the match (first half: 0-15, 15-30, and 30-45 minutes; second half: 45-60, 60-75, and 75-90 minutes) and 10 minutes into the halftime break. Metabolic responses (blood glucose and blood lactate concentrations) and markers of exercise intensity (heart rate) were recorded. Supplementation influenced the blood glucose response to exercise (time × treatment interaction effect: P ≤ .05), such that glucose concentrations were higher at 30 to 45 minutes in the CHO than in the placebo condition. However, in the second half, blood glucose concentrations were similar between conditions because of transient reductions from peak values occurring in both trials at halftime. Blood lactate concentrations were elevated above those at rest in the first 15 minutes of exercise (time-of-sample effect: P < .001) and remained elevated throughout exercise. Supplementation did not influence the pattern of

  6. Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

    PubMed

    Meek, Thomas H; Dorfman, Mauricio D; Matsen, Miles E; Fischer, Jonathan D; Cubelo, Alexis; Kumar, Monica R; Taborsky, Gerald J; Morton, Gregory J

    2015-07-01

    Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  7. Blood Test: Glucose

    MedlinePlus

    ... Videos for Educators Search English Español Blood Test: Glucose KidsHealth / For Parents / Blood Test: Glucose What's in ... liver or kidneys) is working. What Is a Glucose Test? A glucose test measures how much glucose ...

  8. High glucose environment inhibits cranial neural crest survival by activating excessive autophagy in the chick embryo

    PubMed Central

    Wang, Xiao-Yu; Li, Shuai; Wang, Guang; Ma, Zheng-Lai; Chuai, Manli; Cao, Liu; Yang, Xuesong

    2015-01-01

    High glucose levels induced by maternal diabetes could lead to defects in neural crest development during embryogenesis, but the cellular mechanism is still not understood. In this study, we observed a defect in chick cranial skeleton, especially parietal bone development in the presence of high glucose levels, which is derived from cranial neural crest cells (CNCC). In early chick embryo, we found that inducing high glucose levels could inhibit the development of CNCC, however, cell proliferation was not significantly involved. Nevertheless, apoptotic CNCC increased in the presence of high levels of glucose. In addition, the expression of apoptosis and autophagy relevant genes were elevated by high glucose treatment. Next, the application of beads soaked in either an autophagy stimulator (Tunicamycin) or inhibitor (Hydroxychloroquine) functionally proved that autophagy was involved in regulating the production of CNCC in the presence of high glucose levels. Our observations suggest that the ERK pathway, rather than the mTOR pathway, most likely participates in mediating the autophagy induced by high glucose. Taken together, our observations indicated that exposure to high levels of glucose could inhibit the survival of CNCC by affecting cell apoptosis, which might result from the dysregulation of the autophagic process. PMID:26671447

  9. Glucose-Responsive Trehalose Hydrogel for Insulin Stabilization and Delivery.

    PubMed

    Lee, Juneyoung; Ko, Jeong Hoon; Mansfield, Kathryn M; Nauka, Peter C; Bat, Erhan; Maynard, Heather D

    2018-05-01

    Effective delivery of therapeutic proteins is important for many biomedical applications. Yet, the stabilization of proteins during delivery and long-term storage remains a significant challenge. Herein, a trehalose-based hydrogel is reported that stabilizes insulin to elevated temperatures prior to glucose-triggered release. The hydrogel is synthesized using a polymer with trehalose side chains and a phenylboronic acid end-functionalized 8-arm poly(ethylene glycol) (PEG). The hydroxyls of the trehalose side chains form boronate ester linkages with the PEG boronic acid cross-linker to yield hydrogels without any further modification of the original trehalose polymer. Dissolution of the hydrogel is triggered upon addition of glucose as a stronger binder to boronic acid (K b = 2.57 vs 0.48 m -1 for trehalose), allowing the insulin that is entrapped during gelation to be released in a glucose-responsive manner. Moreover, the trehalose hydrogel stabilizes the insulin as determined by immunobinding after heating up to 90 °C. After 30 min heating, 74% of insulin is detected by enzyme-linked immunosorbent assay in the presence of the trehalose hydrogel, whereas only 2% is detected without any additives. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Insulin and glucose excursion following premeal insulin lispro or repaglinide in cystic fibrosis-related diabetes.

    PubMed

    Moran, A; Phillips, J; Milla, C

    2001-10-01

    Insulin and glucose levels in response to premeal insulin lispro or repaglinide were evaluated in adult patients with cystic fibrosis-related diabetes (CFRD) without fasting hyperglycemia. Seven patients with CFRD were fed 1,000-kcal liquid mixed meals. Three study conditions were administered in random order on separate mornings: 1) no premeal diabetes medication, 2) insulin lispro, 0.1 unit/kg body wt premeal and 3) repaglinide 1 mg premeal. Glucose and insulin levels were measured every 20 min for 5 h. Fasting insulin and glucose levels were normal in patients with CFRD, but the peak glucose level was elevated. Insulin lispro significantly decreased the peak glucose level (P = 0.0004) and the 2-h (P = 0.001) and 5-h (P < 0.0001) glucose area under the curve (AUC). Repaglinide significantly decreased the 5-h glucose AUC (P = 0.03). Neither drug completely normalized cystic fibrosis glucose excursion at the doses used for this study. Insulin lispro significantly increased the 5-h insulin AUC (P = 0.04). In response to subcutaneous insulin lispro, postprandial glucose excursion was significantly diminished and insulin secretion was enhanced compared with a control meal in which no medication was given to patients with CFRD. The oral agent repaglinide resulted in lesser corrections in these parameters. Neither drug completely normalized glucose or insulin levels, suggesting that the doses chosen for this study were suboptimal. Placebo-controlled longitudinal studies comparing the effectiveness of repaglinide and insulin on glucose metabolic control as well as overall nutrition and body weight are needed to help determine optimal medical treatment of CFRD.

  11. Inhibitors of Fatty Acid Synthesis Induce PPARα-Regulated Fatty Acid β-Oxidative Genes: Synergistic Roles of L-FABP and Glucose

    PubMed Central

    Huang, Huan; McIntosh, Avery L.; Martin, Gregory G.; Petrescu, Anca D.; Landrock, Kerstin K.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α (PPARα) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPARα transcription of the fatty acid β-oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPARα in the context of high glucose at levels similar to those in uncontrolled diabetes. PMID:23533380

  12. A multiscale, model-based analysis of the multi-tissue interplay underlying blood glucose regulation in type I diabetes.

    PubMed

    Wadehn, Federico; Schaller, Stephan; Eissing, Thomas; Krauss, Markus; Kupfer, Lars

    2016-08-01

    A multiscale model for blood glucose regulation in diabetes type I patients is constructed by integrating detailed metabolic network models for fat, liver and muscle cells into a whole body physiologically-based pharmacokinetic/pharmacodynamic (pBPK/PD) model. The blood glucose regulation PBPK/PD model simulates the distribution and metabolization of glucose, insulin and glucagon on an organ and whole body level. The genome-scale metabolic networks in contrast describe intracellular reactions. The developed multiscale model is fitted to insulin, glucagon and glucose measurements of a 48h clinical trial featuring 6 subjects and is subsequently used to simulate (in silico) the influence of geneknockouts and drug-induced enzyme inhibitions on whole body blood glucose levels. Simulations of diabetes associated gene knockouts and impaired cellular glucose metabolism, resulted in elevated whole body blood-glucose levels, but also in a metabolic shift within the cell's reaction network. Such multiscale models have the potential to be employed in the exploration of novel drug-targets or to be integrated into control algorithms for artificial pancreas systems.

  13. Blood glucose level reconstruction as a function of transcapillary glucose transport.

    PubMed

    Koutny, Tomas

    2014-10-01

    A diabetic patient occasionally undergoes a detailed monitoring of their glucose levels. Over the course of a few days, a monitoring system provides a detailed track of their interstitial fluid glucose levels measured in their subcutaneous tissue. A discrepancy in the blood and interstitial fluid glucose levels is unimportant because the blood glucose levels are not measured continuously. Approximately five blood glucose level samples are taken per day, and the interstitial fluid glucose level is usually measured every 5min. An increased frequency of blood glucose level sampling would cause discomfort for the patient; thus, there is a need for methods to estimate blood glucose levels from the glucose levels measured in subcutaneous tissue. The Steil-Rebrin model is widely used to describe the relationship between blood and interstitial fluid glucose dynamics. However, we measured glucose level patterns for which the Steil-Rebrin model does not hold. Therefore, we based our research on a different model that relates present blood and interstitial fluid glucose levels to future interstitial fluid glucose levels. Using this model, we derived an improved model for calculating blood glucose levels. In the experiments conducted, this model outperformed the Steil-Rebrin model while introducing no additional requirements for glucose sample collection. In subcutaneous tissue, 26.71% of the calculated blood glucose levels had absolute values of relative differences from smoothed measured blood glucose levels less than or equal to 5% using the Steil-Rebrin model. However, the same difference interval was encountered in 63.01% of the calculated blood glucose levels using the proposed model. In addition, 79.45% of the levels calculated with the Steil-Rebrin model compared with 95.21% of the levels calculated with the proposed model had 20% difference intervals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Autophagy fails to prevent glucose deprivation/glucose reintroduction-induced neuronal death due to calpain-mediated lysosomal dysfunction in cortical neurons.

    PubMed

    Gerónimo-Olvera, Cristian; Montiel, Teresa; Rincon-Heredia, Ruth; Castro-Obregón, Susana; Massieu, Lourdes

    2017-06-29

    Autophagy is triggered during nutrient and energy deprivation in a variety of cells as a homeostatic response to metabolic stress. In the CNS, deficient autophagy has been implicated in neurodegenerative diseases and ischemic brain injury. However, its role in hypoglycemic damage is poorly understood and the dynamics of autophagy during the hypoglycemic and the glucose reperfusion periods, has not been fully described. In the present study, we analyzed the changes in the content of the autophagy proteins BECN1, LC3-II and p62/SQSTM1 by western blot, and autophagosome formation was followed through time-lapse experiments, during glucose deprivation (GD) and glucose reintroduction (GR) in cortical cultures. According to the results, autophagosome formation rapidly increased during GD, and was followed by an active autophagic flux early after glucose replenishment. However, cells progressively died during GR and autophagy inhibition reduced neuronal death. Neurons undergoing apoptosis during GR did not form autophagosomes, while those surviving up to late GR showed autophagosomes. Calpain activity strongly increased during GR and remained elevated during progressive neuronal death. Its activation led to the cleavage of LAMP2 resulting in lysosome membrane permeabilization (LMP) and release of cathepsin B to the cytosol. Calpain inhibition prevented LMP and increased the number of neurons containing lysosomes and autophagosomes increasing cell viability. Taken together, the present results suggest that calpain-mediated lysosome dysfunction during GR turns an adaptive autophagy response to energy stress into a defective autophagy pathway, which contributes to neuronal death. In these conditions, autophagy inhibition results in the improvement of cell survival.

  15. Random plasma glucose in serendipitous screening for glucose intolerance: screening for impaired glucose tolerance study 2.

    PubMed

    Ziemer, David C; Kolm, Paul; Foster, Jovonne K; Weintraub, William S; Vaccarino, Viola; Rhee, Mary K; Varughese, Rincy M; Tsui, Circe W; Koch, David D; Twombly, Jennifer G; Narayan, K M Venkat; Phillips, Lawrence S

    2008-05-01

    With positive results from diabetes prevention studies, there is interest in convenient ways to incorporate screening for glucose intolerance into routine care and to limit the need for fasting diagnostic tests. The aim of this study is to determine whether random plasma glucose (RPG) could be used to screen for glucose intolerance. This is a cross-sectional study. The participants of this study include a voluntary sample of 990 adults not known to have diabetes. RPG was measured, and each subject had a 75-g oral glucose tolerance test several weeks later. Glucose intolerance targets included diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose(110) (IFG(110); fasting glucose, 110-125 mg/dl, and 2 h glucose < 140 mg/dl). Screening performance was measured by area under receiver operating characteristic curves (AROC). Mean age was 48 years, and body mass index (BMI) was 30.4 kg/m(2); 66% were women, and 52% were black; 5.1% had previously unrecognized diabetes, and 24.0% had any "high-risk" glucose intolerance (diabetes or IGT or IFG(110)). The AROC was 0.80 (95% CI 0.74-0.86) for RPG to identify diabetes and 0.72 (0.68-0.75) to identify any glucose intolerance, both highly significant (p < 0.001). Screening performance was generally consistent at different times of the day, regardless of meal status, and across a range of risk factors such as age, BMI, high density lipoprotein cholesterol, triglycerides, and blood pressure. RPG values should be considered by health care providers to be an opportunistic initial screening test and used to prompt further evaluation of patients at risk of glucose intolerance. Such "serendipitous screening" could help to identify unrecognized diabetes and prediabetes.

  16. Corticosterone administration and dietary glucose supplementation enhance fat accumulation in broiler chickens.

    PubMed

    Jiang, K J; Jiao, H C; Song, Z G; Yuan, L; Zhao, J P; Lin, H

    2008-09-01

    1. The effects of exogenous corticosterone administration and glucose supplementation on energy intake, lipid metabolism and fat deposition of broiler chickens were investigated. 2. A total of 144 three-d-old male chickens were randomly assigned to one of the following 4 treatments for 7 d: a low energy diet (10.9 MJ ME/kg, 200 g/kg CP) with or without corticosterone (30 mg/kg diet) and drinking water supplemented with glucose (80 g/l) or saccharine (2 g/l, control). 3. Body weight (BW) gain and breast and thigh muscle yields (% body mass) were all significantly decreased by corticosterone treatment. The relative cumulative feed intake (RCFI) and relative ME intake (RMEI), rather than the feed (FI) or ME intake (MEI) were increased by corticosterone administration. Both feed efficiency (FE) and caloric efficiency (CE) were decreased by corticosterone administration. Corticosterone administration had no obvious effect on water consumption. 4. Glucose supplementation had no influence on BW gain and breast and thigh muscle yield (as % of body mass). FI or RCFI was decreased while MEI or RMEI was increased by glucose supplementation. FE was improved by glucose treatment, whereas CE was reduced. 5. Liver weight and abdominal, cervical and thigh fat deposits were all significantly increased by either corticosterone or glucose treatment. 6. Plasma concentrations of glucose, urate, triglyceride, non-esterified fatty acids (NEFA), very low density lipoprotein and insulin were all significantly increased by corticosterone treatment. Glucose supplementation had no obvious influence on any of the measured plasma parameters except for NEFA, which were significantly increased. 7. Lipoprotein lipase activities in either cervical or abdominal adipose tissues, rather than in thigh fat tissue, were significantly elevated by either glucose or corticosterone treatment.

  17. The trials of Hanna Porn: the campaign to abolish midwifery in Massachusetts.

    PubMed Central

    Declercq, E R

    1994-01-01

    The case of Hanna Porn affords an opportunity to examine how the laws that led to the abolition of midwifery in Massachusetts evolved and were applied to the midwife whose case set the state legal precedent. Mrs Porn served primarily a Finnish-Swedish clientele of wives of laborers. The outcomes of the births she attended appear to have been positive, and she maintained a neonatal mortality rate of less than half that of local physicians. She also repeatedly defied court orders to stop practicing. Her case exemplifies the efforts that occurred nationally to abolish midwifery in the United States. PMID:8203670

  18. The trials of Hanna Porn: the campaign to abolish midwifery in Massachusetts.

    PubMed

    Declercq, E R

    1994-06-01

    The case of Hanna Porn affords an opportunity to examine how the laws that led to the abolition of midwifery in Massachusetts evolved and were applied to the midwife whose case set the state legal precedent. Mrs Porn served primarily a Finnish-Swedish clientele of wives of laborers. The outcomes of the births she attended appear to have been positive, and she maintained a neonatal mortality rate of less than half that of local physicians. She also repeatedly defied court orders to stop practicing. Her case exemplifies the efforts that occurred nationally to abolish midwifery in the United States.

  19. Effectiveness of Botulinum Toxin Administered to Abolish Acquired Nystagmus

    NASA Technical Reports Server (NTRS)

    Leigh, R. John; Tomsak, Robert L.; Grant, Michael P.; Remler, Bernd F.; Yaniglos, Stacy S.; Lystad, Lisa; Dell'Osso, Louis F.

    1992-01-01

    We injected botulinum toxin into the horizontal rectus muscles of the right eyes of two patients who had acquired pendular nystagmus with horizontal, vertical, and torsional components. This treatment successfully abolished the horizontal component of the nystagmus in the injected eye in both patients for approximately 2 months. Both patients showed a small but measurable improvement of vision in the injected eye that may have been limited by coexistent disease of the visual pathways. The vertical and torsional components of the nystagmus persisted in both patients. In one patient, the horizontal component of nystagmus in the noninjected eye increased; we ascribe this finding to plastic-adaptive changes in response to paresis caused by the botulinum toxin. Such plastic-adaptive changes and direct side effects of the injections - such as diplopia and ptosis - may limit the effectiveness of botulinum toxin in the treatment of acquired nystagmus. Neither patient elected to repeat the botulinum treatment.

  20. Properties of a novel thermostable glucose isomerase mined from Thermus oshimai and its application to preparation of high fructose corn syrup.

    PubMed

    Jia, Dong-Xu; Zhou, Lin; Zheng, Yu-Guo

    2017-04-01

    Glucose isomerase (GI) is used in vitro to convert d-glucose to d-fructose, which is capable of commercial producing high fructose corn syrup (HFCS). To manufacture HFCS at elevated temperature and reduce the cost of enriching syrups, novel refractory GIs from Thermoanaerobacterium xylanolyticum (TxGI), Thermus oshimai (ToGI), Geobacillus thermocatenulatus (GtGI) and Thermoanaerobacter siderophilus (TsGI) were screened via genome mining approach. The enzymatic characteristics research showed that ToGI had higher catalytic efficiency and superior thermostability toward d-glucose among the screened GIs. Its optimum temperature reached 95°C and could retain more than 80% of initial activity in the presence of 20mM Mn 2+ at 85°C for 48h. The K m and k cat /K m values for ToGI were 81.46mM and 21.77min -1 mM -1 , respectively. Furthermore, the maximum conversion yield of 400g/L d-glucose to d-fructose at 85°C was 52.16%. Considering its excellent high thermostability and ameliorable application performance, ToGI might be promising for realization of future industrial production of HFCS at elevated temperature. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Noninvasive Monitoring of Blood Glucose with Raman Spectroscopy.

    PubMed

    Pandey, Rishikesh; Paidi, Santosh Kumar; Valdez, Tulio A; Zhang, Chi; Spegazzini, Nicolas; Dasari, Ramachandra Rao; Barman, Ishan

    2017-02-21

    The successful development of a noninvasive blood glucose sensor that can operate reliably over sustained periods of time has been a much sought after but elusive goal in diabetes management. Since diabetes has no well-established cure, control of elevated glucose levels is critical for avoiding severe secondary health complications in multiple organs including the retina, kidney and vasculature. While fingerstick testing continues to be the mainstay of blood glucose detection, advances in electrochemical sensing-based minimally invasive approaches have opened the door for alternate methods that would considerably improve the quality of life for people with diabetes. In the quest for better sensing approaches, optical technologies have surfaced as attractive candidates as researchers have sought to exploit the endogenous contrast of glucose, notably its absorption, scattering, and polarization properties. Vibrational spectroscopy, especially spontaneous Raman scattering, has exhibited substantial promise due to its exquisite molecular specificity and minimal interference of water in the spectral profiles acquired from the blood-tissue matrix. Yet, it has hitherto been challenging to leverage the Raman scattering signatures of glucose for prediction in all but the most basic studies and under the least demanding conditions. In this Account, we discuss the newly developed array of methodologies that address the key challenges in measuring blood glucose accurately using Raman spectroscopy and unlock new prospects for translation to sustained noninvasive measurements in people with diabetes. Owing to the weak intensity of spontaneous Raman scattering, recent research has focused on enhancement of signals from the blood constituents by designing novel excitation-collection geometries and tissue modulation methods while our attempts have led to the incorporation of nonimaging optical elements. Additionally, invoking mass transfer modeling into chemometric algorithms has

  2. Electrochemical studies of biocatalytic anode of sulfonated graphene/ferritin/glucose oxidase layer-by-layer biocomposite films for mediated electron transfer.

    PubMed

    Inamuddin; Haque, Sufia Ul; Naushad, Mu

    2016-06-01

    In this study, a bioanode was developed by using layer-by-layer (LBL) assembly of sulfonated graphene (SG)/ferritin (Frt)/glucose oxidase (GOx). The SG/Frt biocomposite was used as an electron transfer elevator and mediator, respectively. Glucose oxidase (GOx) from Aspergillus niger was applied as a glucose oxidation biocatalyst. The electrocatalytic oxidation of glucose using GOx modified electrode increases with an increase in the concentration of glucose in the range of 10-50mM. The electrochemical measurements of the electrode was carried out by using cyclic voltammetry (CV) at different scan rates (20-100mVs(-1)) in 30mM of glucose solution prepared in 0.3M potassium ferrocyanide (K4Fe(CN)6) and linear sweep voltammetry (LSV). A saturation current density of 50±2mAcm(-2) at a scan rate of 100mVs(-1) for the oxidation of 30Mm glucose is achieved. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Carbon Disulfide (CS2) Interference in Glucose Metabolism from Unconventional Oil and Gas Extraction and Processing Emissions.

    PubMed

    Rich, Alisa L; Patel, Jay T; Al-Angari, Samiah S

    2016-01-01

    Carbon disulfide (CS2) has been historically associated with the manufacturing of rayon, cellophane, and carbon tetrachloride production. This study is one of the first to identify elevated atmospheric levels of CS2 above national background levels and its mechanisms to dysregulate normal glucose metabolism. Interference in glucose metabolism can indirectly cause other complications (diabetes, neurodegenerative disease, and retinopathy), which may be preventable if proper precautions are taken. Rich et al found CS2 and 12 associated sulfide compounds present in the atmosphere in residential areas where unconventional shale oil and gas extraction and processing operations were occurring. Ambient atmospheric concentrations of CS2 ranged from 0.7 parts per billion by volume (ppbv) to 103 ppbv over a continuous 24-hour monitoring period. One-hour ambient atmospheric concentrations ranged from 3.4 ppbv to 504.6 ppbv. Using the U.S. Environmental Protection Agency Urban Air Toxic Monitoring Program study as a baseline comparison for atmospheric CS2 concentrations found in this study, it was determined that CS2 atmospheric levels were consistently elevated in areas where unconventional oil and gas extraction and processing occurred. The mechanisms by which CS2 interferes in normal glucose metabolism by dysregulation of the tryptophan metabolism pathway are presented in this study. The literature review found an increased potential for alteration of normal glucose metabolism in viscose rayon occupational workers exposed to CS2. Occupational workers in the energy extraction industry exposed to CS2 and other sulfide compounds may have an increased potential for glucose metabolism interference, which has been an indicator for diabetogenic effect and other related health impacts. The recommendation of this study is for implementation of regular monitoring of blood glucose levels in CS2-exposed populations as a preventative health measure.

  4. β-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL.

    PubMed

    Nyirjesy, Sarah C; Sheikh, Saba; Hadjiliadis, Denis; De Leon, Diva D; Peleckis, Amy J; Eiel, Jack N; Kubrak, Christina; Stefanovski, Darko; Rubenstein, Ronald C; Rickels, Michael R; Kelly, Andrea

    2018-06-08

    Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 mg/dL and 2-hour <140 mg/dL [7.8 mmol/L]; n = 13), PI-EGI (1-hour ≥155 mg/dL and 2-hour <140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis-related diabetes, CFRD: 2-hour ≥200 mg/dL; n = 8) participated. Post-prandial glucose tolerance and insulin secretion, and β-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTTs), and glucose-potentiated arginine (GPA) tests, respectively. PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P < .05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to GPA (P < .01 vs PI-NGT), measures of β-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P < .05 vs PI-NGT), and correlated with 1-hour glucose in PI-CF (P < .01). PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

    PubMed Central

    Pachanski, Michele J.; Kirkland, Melissa E.; Kosinski, Daniel T.; Mane, Joel; Cheewatrakoolpong, Boonlert; Xue, Jiyan; Szeto, Daphne; Forrest, Gail; Miller, Corin; Bunzel, Michelle; Plummer, Christopher W.; Chobanian, Harry R.; Miller, Michael W.; Souza, Sarah; Thomas-Fowlkes, Brande S.; Ogawa, Aimie M.; Weinglass, Adam B.; Di Salvo, Jerry; Li, Xiaoyan; Feng, Yue; Tatosian, Daniel A.; Howard, Andrew D.; Colletti, Steven L.

    2017-01-01

    GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient. PMID:29053717

  6. Abnormal oral glucose tolerance and glucose malabsorption after vagotomy and pyloroplasty. A tracer method for measuring glucose absorption rates

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Radziuk, J.; Bondy, D.C.

    1982-11-01

    The mechanisms underlying the abnormal glucose tolerance in patients who had undergone vagotomy and pyloroplasty were investigated by measuring the rates of absorption of ingested glucose and the clearance rate of glucose using tracer methods. These methods are based on labeling a 100-g oral glucose load with (1-/sup 14/C)glucose and measuring glucose clearance using plasma levels of infused (3-/sup 3/H)glucose. The rate of appearance of both ingested and total glucose is then calculated continuously using a two-compartment model of glucose kinetics. It was found that about 30% of the ingested glucose (100 g) failed to appear in the systemic circulation.more » That this was due to malabsorption was confirmed using breath-hydrogen analysis. The absorption period is short (101 +/- 11 min) compared with normal values but the clearance of glucose is identical to that in control subjects, and it peaks 132 +/- 7 min after glucose loading. The peak plasma insulin values were more than four times higher in patients than in normal subjects, and this may afford an explanation of rates of glucose clearance that are inappropriate for the short absorption period. The combination of glucose malabsorption and this clearance pattern could yield the hypoglycemia that may be observed in patients after gastric surgery.« less

  7. 77 FR 11383 - Prevailing Rate Systems; Abolishment of Monmouth, NJ, as a Nonappropriated Fund Federal Wage...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-27

    ...;Prices of new books are listed in the first FEDERAL REGISTER issue of each #0;week. #0; #0; #0; #0;#0... abolish the Monmouth, New Jersey, nonappropriated fund (NAF) Federal Wage System (FWS) wage area and... closure of Fort Monmouth left the Monmouth wage area without an activity having the capability to conduct...

  8. Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial.

    PubMed

    Shepherd, Anthony I; Wilkerson, Daryl P; Fulford, Jon; Winyard, Paul G; Benjamin, Nigel; Shore, Angela C; Gilchrist, Mark

    2016-09-01

    Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults. Copyright © 2016 the American Physiological Society.

  9. Effect of nitrate supplementation on hepatic blood flow and glucose homeostasis: a double-blind, placebo-controlled, randomized control trial

    PubMed Central

    Wilkerson, Daryl P.; Fulford, Jon; Winyard, Paul G.; Benjamin, Nigel; Shore, Angela C.

    2016-01-01

    Nitric oxide alters gastric blood flow, improves vascular function, and mediates glucose uptake within the intestines and skeletal muscle. Dietary nitrate, acting as a source of nitric oxide, appears to be a potential low-cost therapy that may help maintain glucose homeostasis. In a randomized, double-blind, placebo-controlled crossover study, 31 young and older adult participants had a standardized breakfast, supplemented with either nitrate-rich beetroot juice (11.91 mmol nitrate) or nitrate-depleted beetroot juice as placebo (0.01 mmol nitrate). MRI was used to assess apparent diffusion coefficient (ADC), portal vein flux, and velocity. Plasma glucose, incretin, and C-peptide concentrations and blood pressure were assessed. Outcome variables were measured at baseline and hourly for 3 h. Compared with a placebo, beetroot juice resulted in a significant elevation in plasma nitrate and plasma nitrite concentration. No differences were seen for the young or older adult cohorts between placebo and beetroot juice for ADC, or portal vein flux. There was an interaction effect in the young adults between visits for portal vein velocity. Nitrate supplementation did not reduce plasma glucose, active GLP-1, total GLP-1, or plasma C-peptide concentrations for the young or older adult cohorts. Despite a significant elevation in plasma nitrite concentration following an acute dose of (11.91 mmol) nitrate, there was no effect on hepatic blood flow, plasma glucose, C-peptide, or incretin concentration in healthy adults. PMID:27418682

  10. Influence of Amino Acids in Dairy Products on Glucose Homeostasis: The Clinical Evidence.

    PubMed

    Chartrand, Dominic; Da Silva, Marine S; Julien, Pierre; Rudkowska, Iwona

    2017-06-01

    Dairy products have been hypothesized to protect against type 2 diabetes because of their high content of whey proteins, rich in branched-chain amino acids (BCAAs) - leucine, isoleucine and valine - and lysine, which may decrease postprandial glucose responses and stimulate insulin secretion. Paradoxically, epidemiologic studies also show that higher levels of plasma BCAAs have been linked to insulin resistance and type 2 diabetes. Therefore, the objective was to review the recent clinical evidence concerning the intake of amino acids found in dairy proteins so as to determine their impact on glucose homeostasis in healthy persons and in those with prediabetes and type 2 diabetes. Clinical studies have reported that the major dairy amino acids, namely, leucine, isoleucine, glutamine, phenylalanine, proline and lysine, have beneficial effects on glucose homeostasis. Yet the reported doses of amino acids investigated are too elevated to be reached through adequate dairy product intake. The minor dairy amino acids, arginine and glycine, may improve glucose homeostasis by improving other risk factors for type 2 diabetes. Further, the combination of amino acids may also improve glucose-related outcomes, suggesting additive or synergistic effects. Nevertheless, additional long-term studies in individuals with prediabetes and type 2 diabetes are needed to ascertain the benefits for glucose homeostasis of amino acids found in dairy foods. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  11. Personality traits and abnormal glucose regulation in middle-aged Swedish men and women.

    PubMed

    Eriksson, Anna-Karin; Gustavsson, J Petter; Hilding, Agneta; Granath, Fredrik; Ekbom, Anders; Ostenson, Claes-Göran

    2012-01-01

    To examine associations between personality and abnormal glucose regulation. This cross-sectional study comprised 2152 men and 3143 women (43-66 years). Oral glucose tolerance test identified 316 men and 213 women with previously unknown impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG+IGT, or type 2 diabetes. Personality traits antagonism (low agreeableness), impulsivity (low conscientiousness), hedonic capacity (high extraversion), negative affectivity (high neuroticism) and alexithymia (low openness) were measured by a self-report inventory. Based on distribution of scores, responses were divided into "low" (<1 SD), "middle" (±1 SD) and "high" (>1 SD). Middle groups were considered reference groups. Prevalence odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. In men, OR for low antagonism was 0.3 (CI 0.2-0.6) (age- and multi-adjusted models) while in women, neither high nor low antagonism was associated to abnormal glucose regulation. Men and women with high hedonic capacity had ORs 0.5 (0.3-0.9) and 0.6 (0.4-1.0), respectively (age- and multi-adjusted models). The other scales illustrated no significant associations. No elevated risk of abnormal glucose regulation was observed for deviating scores on personality scales. Instead, reduced risks were indicated in men with low antagonism, and in men and women with high hedonic capacity. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Characterization of Renal Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes

    PubMed Central

    DeFronzo, Ralph A.; Hompesch, Marcus; Kasichayanula, Sreeneeranj; Liu, Xiaoni; Hong, Ying; Pfister, Marc; Morrow, Linda A.; Leslie, Bruce R.; Boulton, David W.; Ching, Agatha; LaCreta, Frank P.; Griffen, Steven C.

    2013-01-01

    OBJECTIVE To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS Subjects with type 2 diabetes (n = 12) and matched healthy subjects (n = 12) underwent pancreatic/SHC (plasma glucose range 5.5–30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine. PMID:23735727

  13. Evidence of extensive plasma glucose recycling following a glucose load in seabass.

    PubMed

    Rito, João; Viegas, Ivan; Pardal, Miguel A; Jones, John G

    2017-09-01

    Seabass and other carnivorous fish are highly dependent on gluconeogenesis from dietary amino acids to maintain glycemia. Glucose recycling (glucose→C3-intermediate→glucose) may potentiate the effects of glucose administration in sparing amino acid gluconeogenesis. To date, very few measurements of glucose recycling have been reported in fish. Thus, to determine the extent of glucose recycling following a glycemic challenge, juvenile seabass were given an intraperitoneal glucose load (2gkg -1 ) enriched with [U- 13 C]glucose. 13 C NMR analysis of plasma glucose 13 C-isotopomers was used to determine the fractional contributions of glucose derived directly from the load versus that from glucose recycling at 48h after the load. Both fed and 21-day fasted fish (20 per condition) were studied. In fasted fish, 18±4% of plasma glucose was directly derived from the load while 13±2% was derived from glucose recycling. In fed fish, the load accounted for 6±1% of plasma glucose levels while glucose recycling contributed 16±4%. 13 C NMR analysis of plasma lactate revealed 13 C-isotopomers corresponding to the expected C3-intermediates of peripheral [U- 13 C]glucose catabolism indicating that circulating lactate was a key intermediate in glucose carbon recycling under these conditions. In conclusion, glucose recycling was shown to contribute a significant portion of plasma glucose levels in both fed and fasted seabass 48h after an intraperitoneal glucose challenge and circulating lactate was shown to be an intermediate of this pathway. Copyright © 2017. Published by Elsevier Inc.

  14. Antimetabolic Effects of Polyphenols in Breast Cancer Cells: Focus on Glucose Uptake and Metabolism.

    PubMed

    Keating, Elisa; Martel, Fátima

    2018-01-01

    In the last years, metabolic reprogramming became a new key hallmark of tumor cells. One of its components is a deviant energetic metabolism, known as Warburg effect-an aerobic lactatogenesis- characterized by elevated rates of glucose uptake and consumption with high-lactate production even in the presence of oxygen. Because many cancer cells display a greater sensitivity to glucose deprivation-induced cytotoxicity than normal cells, inhibitors of glucose cellular uptake (facilitative glucose transporter 1 inhibitors) and oxidative metabolism (glycolysis inhibitors) are potential therapeutic targets in cancer treatment. Polyphenols, abundantly contained in fruits and vegetables, are dietary components with an established protective role against cancer. Several molecular mechanisms are involved in the anticancer effect of polyphenols, including effects on apoptosis, cell cycle regulation, plasma membrane receptors, signaling pathways, and epigenetic mechanisms. Additionally, inhibition of glucose cellular uptake and metabolism in cancer cell lines has been described for several polyphenols, and this effect was shown to be associated with their anticarcinogenic effect. This work will review data showing an antimetabolic effect of polyphenols and its involvement in the chemopreventive/chemotherapeutic potential of these dietary compounds, in relation to breast cancer.

  15. Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

    PubMed Central

    Morris, Christopher J.; Yang, Jessica N.; Garcia, Joanna I.; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M.; Shea, Steven A.; Scheer, Frank A. J. L.

    2015-01-01

    Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers. PMID:25870289

  16. The Effect of PCSK1 Variants on Waist, Waist-Hip Ratio and Glucose Metabolism Is Modified by Sex and Glucose Tolerance Status

    PubMed Central

    Gjesing, Anette P.; Vestmar, Marie A.; Jørgensen, Torben; Heni, Martin; Holst, Jens J.; Witte, Daniel R.; Hansen, Torben; Pedersen, Oluf

    2011-01-01

    Background We aimed to evaluate the effects of the G-allele of rs6232 and the C-allele of rs6235 within PCSK1 on measures of body fat and glucose homeostasis in Danish individuals and to assess interactions of genotypes with age, sex and glucose tolerance status. Data were included in meta-analyses of additional Europeans. Methodology/Principal Findings Rs6232 and rs6235 were genotyped in 6,164 Danes from the Inter99 study of middle-aged people. Results from these analyses were combined with previously published studies in meta-analyses of a total of 27,786 individuals. The impact of the variants was also investigated in a subset of 62 glucose-tolerant men during a meal challenge including measures of serum incretins. In men we found an effect on body composition in sex-stratified analyses where the rs6235 C-allele conferred an increased waist circumference of 0.8 cm per allele (0.2–1.5, p = 0.008) and increased waist-to-hip ratio of 0.004 (0.0005–0.008, p = 0.027). In the meta-analyses where men and women were combined, the rs6232 G-allele associated with increased waist-to-hip ratio (p = 0.02) and the rs6235 C-allele associated with increased waist circumference (p = 0.01). Furthermore, the rs6235 C-allele was associated nominally with a 0.6% (0.1–1%, p = 0.01) reduction in fasting glucose, it interacted with glucose tolerance status for traits related to glucose metabolism and analysis among individuals having abnormal glucose tolerance revealed a 5% (−0.7–9%, p = 0.02) elevated level of acute insulin response for this variant. Finally, we found that the rs6232 G-allele associated with higher levels of GLP-1, GLP-2 and glucagon and that the rs6235 C-allele associated with higher levels of GIP and glucagon during a meal-test. Conclusions/Significance PCSK1 rs6232 G-allele and rs6235 C-allele have an effect on body composition which may be modified by sex, whereas the effect of rs6235 C-allele on fasting and stimulated circulating

  17. Brain metabolism in autism. Resting cerebral glucose utilization rates as measured with positron emission tomography

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rumsey, J.M.; Duara, R.; Grady, C.

    The cerebral metabolic rate for glucose was studied in ten men (mean age = 26 years) with well-documented histories of infantile autism and in 15 age-matched normal male controls using positron emission tomography and (F-18) 2-fluoro-2-deoxy-D-glucose. Positron emission tomography was completed during rest, with reduced visual and auditory stimulation. While the autistic group as a whole showed significantly elevated glucose utilization in widespread regions of the brain, there was considerable overlap between the two groups. No brain region showed a reduced metabolic rate in the autistic group. Significantly more autistic, as compared with control, subjects showed extreme relative metabolic ratesmore » (ratios of regional metabolic rates to whole brain rates and asymmetries) in one or more brain regions.« less

  18. Dietary fructose and glucose differentially affect lipid and glucose homeostasis.

    PubMed

    Schaefer, Ernst J; Gleason, Joi A; Dansinger, Michael L

    2009-06-01

    Absorbed glucose and fructose differ in that glucose largely escapes first-pass removal by the liver, whereas fructose does not, resulting in different metabolic effects of these 2 monosaccharides. In short-term controlled feeding studies, dietary fructose significantly increases postprandial triglyceride (TG) levels and has little effect on serum glucose concentrations, whereas dietary glucose has the opposite effects. When dietary glucose and fructose have been directly compared at approximately 20-25% of energy over a 4- to 6-wk period, dietary fructose caused significant increases in fasting TG and LDL cholesterol concentrations, whereas dietary glucose did not, but dietary glucose did increase serum glucose and insulin concentrations in the postprandial state whereas dietary fructose did not. When fructose at 30-60 g ( approximately 4-12% of energy) was added to the diet in the free-living state, there were no significant effects on lipid or glucose biomarkers. Sucrose and high-fructose corn syrup (HFCS) contain approximately equal amounts of fructose and glucose and no metabolic differences between them have been noted. Controlled feeding studies at more physiologic dietary intakes of fructose and glucose need to be conducted. In our view, to decrease the current high prevalence of obesity, dyslipidemia, insulin resistance, and diabetes, the focus should be on restricting the intake of excess energy, sucrose, HFCS, and animal and trans fats and increasing exercise and the intake of vegetables, vegetable oils, fish, fruit, whole grains, and fiber.

  19. Sleep duration and disorders in pregnancy: implications for glucose metabolism and pregnancy outcomes

    PubMed Central

    O’Keeffe, M; St-Onge, M-P

    2013-01-01

    Humans have an innate requirement for sleep that is intrinsically governed by circadian and endocrine systems. More recently, reduced sleep duration has gained significant attention for its possible contribution to metabolic dysfunction. Significant evidence suggests that reduced sleep duration may elevate the risk for impaired glucose functioning, insulin resistance and type 2 diabetes. However, to date, few studies have determined the implications of reduced sleep duration with regard to glucose control during pregnancy. With the high prevalence of overweight and obesity in women of reproductive age, the occurrence of gestational diabetes mellitus (GDM) is increasing. GDM results in elevated risk of maternal and fetal complications, as well as increased risk of type 2 diabetes postpartum. Infants born to women with GDM also carry a life-long risk of obesity and type 2 diabetes. The impact of reduced sleep on glucose management during pregnancy has not yet been fully assessed and a paucity of literature currently exits. Herein, we review the association between reduced sleep and impaired carbohydrate metabolism and propose how reduced sleep during pregnancy may result in further dysfunction of the carbohydrate axis. A particular focus will be given to sleep-disordered breathing, as well as GDM-complicated pregnancies. Putative mechanisms of action by which reduced sleep may adversely affect maternal and infant outcomes are also discussed. Finally, we will outline important research questions that need to be addressed. PMID:22945608

  20. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

    PubMed

    Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

  1. Estimating Plasma Glucose from Interstitial Glucose: The Issue of Calibration Algorithms in Commercial Continuous Glucose Monitoring Devices

    PubMed Central

    Rossetti, Paolo; Bondia, Jorge; Vehí, Josep; Fanelli, Carmine G.

    2010-01-01

    Evaluation of metabolic control of diabetic people has been classically performed measuring glucose concentrations in blood samples. Due to the potential improvement it offers in diabetes care, continuous glucose monitoring (CGM) in the subcutaneous tissue is gaining popularity among both patients and physicians. However, devices for CGM measure glucose concentration in compartments other than blood, usually the interstitial space. This means that CGM need calibration against blood glucose values, and the accuracy of the estimation of blood glucose will also depend on the calibration algorithm. The complexity of the relationship between glucose dynamics in blood and the interstitial space, contrasts with the simplistic approach of calibration algorithms currently implemented in commercial CGM devices, translating in suboptimal accuracy. The present review will analyze the issue of calibration algorithms for CGM, focusing exclusively on the commercially available glucose sensors. PMID:22163505

  2. Synthesis of glycogen from fructose in the presence of elevated levels of glycogen phosphorylase a in rat hepatocytes.

    PubMed

    Ciudad, C J; Massagué, J; Salavert, A; Guinovart, J J

    1980-03-20

    Incubation of hepatocytes with glucose promoted the increase in the glycogen synthase (-glucose 6-phosphate/+glucose 6-phosphate) activity ratio, the decrease in the levels of phosphorylase a and a marked increase in the intracellular glycogen level. Incubation with fructose alone promoted the simultaneous activation of glycogen synthase and increase in the levels of phosphorylase a. Strikingly, glycogen deposition occurred in spite of the elevated levels of phosphorylase a. When glucose and fructose were added to the media the activation of glycogen synthase was always higher than when the hexoses were added separately. On the other hand the effects on glycogen phosphorylase were a function of the relative concentrations of both sugars. Inactivation of glycogen phosphorylase occurred when the fructose to glucose ratio was low while activation took place when the ratio was high. The simultaneous presence of glucose and fructose resulted, in all cases, in an enhancement in the deposition of glycogen. The effects described were not limited to fructose as D-glyceraldehyde, dihydroxyacetone, L-sorbose, D-tagatose and sorbitol, compounds metabolically related to fructose, provoked the same behaviour.

  3. Prolonged Baroreflex Activation Abolishes Salt-Induced Hypertension After Reductions in Kidney Mass.

    PubMed

    Hildebrandt, Drew A; Irwin, Eric D; Lohmeier, Thomas E

    2016-12-01

    Chronic electric activation of the carotid baroreflex produces sustained reductions in sympathetic activity and arterial pressure and is currently being evaluated for therapy in patients with resistant hypertension. However, patients with significant impairment of renal function have been largely excluded from clinical trials. Thus, there is little information on blood pressure and renal responses to baroreflex activation in subjects with advanced chronic kidney disease, which is common in resistant hypertension. Changes in arterial pressure and glomerular filtration rate were determined in 5 dogs after combined unilateral nephrectomy and surgical excision of the poles of the remaining kidney to produce ≈70% reduction in renal mass. After control measurements, sodium intake was increased from ≈45 to 450 mol/d. While maintained on high salt, animals experienced increases in mean arterial pressure from 102±4 to 121±6 mm Hg and glomerular filtration rate from 40±2 to 45±2 mL/min. During 7 days of baroreflex activation, the hypertension induced by high salt was abolished (103±6 mm Hg) along with striking suppression of plasma norepinephrine concentration from 139±21 to 81±9 pg/mL, but despite pronounced blood pressure lowering, there were no significant changes in glomerular filtration rate (43±2 mL/min). All variables returned to prestimulation values during a recovery period. These findings indicate that after appreciable nephron loss, chronic suppression of central sympathetic outflow by baroreflex activation abolishes hypertension induced by high salt intake. The sustained antihypertensive effects of baroreflex activation occur without significantly compromising glomerular filtration rate in remnant nephrons. © 2016 American Heart Association, Inc.

  4. Postprandial glucose response to selected tropical fruits in normal glucose-tolerant Nigerians.

    PubMed

    Edo, A; Eregie, A; Adediran, O; Ohwovoriole, A; Ebengho, S

    2011-01-01

    The glycemic response to commonly eaten fruits in Nigeria has not been reported. Therefore, this study assessed the plasma glucose response to selected fruits in Nigeria. Ten normal glucose-tolerant subjects randomly consumed 50 g carbohydrate portions of three fruits: banana (Musa paradisiaca), pineapple (Ananus comosus), and pawpaw (Carica papaya), and a 50-g glucose load at 1-week intervals. Blood samples were collected in the fasting state and half-hourly over a 2-h period post-ingestion of the fruits or glucose. The samples were analyzed for plasma glucose concentrations. Plasma glucose responses were assessed by the peak plasma glucose concentration, maximum increase in plasma glucose, 2-h postprandial plasma glucose level, and incremental area under the glucose curve and glycemic index (GI). The results showed that the blood glucose response to these three fruits was similar in terms of their incremental areas under the glucose curve, maximum increase in plasma glucose, and glycemic indices (GIs). The 2-h postprandial plasma glucose level of banana was significantly higher than that of pineapple, P < 0.025. The mean ± SEM GI values were as follows: pawpaw; 86 ± 26.8%; banana, 75.1 ± 21.8%; pineapple, 64.5 ± 11.3%. The GI of glucose is taken as 100. The GI of pineapple was significantly lower than that of glucose (P < 0.05). Banana, pawpaw, and pineapple produced a similar postprandial glucose response. Measured portions of these fruits may be used as fruit exchanges with pineapple having the most favorable glycemic response.

  5. Dissociable Behavioral, Physiological and Neural Effects of Acute Glucose and Fructose Ingestion: A Pilot Study

    PubMed Central

    Schmidt, André; Zimak, Nina; Peterli, Ralph; Beglinger, Christoph; Borgwardt, Stefan

    2015-01-01

    Previous research has revealed that glucose and fructose ingestion differentially modulate release of satiation hormones. Recent studies have begun to elucidate brain-gut interactions with neuroimaging approaches such as magnetic resonance imaging (MRI), but the neural mechanism underlying different behavioral and physiological effects of glucose and fructose are unclear. In this paper, we have used resting state functional MRI to explore whether acute glucose and fructose ingestion also induced dissociable effects in the neural system. Using a cross-over, double-blind, placebo-controlled design, we compared resting state functional connectivity (rsFC) strengths within the basal ganglia/limbic network in 12 healthy lean males. Each subject was administered fructose, glucose and placebo on three separate occasions. Subsequent correlation analysis was used to examine relations between rsFC findings and plasma concentrations of satiation hormones and subjective feelings of appetite. Glucose ingestion induced significantly greater elevations in plasma glucose, insulin, GLP-1 and GIP, while feelings of fullness increased and prospective food consumption decreased relative to fructose. Furthermore, glucose increased rsFC of the left caudatus and putamen, precuneus and lingual gyrus more than fructose, whereas within the basal ganglia/limbic network, fructose increased rsFC of the left amygdala, left hippocampus, right parahippocampus, orbitofrontal cortex and precentral gyrus more than glucose. Moreover, compared to fructose, the increased rsFC after glucose positively correlated with the glucose-induced increase in insulin. Our findings suggest that glucose and fructose induce dissociable effects on rsFC within the basal ganglia/limbic network, which are probably mediated by different insulin levels. A larger study would be recommended in order to confirm these findings. PMID:26107810

  6. Regulation of glucose-dependent gene expression by the RNA helicase Dbp2 in Saccharomyces cerevisiae.

    PubMed

    Beck, Zachary T; Cloutier, Sara C; Schipma, Matthew J; Petell, Christopher J; Ma, Wai Kit; Tran, Elizabeth J

    2014-11-01

    Cellular homeostasis requires a fine balance between energy uptake, utilization, and growth. Dbp2 is a member of the DEAD-box protein family in Saccharomyces cerevisiae with characterized ATPase and helicase activity in vitro. DEAD-box RNA helicases are a class of enzymes that utilize ATP hydrolysis to remodel RNA and/or RNA-protein (RNP) composition. Dbp2 has been proposed to utilize its helicase activity in vivo to promote RNA-protein complex assembly of both messenger (m)RNAs and long noncoding (lnc)RNAs. Previous work from our laboratory demonstrated that loss of DBP2 enhances the lncRNA-dependent transcriptional induction of the GAL genes by abolishing glucose-dependent repression. Herein, we report that either a carbon source switch or glucose deprivation results in rapid export of Dbp2 to the cytoplasm. Genome-wide RNA sequencing identified a new class of antisense hexose transporter transcripts that are specifically upregulated upon loss of DBP2. Further investigation revealed that both sense and antisense hexose transporter (HXT) transcripts are aberrantly expressed in DBP2-deficient cells and that this expression pathway can be partially mimicked in wild-type cells by glucose depletion. We also find that Dbp2 promotes ribosome biogenesis and represses alternative ATP-producing pathways, as loss of DBP2 alters the transcript levels of ribosome biosynthesis (snoRNAs and associated proteins) and respiration gene products. This suggests that Dbp2 is a key integrator of nutritional status and gene expression programs required for energy homeostasis. Copyright © 2014 by the Genetics Society of America.

  7. Glucose-sensitive silicone hydrogel contact lens toward tear glucose monitoring.

    PubMed

    Badugu, Ramachandram; Reece, Edward Albert; Lakowicz, Joseph R

    2018-05-01

    Accurate and reliable monitoring of blood glucose is needed for the treatment of diabetes, which has many challenges, including lack of patient compliance. Measuring tear glucose is an alternative to traditional finger-stick tests used to track blood sugar levels, but glucose sensing using tears has yet to be achieved. We report a methodology for possible tear glucose monitoring using glucose-sensitive silicone hydrogel (SiHG) contact lenses, the primary type of lenses available in today's market. Initially, we assessed the interpenetrating polymer network, with nearly pure silicone and water regions, existing in the SiHGs using a polarity-sensitive probe Prodan. We then synthesized a glucose-sensitive fluorophore Quin-C18 with a hydrophobic side chain for localization of probe at the interfacial region. Using our glucose-sensing contact lens, we were able to measure varying concentrations of glucose in an in-vitro system. The Quin-C18 strongly bound to the lenses with insignificant leaching even after multiple rinses. The lenses displayed a similar response to glucose after three months of storage in water. This study demonstrates that it may be possible to develop a contact lens for continuous glucose monitoring in the near term, using our concept of fluorophore binding at the silicone-water interface. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

  8. Identification of the signals for glucose-induced insulin secretion in INS1 (832/13) β-cells using metformin-induced metabolic deceleration as a model.

    PubMed

    Lamontagne, Julien; Al-Mass, Anfal; Nolan, Christopher J; Corkey, Barbara E; Madiraju, S R Murthy; Joly, Erik; Prentki, Marc

    2017-11-24

    Metabolic deceleration in pancreatic β-cells is associated with inhibition of glucose-induced insulin secretion (GIIS), but only in the presence of intermediate/submaximal glucose concentrations. Here, we used acute metformin treatment as a tool to induce metabolic deceleration in INS1 (832/13) β-cells, with the goal of identifying key pathways and metabolites involved in GIIS. Metabolites and pathways previously implicated as signals for GIIS were measured in the cells at 2-25 mm glucose, with or without 5 mm metformin. We defined three criteria to identify candidate signals: 1) glucose-responsiveness, 2) sensitivity to metformin-induced inhibition of the glucose effect at intermediate glucose concentrations, and 3) alleviation of metformin inhibition by elevated glucose concentrations. Despite the lack of recovery from metformin-induced impairment of mitochondrial energy metabolism (glucose oxidation, O 2 consumption, and ATP production), insulin secretion was almost completely restored at elevated glucose concentrations. Meeting the criteria for candidates involved in promoting GIIS were the following metabolic indicators and metabolites: cytosolic NAD + /NADH ratio (inferred from the dihydroxyacetone phosphate:glycerol-3-phosphate ratio), mitochondrial membrane potential, ADP, Ca 2+ , 1-monoacylglycerol, diacylglycerol, malonyl-CoA, and HMG-CoA. On the contrary, most of the purine and nicotinamide nucleotides, acetoacetyl-CoA, H 2 O 2 , reduced glutathione, and 2-monoacylglycerol were not glucose-responsive. Overall these results underscore the significance of mitochondrial energy metabolism-independent signals in GIIS regulation; in particular, the candidate lipid signaling molecules 1-monoacylglycerol, diacylglycerol, and malonyl-CoA; the predominance of K ATP /Ca 2+ signaling control by low ADP·Mg 2+ rather than by high ATP levels; and a role for a more oxidized state (NAD + /NADH) in the cytosol during GIIS that favors high glycolysis rates. © 2017 by

  9. Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

    PubMed Central

    Hirvonen, Jussi; Virtanen, Kirsi A.; Nummenmaa, Lauri; Hannukainen, Jarna C.; Honka, Miikka-Juhani; Bucci, Marco; Nesterov, Sergey V.; Parkkola, Riitta; Rinne, Juha; Iozzo, Patricia; Nuutila, Pirjo

    2011-01-01

    OBJECTIVE Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. PMID:21270256

  10. Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

    PubMed

    Chichger, Havovi; Cleasby, Mark E; Srai, Surjit K; Unwin, Robert J; Debnam, Edward S; Marks, Joanne

    2016-06-01

    What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC

  11. A Paradoxical Effect of Presession Attention on Stereotypy: Antecedent Attention as an Establishing, Not an Abolishing, Operation

    ERIC Educational Resources Information Center

    Roantree, Christina F.; Kennedy, Craig H.

    2006-01-01

    Previous studies have shown that presession attention for problem behavior can serve as an abolishing operation when attention functions as a positive reinforcer. In the current study, we show that the stereotypy of a child with severe disabilities was undifferentiated during standard analogue functional analysis conditions. However, when…

  12. Progesterone receptor knockout mice have an improved glucose homeostasis secondary to -cell proliferation

    NASA Astrophysics Data System (ADS)

    Picard, Frédéric; Wanatabe, Mitsuhiro; Schoonjans, Kristina; Lydon, John; O'Malley, Bert W.; Auwerx, Johan

    2002-11-01

    Gestational diabetes coincides with elevated circulating progesterone levels. We show that progesterone accelerates the progression of diabetes in female db/db mice. In contrast, RU486, an antagonist of the progesterone receptor (PR), reduces blood glucose levels in both female WT and db/db mice. Furthermore, female, but not male, PR-/- mice had lower fasting glycemia than PR+/+ mice and showed higher insulin levels on glucose injection. Pancreatic islets from female PR-/- mice were larger and secreted more insulin consequent to an increase in -cell mass due to an increase in -cell proliferation. These findings demonstrate an important role of progesterone signaling in insulin release and pancreatic function and suggest that it affects the susceptibility to diabetes.

  13. Elevated α-Hydroxybutyrate and Branched-Chain Amino Acid Levels Predict Deterioration of Glycemic Control in Adolescents.

    PubMed

    Tricò, Domenico; Prinsen, Hetty; Giannini, Cosimo; de Graaf, Robin; Juchem, Christoph; Li, Fangyong; Caprio, Sonia; Santoro, Nicola; Herzog, Raimund I

    2017-07-01

    Traditional risk factors for type 2 diabetes mellitus are weak predictors of changes in glucose tolerance and insulin sensitivity in youth. To identify early metabolic features of insulin resistance (IR) in youth and whether they predict deterioration of glycemic control. A cross-sectional and longitudinal study was conducted at the Yale Pediatric Obesity Clinic. Concentrations of α-hydroxybutyrate, β-hydroxybutyrate, lactate, and branched-chain amino acids (BCAAs) were measured by nuclear magnetic resonance spectroscopy in 78 nondiabetic adolescents during an oral glucose tolerance test (OGTT). Associations between baseline metabolic alterations and longitudinal changes in glucose control were tested in 16 subjects after a mean follow-up of 2.3 years. The relationship between metabolite levels, parameters of IR, and glycemic control, and their progression over time. Elevated fasting α-hydroxybutyrate levels were observed in adolescents with reduced insulin sensitivity after adjusting for age, sex, ethnicity, Tanner stage, and body mass index z-score (P = 0.014). Plasma α-hydroxybutyrate and BCAAs were increased throughout the course of the OGTT in this group (P < 0.03). Notably, borderline IR was associated with a progressive α-hydroxybutyrate decrease from elevated baseline concentrations to normal levels (P = 0.02). Increased baseline α-hydroxybutyrate concentrations were further associated with progressive worsening of glucose tolerance and disposition index. α-Hydroxybutyrate and BCAA concentrations during an OGTT characterize insulin-resistant youth and predict worsening of glycemic control. These findings provide potential biomarkers for risk assessment of type 2 diabetes and new insights into IR pathogenesis. Copyright © 2017 Endocrine Society

  14. Effect of chromium chloride supplementation on glucose tolerance and serum lipids including high-density lipoprotein of adult men.

    PubMed

    Riales, R; Albrink, M J

    1981-12-01

    Chromium deficiency may cause insulin resistance, hyperinsulinemia, impaired glucose tolerance, and hyperlipidemia, recovered by chromium supplementation. The effect of chromium supplementation on serum lipids and glucose tolerance was tested in a double-blind 12-wk study of 23 healthy adult men aged 31 to 60 yr. Either 200 micrograms trivalent chromium in 5 ml water (Cr) or 5 ml plain water (W) was ingested daily 5 days each week. Half the subjects volunteered for glucose tolerance tests with insulin levels. At 12 wk high-density lipoprotein cholesterol increased in the Cr group from 35 to 39 mg/dl (p less than 0.05) but did not change in the water group (34 mg/dl). The largest increase in high-density lipoprotein cholesterol and decreases in insulin and glucose were found in those subjects having normal glucose levels together with elevated insulin levels at base-line. The data are thus consistent with the hypothesis that Cr supplementation raises high-density lipoprotein cholesterol and improves insulin sensitivity in those with evidence of insulin resistance but normal glucose tolerance.

  15. Exposure to 2,4-dichlorophenoxyacetic acid induced PPARβ-dependent disruption of glucose metabolism in HepG2 cells.

    PubMed

    Sun, Haidong; Shao, Wentao; Liu, Hui; Jiang, Zhaoyan

    2018-04-09

    2,4-Dichlorophenoxyacetic acid is one of the most widely used herbicides. Its impact on health is increasingly attracting great attentions. This study aimed to investigate the effect of 2,4-dichlorophenoxyacetic acid on glucose metabolism in HepG2 cells and the underlying mechanism. After 24 h exposure to 2,4-dichlorophenoxyacetic acid, glycogen was measured by PAS staining and glucose by ELISA in HepG2 cells. The expression of genes involved in glucose metabolism was measured by real-time PCR, Western blotting, and immunofluorescence. HepG2 cells presented more extracellular glucose consumption and glycogen content after exposed to 2,4-dichlorophenoxyacetic acid. Expression of gluconeogenesis-related genes, FoxO1, and CREB is significantly elevated. Moreover, PPARβ was up-regulated dose-dependently. SiRNA knockdown of PPARβ completely rescued the increase of glycogen accumulation and glucose uptake, and the up-regulation of FOXO1 and CREB expression. Our findings propose novel mechanisms that 2,4-dichlorophenoxyacetic acid causes glucose metabolism dysfunction through PPARβ in HepG2 cells.

  16. AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice

    PubMed Central

    Nakano, Kazuhiro; Takeshita, Sen; Kawasaki, Noriko; Miyanaga, Wataru; Okamatsu, Yoriko; Dohi, Mizuki; Nakagawa, Tadakiyo

    2017-01-01

    Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl) phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle. PMID:28290602

  17. AJS1669, a novel small-molecule muscle glycogen synthase activator, improves glucose metabolism and reduces body fat mass in mice.

    PubMed

    Nakano, Kazuhiro; Takeshita, Sen; Kawasaki, Noriko; Miyanaga, Wataru; Okamatsu, Yoriko; Dohi, Mizuki; Nakagawa, Tadakiyo

    2017-04-01

    Impaired glycogen synthesis and turnover are common in insulin resistance and type 2 diabetes. As glycogen synthase (GS) is a key enzyme involved in the synthetic process, it presents a promising therapeutic target for the treatment of type 2 diabetes. In the present study, we identified a novel, potent and orally available GS activator AJS1669 {sodium 2-[[5-[[4-(4,5-difluoro-2-methylsulfanyl-phenyl)phenoxy] methyl]furan-2-carbonyl]-(2-furylmethyl)amino] acetate}. In vitro, we performed a glycogen synthase 1 (GYS1) activation assay for screening GS activators and identified that the activity of AJS1669 was further potentiated in the presence of glucose-6-phosphate (G6P). In vivo, we used ob/ob mice to evaluate the novel anti-diabetic effects of AJS1669 by measuring basal blood glucose levels, glucose tolerance and body fat mass index. Repeated administration of AJS1669 over 4 weeks reduced blood glucose and hemoglobin A1c (HbA1c) levels in ob/ob mice. AJS1669 also improved glucose tolerance in a dose-dependent manner, and decreased body fat mass. The mRNA levels of genes involved in mitochondrial fatty acid oxidation and mitochondrial biogenesis were elevated in skeletal muscle tissue following AJS1669 treatment. Hepatic tissue of treated mice also exhibited elevated expression of genes associated with fatty acid oxidation. In contrast to ob/ob mice, in C57Bl/6 mice AJS1669 administration did not alter body weight or reduce glucose levels. These results demonstrate that pharmacological agents that activate GYS1, the main GS subtype found in skeletal muscle, have potential for use as novel treatments for diabetes that improve glucose metabolism in skeletal muscle.

  18. Cardiac Expression of Human Type 2 Iodothyronine Deiodinase Increases Glucose Metabolism and Protects Against Doxorubicin-induced Cardiac Dysfunction in Male Mice

    PubMed Central

    Hong, Eun-Gyoung; Kim, Brian W.; Young Jung, Dae; Hun Kim, Jong; Yu, Tim; Seixas Da Silva, Wagner; Friedline, Randall H.; Bianco, Suzy D.; Seslar, Stephen P.; Wakimoto, Hiroko; Berul, Charles I.; Russell, Kerry S.; Won Lee, Ki; Larsen, P. Reed; Bianco, Antonio C.

    2013-01-01

    Altered glucose metabolism in the heart is an important characteristic of cardiovascular and metabolic disease. Because thyroid hormones have major effects on peripheral metabolism, we examined the metabolic effects of heart-selective increase in T3 using transgenic mice expressing human type 2 iodothyronine deiodinase (D2) under the control of the α-myosin heavy chain promoter (MHC-D2). Hyperinsulinemic-euglycemic clamps showed normal whole-body glucose disposal but increased hepatic insulin action in MHC-D2 mice as compared to wild-type (WT) littermates. Insulin-stimulated glucose uptake in heart was not altered, but basal myocardial glucose metabolism was increased by more than two-fold in MHC-D2 mice. Myocardial lipid levels were also elevated in MHC-D2 mice, suggesting an overall up-regulation of cardiac metabolism in these mice. The effects of doxorubicin (DOX) treatment on cardiac function and structure were examined using M-mode echocardiography. DOX treatment caused a significant reduction in ventricular fractional shortening and resulted in more than 50% death in WT mice. In contrast, MHC-D2 mice showed increased survival rate after DOX treatment, and this was associated with a six-fold increase in myocardial glucose metabolism and improved cardiac function. Myocardial activity and expression of AMPK, GLUT1, and Akt were also elevated in MHC-D2 and WT mice following DOX treatment. Thus, our findings indicate an important role of thyroid hormone in cardiac metabolism and further suggest a protective role of glucose utilization in DOX-mediated cardiac dysfunction. PMID:23861374

  19. MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity.

    PubMed

    Vaitheesvaran, B; LeRoith, D; Kurland, I J

    2010-10-01

    Recent work has shown that there can be significant differences when glucose disposal is assessed for high-fat induced insulin resistance by static clamp methods vs dynamic assessment during a stable isotope i.p. glucose tolerance test. MKR mice, though lean, have severe insulin resistance and decreased muscle fatty acid oxidation. Our goal was to assess dynamic vs static glucose disposal in MKR mice, and to correlate glucose disposal and muscle-adipose-liver flux interactions with metabolic flexibility (indirect calorimetry) and muscle characteristics. Stable isotope flux phenotyping was performed using [6,6-(2)H(2)]glucose, [U-(13)C(6)]glucose and [2-(13)C]glycerol. Muscle triacylglycerol (TAG) and diacylglycerol (DAG) content was assessed by thin layer chromatography, and histological determination of fibre type and cytochrome c activity performed. Metabolic flexibility was assessed by indirect calorimetry. Indirect calorimetry showed that MKR mice used more glucose than FVB/N mice during fasting (respiratory exchange ratio [RER] 0.88 vs 0.77, respectively). Compared with FVB/N mice, MKR mice had faster dynamic glucose disposal, despite increased whole-muscle DAG and TAG, and similar hepatic glucose production with higher fasting insulin and unchanged basal glucose. Fed MKR muscle had more glycogen, and increased levels of GLUT1 and GLUT4 than FVB/N muscle. Histology indicated that MKR soleus had mildly decreased cytochrome c activity overall and more type II (glycolytic) fibres compared with that in FVB/N mice. MKR muscle adapts to using glucose, with more type II fibres present in red muscle. Fasting RER is elevated and glucose disposal during an i.p. glucose tolerance test is accelerated despite increased muscle DAG and TAG. Metabolic inflexibility may result from the compensatory use of fuel that can be best utilised for energy requirements; static vs dynamic glucose disposal assessments may measure complementary aspects of metabolic flexibility and insulin

  20. Pseudo-bi-enzyme glucose sensor: ZnS hollow spheres and glucose oxidase concerted catalysis glucose.

    PubMed

    Shuai, Ying; Liu, Changhua; Wang, Jia; Cui, Xiaoyan; Nie, Ling

    2013-06-07

    This work creatively uses peroxidase-like ZnS hollow spheres (ZnS HSs) to cooperate with glucose oxidase (GOx) for glucose determinations. This approach is that the ZnS HSs electrocatalytically oxidate the enzymatically generated H2O2 to O2, and then the O2 circularly participates in the previous glucose oxidation by glucose oxidase. Au nanoparticles (AuNPs) and carbon nanotubes (CNTs) are used as electron transfer and enzyme immobilization matrices, respectively. The biosensor of glucose oxidase-carbon nanotubes-Au nanoparticles-ZnS hollow spheres-gold electrode (GOx-CNT-AuNPs-ZnS HSs-GE) exhibits a rapid response, a low detection limit (10 μM), a wide linear range (20 μM to 7 mM) as well as good anti-interference, long-term longevity and reproducibility.

  1. Glucocorticoid deprivation alters in vivo glucose uptake by muscle and adipose tissues of GTG-obese mice.

    PubMed

    Blair, S C; Caterson, I D; Cooney, G J

    1995-11-01

    The effect of 1 wk of glucocorticoid deprivation by surgical adrenalectomy (ADX) on tissue 2-deoxy(-)[U-14C]glucose (2-DG) uptake and hepatic glucose production (HGP) was assessed in conscious, catheterized mice 5 wk after the induction of obesity with gold thioglucose (GTG). Despite the prevailing hyperglycemia and hyperinsulinemia, glucose uptake by heart, quadriceps muscle, and interscapular brown adipose tissue (BAT) of GTG-obese mice was unchanged compared with controls, suggesting that the hyperglycemia of GTG-obese mice is able to compensate for the insulin resistance of these tissues. In contrast, epididymal white adipose tissue (WAT) of GTG-obese mice showed increased glucose uptake with hyperglycemia and hyperinsulinemia. ADX decreased the hyperglycemia and lowered the elevated glycogen content of the liver of GTG-obese mice. ADX reduced glucose uptake by heart and WAT of control and GTG-obese mice, consistent with the concomitant decrease in insulinemia. Glucose uptake by muscle of control and GTG-obese mice was not significantly decreased after ADX despite the decrease in insulin, and ADX increased glucose uptake by BAT of GTG-obese mice, suggesting increased sympathetically mediated thermogenesis in this tissue. HGP was increased in GTG-obese mice compared with controls, and ADX significantly reduced HGP in both GTG-obese and control mice. These results suggest that the improved glucose tolerance of ADX GTG-obese mice and ADX control mice is due to a decrease in HGP rather than an increase in peripheral glucose uptake.

  2. Fabrication of interdigitated high-performance zinc oxide nanowire modified electrodes for glucose sensing.

    PubMed

    Haarindraprasad, R; Hashim, Uda; Gopinath, Subash C B; Perumal, Veeradasan; Liu, Wei-Wen; Balakrishnan, S R

    2016-06-21

    Diabetes is a metabolic disease with a prolonged elevated level of glucose in the blood leads to long-term complications and increases the chances for cardiovascular diseases. The present study describes the fabrication of a ZnO nanowire (NW)-modified interdigitated electrode (IDE) to monitor the level of blood glucose. A silver IDE was generated by wet etching-assisted conventional lithography, with a gap between adjacent electrodes of 98.80 μm. The ZnO-based thin films and NWs were amended by sol-gel and hydrothermal routes. High-quality crystalline and c-axis orientated ZnO thin films were observed by XRD analyses. The ZnO thin film was annealed for 1, 3 and 5 h, yielding a good-quality crystallite with sizes of 50, 100 and 110 nm, and the band gaps were measured as 3.26, 3.20 and 3.17 eV, respectively. Furthermore, a flower-modeled NW was obtained with the lowest diameter of 21 nm. Our designed ZnO NW-modified IDE was shown to have a detection limit as low as 0.03 mg/dL (correlation coefficient = 0.98952) of glucose with a low response time of 3 s, perform better than commercial glucose meter, suitable to instantly monitor the glucose level of diabetes patients. This study demonstrated the high performance of NW-mediated IDEs for glucose sensing as alternative to current glucose sensors. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Effects of oral glucose on exercise thermoregulation in men after water immersion

    NASA Technical Reports Server (NTRS)

    Dearborn, Alan S.; Ertl, Andrew C.; Greenleaf, John E.; Barnes, Paul R.; Jackson, Catherine G. R.; Breckler, Jennifer L.

    1994-01-01

    To test the hypothesis elevated blood glucose would attenuate the rise in exercise rectal temperature, six men age 35 plus or minus S.D. 7 years participated in each of three trials by 4-hr water immersion to the neck: (1) 2.0 g/kg body wt of oral glucose (33.8 percent wt./vol.) was consumed followed by 80 min controlled rest (Glu/Rest), and 70 min horizontal supine cycle exercise at 62.8 percent plus or minus S.E. 0.5 percent (1.97 plus or minus 0.02 L/min) of peak O2 uptake followed by 10 min recovery (2) with (Glu/Ex) and (3) without prior flucose (No Glu/Ex). Blood samples were taken at -25, 0, 15, 45, and 68 min of exercise and after plus 10 min of recovery for measurement of hemoglobin, hematocrit, and blood glucose. Both mean skin (T sub sk) (from six sites) and rectal temperatures (T sub re) were monitored continuously. Sweat rate was measured by resistanc hygrometry. The mean of delta PV for the exercise trials was -12.2 plus or minus 2.1 percent. Mean blood glucose for the Glu/Ex trial was higher than that of the No Glu/Ex trial was (108.4 equal or minus 3.9 and 85.6 plus or minus 1.6 mg/dl, respectively, P less than 0.05. At the end of exercise T(sub sk) for the Glu/Ex trial was lower than for No Glu/Ex(32.0 plus or minus 0.3 and 32.4 equals or minus 0.2 C, respectively, P less than 0.05); T(sub re) for the Glu/Ex trial was lower than for No Glu/Es (38.22 plus or minus 0.17 and 38.60 plus or minus 0.11 C, respectively, P less than 0.05); and forearm sweat rate for the Glu/Ex trial (0.34 plus or minus 0.04 and 0.43 plus or minus g/sq cm, respectively, P less than 0.05). These data suggest that elevation of blood glucose prior to horizontal exercise following hypohydration attenuates the increase in body temperature without altering heat production or exercise hypovolemia.

  4. Antagonism between phytohormone signalling underlies the variation in disease susceptibility of tomato plants under elevated CO2

    PubMed Central

    Zhang, Shuai; Li, Xin; Sun, Zenghui; Shao, Shujun; Hu, Lingfei; Ye, Meng; Zhou, Yanhong; Xia, Xiaojian; Yu, Jingquan; Shi, Kai

    2015-01-01

    Increasing CO2 concentrations ([CO2]) have the potential to disrupt plant–pathogen interactions in natural and agricultural ecosystems, but the research in this area has often produced conflicting results. Variations in phytohormone salicylic acid (SA) and jasmonic acid (JA) signalling could be associated with variations in the responses of pathogens to plants grown under elevated [CO2]. In this study, interactions between tomato plants and three pathogens with different infection strategies were compared. Elevated [CO2] generally favoured SA biosynthesis and signalling but repressed the JA pathway. The exposure of plants to elevated [CO2] revealed a lower incidence and severity of disease caused by tobacco mosaic virus (TMV) and by Pseudomonas syringae, whereas plant susceptibility to necrotrophic Botrytis cinerea increased. The elevated [CO2]-induced and basal resistance to TMV and P. syringae were completely abolished in plants in which the SA signalling pathway nonexpressor of pathogenesis-related genes 1 (NPR1) had been silenced or in transgenic plants defective in SA biosynthesis. In contrast, under both ambient and elevated [CO2], the susceptibility to B. cinerea highly increased in plants in which the JA signalling pathway proteinase inhibitors (PI) gene had been silenced or in a mutant affected in JA biosynthesis. However, plants affected in SA signalling remained less susceptible to this disease. These findings highlight the modulated antagonistic relationship between SA and JA that contributes to the variation in disease susceptibility under elevated [CO2]. This information will be critical for investigating how elevated CO2 may affect plant defence and the dynamics between plants and pathogens in both agricultural and natural ecosystems. PMID:25657213

  5. Glucose-responsive hydrogel electrode for biocompatible glucose transistor

    NASA Astrophysics Data System (ADS)

    Kajisa, Taira; Sakata, Toshiya

    2017-12-01

    In this paper, we propose a highly sensitive and biocompatible glucose sensor using a semiconductor-based field effect transistor (FET) with a functionalized hydrogel. The principle of the FET device contributes to the easy detection of ionic charges with high sensitivity, and the hydrogel coated on the electrode enables the specific detection of glucose with biocompatibility. The copolymerized hydrogel on the Au gate electrode of the FET device is optimized by controlling the mixture ratio of biocompatible 2-hydroxyethylmethacrylate (HEMA) as the main monomer and vinylphenylboronic acid (VPBA) as a glucose-responsive monomer. The gate surface potential of the hydrogel FETs shifts in the negative direction with increasing glucose concentration from 10 μM to 40 mM, which results from the increase in the negative charges on the basis of the diol-binding of PBA derivatives with glucose molecules in the hydrogel. Moreover, the hydrogel coated on the gate suppresses the signal noise caused by the nonspecific adsorption of proteins such as albumin. The hydrogel FET can serve as a highly sensitive and biocompatible glucose sensor in in vivo or ex vivo applications such as eye contact lenses and sheets adhering to the skin.

  6. CSF glucose test

    MedlinePlus

    Glucose test - CSF; Cerebrospinal fluid glucose test ... The glucose level in the CSF should be 50 to 80 mg/100 mL (or greater than 2/3 ... Abnormal results include higher and lower glucose levels. Abnormal ... or fungus) Inflammation of the central nervous system Tumor

  7. Prognostic implications of stress hyperglycemia in acute ST elevation myocardial infarction. Prospective observational study.

    PubMed

    Sanjuán, Rafael; Núñez, Julio; Blasco, M Luisa; Miñana, Gema; Martínez-Maicas, Helena; Carbonell, Nieves; Palau, Patricia; Bodí, Vicente; Sanchis, Juan

    2011-03-01

    In patients with acute myocardial infarction, elevation of plasma glucose levels is associated with worse outcomes. The aim of this study was to evaluate the association between stress hyperglycemia and in-hospital mortality in patients with acute myocardial infarction with ST-segment elevation (STEMI). We analyzed 834 consecutive patients admitted for STEMI to the Coronary Care Unit of our center. Association between admission glucose and mortality was assessed with Cox regression analysis. Discriminative accuracy of the multivariate model was assessed by Harrell's C statistic. Eighty-nine (10.7%) patients died during hospitalization. Optimal threshold glycemia level of 140mg/dl on admission to predict mortality was obtained by ROC curves. Those who presented glucose ≥140mg/dl showed higher rates of malignant ventricular tachyarrhythmias (28% vs. 18%, P=.001), complicative bundle branch block (5% vs. 2%, P=.005), new atrioventricular block (9% vs. 5%, P=.05) and in-hospital mortality (15% vs. 5%, P<.001). Multivariate analysis showed that those with glycemia ≥140mg/dl exhibited a 2-fold increase of in-hospital mortality risk (95% CI: 1.2-3.5, P=.008) irrespective of diabetes mellitus status (P-value for interaction=0.487 and 0.653, respectively). Stress hyperglycemia on admission is a predictor of mortality and arrhythmias in patients with STEMI and could be used in the stratification of risk in these patients. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  8. Development, glycolytic activity, and viability of preimplantation mouse embryos subjected to different periods of glucose starvation.

    PubMed

    Leppens-Luisier, G; Sakkas, D

    1997-03-01

    After compaction, the preimplantation mouse embryo switches to a glucose-based metabolism, whereas for the 2- to 4-cell stage embryo, glucose can be inhibitory. In this study, we investigated the adaptability of preimplantation embryos to different periods of glucose starvation by culturing in vitro fertilized (IVF) and in vivo-fertilized 1-cell OF1 mouse embryos. Blastocysts obtained from exposure to glucose starvation for different periods of time were examined for the number of cells in the trophectoderm and inner cell mass, and for glycolytic activity and viability. A high percentage of blastocysts was obtained when 1-cell embryos fertilized in vitro or in vivo were cultured in M16 until the 2-cell stage, were transferred to M16 without glucose (M16-G) until the 4- or 8-cell stage, and then were transferred to fresh M16-G. When in vivo-fertilized 1-cell embryos were cultured to the 2-cell stage and then left in M16, less than 5% formed blastocysts compared to 26% of those transferred into M16-G. Blastocysts obtained when in vivo-fertilized 1-cell embryos were left in M16-G after the 2-cell stage, however, showed a significantly elevated glycolytic activity compared to those transferred to fresh M16 or M16-G medium at the 4- or 8-cell stage. Interestingly, even though these embryos displayed elevated glycolytic activity, they did not exhibit differences in the numbers of inner cell mass and trophectoderm cells or in viability compared to embryos cultured according to other protocols. Blastocysts from all cultured protocols had a significantly lower total cell number and a lower trophectoderm, but not inner cell mass, cell number compared to blastocysts developed in vivo. This study documents the metabolic adaptability of the preimplantation embryo by highlighting its ability to proceed with development and retain viability when challenged with glucose starvation at different periods.

  9. Continuous glucose monitoring, oral glucose tolerance, and insulin - glucose parameters in adolescents with simple obesity.

    PubMed

    El Awwa, A; Soliman, A; Al-Ali, M; Yassin, M; De Sanctis, V

    2012-09-01

    In obese adolescents pancreatic beta-cells may not be able to cope with insulin resistance leading to hyperglycemia and type2 diabetes (T2DM To assess oral glucose tolerance, 72-h continuous blood glucose concentrations (CGM) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in 13 adolescents with simple obesity (BMI SDS=4 ± 1.06). OGTT performed in 13 obese adolescents (13.47 ± 3 years) revealed 3 cases (23%) with impaired fasting glucose (IFG: fasting glucose >5.6 mmol/L), 4 cases (30%) with impaired glucose tolerance (IGT: 2h blood glucose >7.8 <11.1 mmol/L), and none with diabetes. Using the continuous glucose monitoring system ( CGMS), IFG was detected in 4 cases, the maximum serum blood glucose (BG : 2h or more after meal) was >7.8 and <11.1 mmol/L (IGT) in 9 children (69%) and >11.1 mmol/L (diabetes) in one case (7.6%). Five cases had a minimum BG recorded of <2.7 mmol/L (hypoglycemia). No glycemic abnormality was detected using HbA1C (5.7 ± 0.3%). 11/13 patients had HOMA values >2.6 and QUICKI values <0.35 denoting insulin resistance. Beta cell mass percent (B %) = 200 ± 94.8% and insulin sensitivity values (IS)=50.4 ± 45.5% denoted insulin resistance with hyper-insulinaemia and preserved beta cell mass. In obese adolescents, CGMS is superior to OGTT and HbA1C in detecting glycemic abnormalities, which appears to be secondary to insulin resistance.

  10. Abolishing and establishing operation analyses of social attention as positive reinforcement for problem behavior.

    PubMed

    McGinnis, Molly A; Houchins-Juárez, Nealetta; McDaniel, Jill L; Kennedy, Craig H

    2010-03-01

    Three participants whose problem behavior was maintained by contingent attention were exposed to 45-min presessions in which attention was withheld, provided on a fixed-time (FT) 15-s schedule, or provided on an FT 120-s schedule. Following each presession, participants were then tested in a 15-min session similar to the social attention condition of an analogue functional analysis. The results showed establishing operation conditions increased problem behavior during tests and that abolishing operation conditions decreased problem behavior during tests.

  11. Generation of an immortalized mesenchymal stem cell line producing a secreted biosensor protein for glucose monitoring

    PubMed Central

    Weisman, Itamar; Romano, Jacob; Ivics, Zoltán; Izsvák, Zsuzsanna; Barkai, Uriel

    2017-01-01

    Diabetes is a chronic disease characterized by high levels of blood glucose. Diabetic patients should normalize these levels in order to avoid short and long term clinical complications. Presently, blood glucose monitoring is dependent on frequent finger pricking and enzyme based systems that analyze the drawn blood. Continuous blood glucose monitors are already on market but suffer from technical problems, inaccuracy and short operation time. A novel approach for continuous glucose monitoring is the development of implantable cell-based biosensors that emit light signals corresponding to glucose concentrations. Such devices use genetically modified cells expressing chimeric genes with glucose binding properties. MSCs are good candidates as carrier cells, as they can be genetically engineered and expanded into large numbers. They also possess immunomodulatory properties that, by reducing local inflammation, may assist long operation time. Here, we generated a novel immortalized human MSC line co-expressing hTERT and a secreted glucose biosensor transgene using the Sleeping Beauty transposon technology. Genetically modified hMSCs retained their mesenchymal characteristics. Stable transgene expression was validated biochemically. Increased activity of hTERT was accompanied by elevated and constant level of stem cell pluripotency markers and subsequently, by MSC immortalization. Furthermore, these cells efficiently suppressed PBMC proliferation in MLR transwell assays, indicating that they possess immunomodulatory properties. Finally, biosensor protein produced by MSCs was used to quantify glucose in cell-free assays. Our results indicate that our immortalized MSCs are suitable for measuring glucose concentrations in a physiological range. Thus, they are appropriate for incorporation into a cell-based, immune-privileged, glucose-monitoring medical device. PMID:28949988

  12. Generation of an immortalized mesenchymal stem cell line producing a secreted biosensor protein for glucose monitoring.

    PubMed

    Siska, Evangelia K; Weisman, Itamar; Romano, Jacob; Ivics, Zoltán; Izsvák, Zsuzsanna; Barkai, Uriel; Petrakis, Spyros; Koliakos, George

    2017-01-01

    Diabetes is a chronic disease characterized by high levels of blood glucose. Diabetic patients should normalize these levels in order to avoid short and long term clinical complications. Presently, blood glucose monitoring is dependent on frequent finger pricking and enzyme based systems that analyze the drawn blood. Continuous blood glucose monitors are already on market but suffer from technical problems, inaccuracy and short operation time. A novel approach for continuous glucose monitoring is the development of implantable cell-based biosensors that emit light signals corresponding to glucose concentrations. Such devices use genetically modified cells expressing chimeric genes with glucose binding properties. MSCs are good candidates as carrier cells, as they can be genetically engineered and expanded into large numbers. They also possess immunomodulatory properties that, by reducing local inflammation, may assist long operation time. Here, we generated a novel immortalized human MSC line co-expressing hTERT and a secreted glucose biosensor transgene using the Sleeping Beauty transposon technology. Genetically modified hMSCs retained their mesenchymal characteristics. Stable transgene expression was validated biochemically. Increased activity of hTERT was accompanied by elevated and constant level of stem cell pluripotency markers and subsequently, by MSC immortalization. Furthermore, these cells efficiently suppressed PBMC proliferation in MLR transwell assays, indicating that they possess immunomodulatory properties. Finally, biosensor protein produced by MSCs was used to quantify glucose in cell-free assays. Our results indicate that our immortalized MSCs are suitable for measuring glucose concentrations in a physiological range. Thus, they are appropriate for incorporation into a cell-based, immune-privileged, glucose-monitoring medical device.

  13. Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats

    PubMed Central

    Intapad, Suttira; Dasinger, John Henry; Brown, Andrew D.; Fahling, Joel M.; Esters, Joyee; Alexander, Barbara T.

    2015-01-01

    Background The incidence of metabolic disease increases in early menopause. Low birth weight influences the age at menopause. Thus, this study tested the hypothesis that intrauterine growth restriction programs early reproductive aging and impaired glucose homeostasis in female rats. Methods Estrous cyclicity, body composition, and glucose homeostasis were determined in female control and growth-restricted rats at 6 and 12 months of age; sex steroids at 12 months. Results Glucose intolerance was present at 6 months of age prior to cessation of estrous cyclicity and increased adiposity in female growth-restricted rats. However, female growth-restricted rats exhibited persistent estrus and a significant increase in adiposity, fasting glucose and testosterone at 12 months of age (P<0.05). Insulin release in response to a glucose challenge was blunted in conjunction with a reduction in protein expression of pancreatic glucose transporter type 2 and estrogen receptor alpha at 12 months of age in female growth-restricted rats (P<0.05). Conclusion This study demonstrated that slow fetal growth programmed glucose intolerance that developed prior to early estrous acyclicity; yet, fasting glucose levels were elevated in conjunction with increased adiposity, accelerated cessation of estrous cyclicity and a shift towards testosterone excess at 12 months of age in female growth-restricted rats. PMID:26854801

  14. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

    PubMed Central

    Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, Atalanta; Vaccaro, Nicole; Farrell, Kristin; Rothenberg, Paul; Henry, Robert R.

    2013-01-01

    OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. PMID:23412078

  15. Ventromedial hypothalamic glucose sensing and glucose homeostasis vary throughout the estrous cycle

    PubMed Central

    Santiago, Ammy M.; Clegg, Deborah J.; Routh, Vanessa H.

    2016-01-01

    Objective 17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs). Methods These hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed. Results The response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application. Conclusion

  16. Ventromedial hypothalamic glucose sensing and glucose homeostasis vary throughout the estrous cycle.

    PubMed

    Santiago, Ammy M; Clegg, Deborah J; Routh, Vanessa H

    2016-12-01

    17β-Estradiol (17βE) regulates glucose homeostasis in part by centrally mediated mechanisms. In female rodents, the influence of the ovarian cycle on hypoglycemia counterregulation and glucose tolerance is unclear. We found previously that in prepubertal females, 17βE modulates glucose sensing in nonadapting glucose-inhibited (GI) and adapting GI (AdGI) neurons within the ventrolateral portion of the ventromedial nucleus (VL-VMN). Nonadapting GI neurons persistently decrease their activity as glucose increases while AdGI neurons transiently respond to a glucose increase. To begin to understand if endogenous fluctuations in estrogen levels across the estrous cycle impact hypothalamic glucose sensing and glucose homeostasis, we assessed whether hypoglycemia counterregulation and glucose tolerance differed across the phases of the estrous cycle. We hypothesized that the response to insulin-induced hypoglycemia (IIH) and/or glucose tolerance would vary throughout the estrous cycle according to changes in 17βE availability. Moreover, that these changes would correlate with estrous-dependent changes in the glucose sensitivity of VL-VMN glucose-sensing neurons (GSNs). These hypotheses were tested in female mice by measuring the response to IIH, glucose tolerance and the glucose sensitivity of VL-VMN GSNs during each phase of the estrous cycle. Furthermore, a physiological brain concentration of 17βE seen during proestrus was acutely applied to brain slices isolated on the day of diestrous and the response to low glucose in VL-VMN GSNs was assayed. The response to IIH was strongest during diestrous. The response of nonadapting GI and AdGI neurons to a glucose decrease from 2.5 to 0.5mM also peaked during diestrous; an effect which was blunted by the addition of 17βE. In contrast, the glucose sensitivity of the subpopulation of GSNs which are excited by glucose (GE) was not affected by estrous phase or exogenous 17βE application. These data suggest that physiological

  17. Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

    PubMed

    Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E; Joly, Erik; Madiraju, S R Murthy; Prentki, Marc

    2017-05-05

    Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to

  18. Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells

    PubMed Central

    Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E.; Joly, Erik; Madiraju, S. R. Murthy; Prentki, Marc

    2017-01-01

    Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to

  19. Predictive models of glucose control: roles for glucose-sensing neurones.

    PubMed

    Kosse, C; Gonzalez, A; Burdakov, D

    2015-01-01

    The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure (e.g. sight, smell, taste, sound). This allows rapidly measurable sensory information (rather than slowly generated internal feedback signals, e.g. digested nutrients) to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues (e.g. taste, sound), (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control (e.g. using taste to predict nutrient value of food). This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the 'fast' senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate

  20. Ethanol stimulates epithelial sodium channels by elevating reactive oxygen species

    PubMed Central

    Bao, Hui-Fang; Song, John Z.; Duke, Billie J.; Ma, He-Ping; Denson, Donald D.

    2012-01-01

    Alcohol affects total body sodium balance, but the molecular mechanism of its effect remains unclear. We used single-channel methods to examine how ethanol affects epithelial sodium channels (ENaC) in A6 distal nephron cells. The data showed that ethanol significantly increased both ENaC open probability (Po) and the number of active ENaC in patches (N). 1-Propanol and 1-butanol also increased ENaC activity, but iso-alcohols did not. The effects of ethanol were mimicked by acetaldehyde, the first metabolic product of ethanol, but not by acetone, the metabolic product of 2-propanol. Besides increasing open probability and apparent density of active channels, confocal microscopy and surface biotinylation showed that ethanol significantly increased α-ENaC protein in the apical membrane. The effects of ethanol on ENaC Po and N were abolished by a superoxide scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL) and blocked by the phosphatidylinositol 3-kinase inhibitor LY294002. Consistent with an effect of ethanol-induced reactive oxygen species (ROS) on ENaC, primary alcohols and acetaldehyde elevated intracellular ROS, but secondary alcohols did not. Taken together with our previous finding that ROS stimulate ENaC, the current results suggest that ethanol stimulates ENaC by elevating intracellular ROS probably via its metabolic product acetaldehyde. PMID:22895258

  1. Triiodothyronine Acutely Stimulates Glucose Transport into L6 Muscle Cells Without Increasing Surface GLUT4, GLUT1, or GLUT3

    PubMed Central

    Teixeira, Silvania Silva; Tamrakar, Akhilesh K.; Goulart-Silva, Francemilson; Serrano-Nascimento, Caroline; Klip, Amira

    2012-01-01

    Background Thyroid hormones (THs) act genomically to stimulate glucose transport by elevating glucose transporter (Slc2a) expression and glucose utilization by cells. However, nongenomic effects of THs are now emerging. Here, we assess how triiodothyronine (T3) acutely affects glucose transport and the content of GLUT4, GLUT1, and GLUT3 at the surface of muscle cells, and possible interactions between T3 and insulin action. Methods Differentiated L6 myotubes transfected with myc-tagged Slc2a4 (L6-GLUT4myc) or Slc2a1 (L6-GLUT1myc) and wild-type L6 myotubes were studied in the following conditions: control, hypothyroid (Tx), Tx plus T3, Tx plus insulin, and Tx plus insulin and T3. Results Glucose uptake and GLUT4 content at the cell surface decreased in the Tx group relative to controls. T3 treatment for 30 minutes increased glucose transport into L6-GLUT4myc cells without altering surface GLUT4 content, which increased only thereafter. The total amount of GLUT4 protein remained unchanged among the groups studied. The surface GLUT1 content of L6-GLUT1myc cells also remained unaltered after T3 treatment; however, in these cells glucose transport was not stimulated by T3. In wild-type L6 cells, although T3 treatment increased the total amount of GLUT3, it did not change the surface GLUT3 content. Moreover, within 30 minutes, T3 stimulation of glucose uptake was additive to that of insulin in L6-GLUT4myc cells. As expected, insulin elevated surface GLUT4 content and glucose uptake. However, interestingly, surface GLUT4 content remained unchanged or even dropped with T3 plus insulin. Conclusions These data reveal that T3 rapidly increases glucose uptake in L6-GLUT4myc cells, which, at least for 30 minutes, did not depend on an increment in GLUT4 at the cell surface yet potentiates insulin action. We propose that this rapid T3 effect involves activation of GLUT4 transporters at the cell surface, but cannot discount the involvement of an unknown GLUT. PMID:22663547

  2. Enhancing the Effectiveness of a Play Intervention by Abolishing the Reinforcing Value of Stereotypy: A Pilot Study

    ERIC Educational Resources Information Center

    Lang, Russell; O'Reilly, Mark; Sigafoos, Jeff; Lancioni, Giulio E.; Machalicek, Wendy; Rispoli, Mandy; White, Pamela

    2009-01-01

    An alternating treatments design compared one condition in which a child with autism was allowed to engage in stereotypy freely prior to the intervention (abolishing operation component) to a second condition without the free-access period. Levels of stereotypy and problem behavior were lower and levels of functional play were higher in the…

  3. Clonazepam increases in vivo striatal extracellular glucose in diabetic rats after glucose overload.

    PubMed

    Gomez, Rosane; Barros, Helena M T

    2003-12-01

    Hyperglycemia modulates brain function, including neuronal excitability, neurotransmitter release and behavioral changes. There may be connections between the GABAergic system, glucose sensing neurons and glucose in the neuronal environment that shed light on the mechanism by which GABA(A) agents influence depressive behavior in diabetic rats submitted to the forced swimming test. We aimed to investigate whether clonazepam (CNZ), a GABA(A) receptor positive modulator, modifies in vivo striatal extracellular glucose levels in diabetic rats under fasting condition or after oral glucose overload. Streptozotocin diabetic and nondiabetic rats were submitted to in vivo striatal microdialysis. Perfusate samples were collected at baseline, during fasting and following administration of CNZ (0.25 mg/kg) and oral glucose overload. Blood glucose and striatal extracellular glucose were measured simultaneously at several time points. Fasting striatal glucose levels were higher in diabetic than in nondiabetic rats and the differences between these animals were maintained after glucose overload. The increases in extracellular striatal glucose after glucose overload were around 40% and blood to brain transference was decreased in diabetics. CNZ treatment paradoxically increased striatal glucose after glucose overload in diabetic rats, which may mark the dysfunction in brain glucose homeostasis.

  4. Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex.

    PubMed

    Szabó, István; Hormay, Edina; Csetényi, Bettina; Nagy, Bernadett; Lénárd, László; Karádi, Zoltán

    2018-02-01

    Multiple functional attributes of glucose-monitoring neurons in the medial orbitofrontal (ventrolateral prefrontal) cortex. NEUROSCI BIOBEHAV REV 73(1) XXX-XXX, 2017.- Special chemosensory cells, the glucose-monitoring (GM) neurons, reportedly involved in the central feeding control, exist in the medial orbitofrontal (ventrolateral prefrontal) cortex (mVLPFC). Electrophysiological, metabolic and behavioral studies reveal complex functional attributes of these cells and raise their homeostatic significance. Single neuron recordings, by means of the multibarreled microelectrophoretic technique, elucidate differential sensitivities of limbic forebrain neurons in the rat and the rhesus monkey to glucose and other chemicals, whereas gustatory stimulations demonstrate their distinct taste responsiveness. Metabolic examinations provide evidence for alteration of blood glucose level in glucose tolerance test and elevation of plasma triglyceride concentration after destruction of the local GM cells by streptozotocin (STZ). In behavioral studies, STZ microinjection into the mVLPFC fails to interfere with the acquisition of saccharin conditioned taste avoidance, does cause, however, taste perception deficit in taste reactivity tests. Multiple functional attributes of GM neurons in the mVLPFC, within the frame of the hierarchically organized central GM neuronal network, appear to play important role in the maintenance of the homeostatic balance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. (S)-[6]-Gingerol enhances glucose uptake in L6 myotubes by activation of AMPK in response to [Ca2+]i.

    PubMed

    Li, Yiming; Tran, Van H; Koolaji, Nooshin; Duke, Colin; Roufogalis, Basil D

    2013-01-01

    The aim of this study was to investigate the mechanism of (S)-[6]-gingerol in promoting glucose uptake in L6 skeletal muscle cells. The effect of (S)-[6]-gingerol on glucose uptake in L6 myotubes was examined using 2-[1,2-3H]-deoxy-D-glucose. Intracellular Ca2+ concentration was measured using Fluo-4. Phosphorylation of AMPKα was determined by Western blotting analysis. (S)-[6]-Gingerol time-dependently enhanced glucose uptake in L6 myotubes. (S)-[6]-Gingerol elevated intracellular Ca2+ concentration and subsequently induced a dose- and time-dependent enhancement of threonine172 phosphorylated AMPKα in L6 myotubes via modulation by Ca2+/calmodulin-dependent protein kinase kinase. The results indicated that (S)-[6]-gingerol increased glucose uptake in L6 skeletal muscle cells by activating AMPK. (S)-[6]-gingerol, a major component of Zingiber officinale, may have potential for development as an antidiabetic agent.

  6. rTMS of the occipital cortex abolishes Braille reading and repetition priming in blind subjects.

    PubMed

    Kupers, R; Pappens, M; de Noordhout, A Maertens; Schoenen, J; Ptito, M; Fumal, A

    2007-02-27

    To study the functional involvement of the visual cortex in Braille reading, we applied repetitive transcranial magnetic stimulation (rTMS) over midoccipital (MOC) and primary somatosensory (SI) cortex in blind subjects. After rTMS of MOC, but not SI, subjects made significantly more errors and showed an abolishment of the improvement in reading speed following repetitive presentation of the same word list, suggesting a role of the visual cortex in repetition priming in the blind.

  7. Effects of the probiotic strain Lactobacillus johnsonii strain La1 on autonomic nerves and blood glucose in rats.

    PubMed

    Yamano, Toshihiko; Tanida, Mamoru; Niijima, Akira; Maeda, Keiko; Okumura, Nobuaki; Fukushima, Yoichi; Nagai, Katsuya

    2006-10-12

    Oral administration of Lactobacillus casei reportedly reduces blood glucose concentrations in a non-insulin-dependent diabetic KK-Ay mouse model. In order to determine if other lactobacillus strains affect glucose metabolism, we evaluated the effect of the probiotic strain Lactobacillus johnsonii La1 (LJLa1) strain on glucose metabolism in rats. Oral administration of LJLa1 via drinking water for 2 weeks inhibited the hyperglycemia induced by intracranial injection of 2-deoxy-D-glucose (2DG). We found that the hyperglucagonemic response induced by 2DG was also suppressed by LJLa1. Oral administration of LJLa1 for 2 weeks also reduced the elevation of blood glucose and glucagon levels after an oral glucose load in streptozotocin-diabetic rats. In addition, we recently observed that intraduodenal injection of LJLa1 reduced renal sympathetic nerve activity and enhanced gastric vagal nerve activity, suggesting that LJLa1 might affect glucose metabolism by changing autonomic nerve activity. Therefore, we evaluated the effect of intraduodenal administration of LJLa1 on adrenal sympathetic nerve activity (ASNA) in urethane-anesthetized rats, since the autonomic nervous system, including the adrenal sympathetic nerve, may be implicated in the control of the blood glucose levels. Indeed, we found that ASNA was suppressed by intraduodenal administration of LJLa1, suggesting that LJLa1 might improve glucose tolerance by reducing glucagon secretion via alteration of autonomic nerve activities.

  8. Noninvasive Continuous Monitoring of Tear Glucose Using Glucose-Sensing Contact Lenses.

    PubMed

    Ascaso, Francisco J; Huerva, Valentín

    2016-04-01

    : The incidence of diabetes mellitus is dramatically increasing in the developed countries. Tight control of blood glucose concentration is crucial to diabetic patients to prevent microvascular complications. Self-monitoring of blood glucose is widely used for controlling blood glucose levels and usually performed by an invasive test using a portable glucometer. Many technologies have been developed over the past decades with the purpose of obtaining a continuous physiological glycemic monitoring. A contact lens is the ideal vehicle for continuous tear glucose monitoring of glucose concentration in tear film. There are several research groups that are working in the development of contact lenses with embedded biosensors for continuously and noninvasively monitoring tear glucose levels. Although numerous aspects must be improved, contact lens technology is one step closer to helping diabetic subjects better manage their condition, and these contact lenses will be able to measure the level of glucose in the wearer's tears and communicate the information to a mobile phone or computer. This article reviews studies on ocular glucose and its monitoring methods as well as the attempts to continuously monitor the concentration of tear glucose by using contact lens-based sensors.

  9. An incubation medium for the elevation of adenosine triphosphate and 2,3-diphosphoglycerate in fresh and long-preserved human erythrocytes.

    PubMed

    Rubinstein, D; Warrendorf, E

    1975-06-01

    The levels of adenosine triphosphate (ATP) and 2,3-diphosphoglycerate in freshly drawn human erythrocytes can be tripled by a 2 h incubation at 37 degrees C in a medium containing 21 mM glucose, 1.8 mM adenine, 5 mM pyruvate, 10 mM inosine, and 96 mM phosphate. Similar incubation conditions will restore the levels of ATP and 2,3-diphosphoglycerate in erythrocytes from blood levels preserved for 12 and 15 weeks, respectively, to those of fresh cells. Omission of pyruvate from the incubation medium further increases the level of ATP slightly, but there is little elevation of 2,3-diphosphoglycerate. Under these conditions labelled pyruvate and lactate production from [14-C]glucose or [14-C]inosine is not diminished, but labelled fructose 1,6-diphosphate, rather than 2,3-diphosphoglycerate, accumulates. In addition, omission of pyruvate from the incubation medium, with a concomitant decrease in accumulation of 2,3-diphosphoglycerate, diminishes the concentration of inorganic phosphate required for optimal ATP elevation. A 5 h incubation in the glucose-adenine-pyruvate-inosine-phosphate medium elevates the levels of ATP and 2,3-diphosphoglycerate in erythrocytes from blood preserved in the cold for 15 weeks to twice that of fresh cells, indicating that the cells retain their metabolic potential even after prolonged storage at 2 degrees C. The medium may provide a method of rejuvenating 10-12 week cold-preserved erythrocytes for transfusion purposes, by a 1 h incubation at 37 degrees C.

  10. Elevated maternal cortisol leads to relative maternal hyperglycemia and increased stillbirth in ovine pregnancy

    PubMed Central

    Feng, Xiaodi; Wood, Charles E.; Richards, Elaine; Anthony, Russell V.; Dahl, Geoffrey E.; Tao, Sha

    2014-01-01

    In normal pregnancy, cortisol increases; however, further pathological increases in cortisol are associated with maternal and fetal morbidities. These experiments were designed to test the hypothesis that increased maternal cortisol would increase maternal glucose concentrations, suppress fetal growth, and impair neonatal glucose homeostasis. Ewes were infused with cortisol (1 mg·kg−1·day−1) from day 115 of gestation to term; maternal glucose, insulin, ovine placental lactogen, estrone, progesterone, nonesterified free fatty acids (NEFA), β-hydroxybutyrate (BHB), and electrolytes were measured. Infusion of cortisol increased maternal glucose concentration and slowed the glucose disappearance after injection of glucose; maternal infusion of cortisol also increased the incidence of fetal death at or near parturition. The design of the study was altered to terminate the study prior to delivery, and post hoc analysis of the data was performed to test the hypothesis that maternal metabolic factors predict the fetal outcome. In cortisol-infused ewes that had stillborn lambs, plasma insulin was increased relative to control ewes or cortisol-infused ewes with live lambs. Maternal cortisol infusion did not alter maternal food intake or plasma NEFA, BHB, estrone, progesterone or placental lactogen concentrations, and it did not alter fetal body weight, ponderal index, or fetal organ weights. Our study suggests that the adverse effect of elevated maternal cortisol on pregnancy outcome may be related to the effects of cortisol on maternal glucose homeostasis, and that chronic maternal stress or adrenal hypersecretion of cortisol may create fetal pathophysiology paralleling some aspects of maternal gestational diabetes. PMID:24920731

  11. ABOLISHING AND ESTABLISHING OPERATION ANALYSES OF SOCIAL ATTENTION AS POSITIVE REINFORCEMENT FOR PROBLEM BEHAVIOR

    PubMed Central

    McGinnis, Molly A; Houchins-Juárez, Nealetta; McDaniel, Jill L; Kennedy, Craig H

    2010-01-01

    Three participants whose problem behavior was maintained by contingent attention were exposed to 45-min presessions in which attention was withheld, provided on a fixed-time (FT) 15-s schedule, or provided on an FT 120-s schedule. Following each presession, participants were then tested in a 15-min session similar to the social attention condition of an analogue functional analysis. The results showed establishing operation conditions increased problem behavior during tests and that abolishing operation conditions decreased problem behavior during tests. PMID:20808502

  12. Cell based metabolic barriers to glucose diffusion: macrophages and continuous glucose monitoring.

    PubMed

    Klueh, Ulrike; Frailey, Jackman T; Qiao, Yi; Antar, Omar; Kreutzer, Donald L

    2014-03-01

    It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance. We hypothesized that the accumulation of MQ at the glucose sensor-tissue interface will act as "Cell Based Metabolic Barriers" (CBMB) to glucose diffusing from the interstitial tissue compartment to the implanted glucose sensor and as such creating an artificially low sensor output, thereby compromising sensor function and CGM. Our studies demonstrated that 1) direct injections of MQ at in vivo sensor implantation sites dramatically decreased sensor output (measured in nA), 2) addition of MQ to glucose sensors in vitro resulted in a rapid and dramatic fall in sensor output and 3) lymphocytes did not affect sensor function in vitro or in vivo. These data support our hypothesis that MQ can act as metabolic barriers to glucose and O2 diffusion in vivo and in vitro. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Cell Based Metabolic Barriers to Glucose Diffusion: Macrophages and Continuous Glucose Monitoring

    PubMed Central

    Klueh, Ulrike; Frailey, Jackman; Qiao, Yi; Antar, Omar; Kreutzer, Donald L.

    2014-01-01

    It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance. We hypothesized that the accumulation of MQ at the glucose sensor-tissue interface will act as “Cell Based Metabolic Barriers” (CBMB) to glucose diffusing from the interstitial tissue compartment to the implanted glucose sensor and as such creating an artificially low sensor output, thereby compromising sensor function and CGM. Our studies demonstrated that 1) direct injections of MQ at in vivo sensor implantation sites dramatically decreased sensor output (measured in nA), 2) addition of MQ to glucose sensors in vitro resulted in a rapid and dramatic fall in sensor output and 3) lymphocytes did not affect sensor function in vitro or in vivo. These data support our hypothesis that MQ can act as metabolic barriers to glucose and O2 diffusion in vivo and in vitro. PMID:24461328

  14. Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion.

    PubMed

    Li, Tingting; Xu, Jie; Qin, Xinghua; Hou, Zuoxu; Guo, Yongzheng; Liu, Zhenhua; Wu, Jianjiang; Zheng, Hong; Zhang, Xing; Gao, Feng

    2017-11-01

    Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by 18 F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury. Copyright © 2017 the American Physiological Society.

  15. Improving xylitol production at elevated temperature with engineered Kluyveromyces marxianus through over-expressing transporters.

    PubMed

    Zhang, Jia; Zhang, Biao; Wang, Dongmei; Gao, Xiaolian; Hong, Jiong

    2015-01-01

    Three transporter genes including Kluyveromyces marxianus aquaglyceroporin gene (KmFPS1), Candida intermedia glucose/xylose facilitator gene (CiGXF1) or glucose/xylose symporter gene (CiGXS1) were over-expressed in K. marxianus YZJ017 to improve xylitol production at elevated temperatures. The xylitol production of YZJ074 that harbored CiGXF1 was improved to 147.62g/L in Erlenmeyer flask at 42°C. In fermenter, 99.29 and 149.60g/L xylitol were produced from 99.55 and 151.91g/L xylose with productivity of 4.14 and 3.40g/L/h respectively at 42°C. Even at 45°C, YZJ074 could produce 101.30g/L xylitol from 101.41g/L xylose with productivity of 2.81g/L/h. Using fed-batch fermentation through repeatedly adding non-sterilized substrate directly, YZJ074 could produce 312.05g/L xylitol which is the highest yield reported to date. The engineered strains YZJ074 which can produce xylitol at elevated temperatures is an excellent foundation for xylitol bioconversion. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Subcellular localization, mobility, and kinetic activity of glucokinase in glucose-responsive insulin-secreting cells.

    PubMed

    Stubbs, M; Aiston, S; Agius, L

    2000-12-01

    We investigated the subcellular localization, mobility, and activity of glucokinase in MIN6 cells, a glucose-responsive insulin-secreting beta-cell line. Glucokinase is present in the cytoplasm and a vesicular/granule compartment that is partially colocalized with insulin granules. The granular staining of glucokinase is preserved after permeabilization of the cells with digitonin. There was no evidence for changes in distribution of glucokinase between the cytoplasm and the granule compartment during incubation of the cells with glucose. The rate of release of glucokinase and of phosphoglucoisomerase from digitonin-permeabilized cells was slower when cells were incubated at an elevated glucose concentration (S0.5 approximately 15 mmol/l). This effect of glucose was counteracted by competitive inhibitors of glucokinase (5-thioglucose and mannoheptulose) but was unaffected by fructose analogs and may be due to changes in cell shape or conformation of the cytoskeleton that are secondary to glucose metabolism. Based on the similar release of glucokinase and phosphoglucoisomerase, we found no evidence for specific binding of cytoplasmic digitonin-extractable glucokinase. The affinity of beta-cells for glucose is slightly lower than that in cell extracts and, unlike that in hepatocytes, is unaffected by fructose, tagatose, or a high-K+ medium, which is consistent with the lack of change in glucokinase distribution or release. We conclude that glucokinase is present in two locations, cytoplasm and the granular compartment, and that it does not translocate between them. This conclusion is consistent with the lack of adaptive changes in the glucose phosphorylation affinity. The glucokinase activity associated with the insulin granules may have a role in either direct or indirect coupling between glucose phosphorylation and insulin secretion.

  17. Prefrontal cortex damage abolishes brand-cued changes in cola preference.

    PubMed

    Koenigs, Michael; Tranel, Daniel

    2008-03-01

    Human decision-making is remarkably susceptible to commercial advertising, yet the neurobiological basis of this phenomenon remains largely unexplored. With a series of Coke and Pepsi taste tests we show that patients with damage specifically involving ventromedial prefrontal cortex (VMPC), an area important for emotion, did not demonstrate the normal preference bias when exposed to brand information. Both comparison groups (neurologically normal adults and lesion patients with intact VMPC) preferred Pepsi in a blind taste test, but in subsequent taste tests that featured brand information ('semi-blind' taste tests), both comparison groups' preferences were skewed toward Coke, illustrating the so-called 'Pepsi paradox'. Like comparison groups, the VMPC patients preferred Pepsi in the blind taste test, but unlike comparison groups, the VMPC patients maintained their Pepsi preference in the semi-blind test. The result that VMPC damage abolishes the 'Pepsi paradox' suggests that the VMPC is an important part of the neural substrate for translating commercial images into brand preferences.

  18. Prefrontal cortex damage abolishes brand-cued changes in cola preference

    PubMed Central

    Tranel, Daniel

    2008-01-01

    Human decision-making is remarkably susceptible to commercial advertising, yet the neurobiological basis of this phenomenon remains largely unexplored. With a series of Coke and Pepsi taste tests we show that patients with damage specifically involving ventromedial prefrontal cortex (VMPC), an area important for emotion, did not demonstrate the normal preference bias when exposed to brand information. Both comparison groups (neurologically normal adults and lesion patients with intact VMPC) preferred Pepsi in a blind taste test, but in subsequent taste tests that featured brand information (‘semi-blind’ taste tests), both comparison groups’ preferences were skewed toward Coke, illustrating the so-called ‘Pepsi paradox’. Like comparison groups, the VMPC patients preferred Pepsi in the blind taste test, but unlike comparison groups, the VMPC patients maintained their Pepsi preference in the semi-blind test. The result that VMPC damage abolishes the ‘Pepsi paradox’ suggests that the VMPC is an important part of the neural substrate for translating commercial images into brand preferences. PMID:18392113

  19. Curcumin protects cortical neurons against oxygen and glucose deprivation/reoxygenation injury through flotillin-1 and extracellular signal-regulated kinase1/2 pathway.

    PubMed

    Lu, Zhengyu; Liu, Yanping; Shi, Yang; Shi, Xinjie; Wang, Xin; Xu, Chuan; Zhao, Hong; Dong, Qiang

    2018-02-05

    In this study, we provided evidence that curcumin could be a promising therapeutic agent for ischemic stroke by activating neuroprotective signaling pathways. Post oxygen and glucose deprivation/reoxygenation (OGD/R), primary mouse cortical neurons treated with curcumin exhibited a significant decrease in cell death, LDH release and enzyme caspase-3 activity under OGD/R circumstances, which were abolished by flotillin-1 downregulation or extracellular signal-regulated kinase (ERK) inhibitor. Moreover, flotillin-1 knockdown led to suppression of curcumin-mediated ERK phosphorylation under OGD/R condition. Based on these findings, we concluded that curcumin could confer neuroprotection against OGD/R injury through a novel flotillin-1 and ERK1/2 pathway. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Dirty Electricity Elevates Blood Sugar Among Electrically Sensitive Diabetics and May Explain Brittle Diabetes

    PubMed Central

    Havas, Magda

    2008-01-01

    Transient electromagnetic fields (dirty electricity), in the kilohertz range on electrical wiring, may be contributing to elevated blood sugar levels among diabetics and prediabetics. By closely following plasma glucose levels in four Type 1 and Type 2 diabetics, we find that they responded directly to the amount of dirty electricity in their environment. In an electromagnetically clean environment, Type 1 diabetics require less insulin and Type 2 diabetics have lower levels of plasma glucose. Dirty electricity, generated by electronic equipment and wireless devices, is ubiquitous in the environment. Exercise on a treadmill, which produces dirty electricity, increases plasma glucose. These findings may explain why brittle diabetics have difficulty regulating blood sugar. Based on estimates of people who suffer from symptoms of electrical hypersensitivity (3–35%), as many as 5–60 million diabetics worldwide may be affected. Exposure to electromagnetic pollution in its various forms may account for higher plasma glucose levels and may contribute to the misdiagnosis of diabetes. Reducing exposure to electromagnetic pollution by avoidance or with specially designed GS filters may enable some diabetics to better regulate their blood sugar with less medication and borderline or pre-diabetics to remain non diabetic longer. PMID:18568931

  1. The browning value changes and spectral analysis on the Maillard reaction product from glucose and methionine model system

    NASA Astrophysics Data System (ADS)

    Al-Baarri, A. N.; Legowo, A. M.; Widayat

    2018-01-01

    D-glucose has been understood to provide the various effect on the reactivity in Maillard reaction resulting in the changes in physical performance of food product. Therefore this research was done to analyse physical appearance of Maillard reaction product made of D-glucose and methionine as a model system. The changes in browning value and spectral analysis model system were determined. The glucose-methionine model system was produced through the heating treatment at 50°C and RH 70% for 24 hours. The data were collected for every three hour using spectrophotometer. As result, browning value was elevated with the increase of heating time and remarkably high if compare to the D-glucose only. Furthermore, the spectral analysis showed that methionine turned the pattern of peak appearance. As conclusion, methionine raised the browning value and changed the pattern of spectral analysis in Maillard reaction model system.

  2. Beta-endorphin-induced inhibition and stimulation of insulin secretion in normal humans is glucose dependent.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Torella, R; D'Onofrio, F

    1988-09-01

    This study evaluated the effect of human beta-endorphin on pancreatic hormone levels and their responses to nutrient challenges in normal subjects. Infusion of 0.5 mg/h beta-endorphin caused a significant rise in plasma glucose concentrations preceded by a significant increase in peripheral glucagon levels. No changes occurred in the plasma concentrations of insulin and C-peptide. Acute insulin and C-peptide responses to intravenous pulses of different glucose amounts (0.33 g/kg and 5 g) and arginine (3 g) were significantly reduced by beta-endorphin infusion (P less than .01). This effect was associated with a significant reduction of the glucose disappearance rates, suggesting that the inhibition of insulin was of biological relevance. beta-Endorphin also inhibited glucose suppression of glucagon levels and augmented the glucagon response to arginine. To verify whether the modification of prestimulus glucose level could be important in these hormonal responses to beta-endorphin, basal plasma glucose concentrations were raised by a primed (0.5 g/kg) continuous (20 mg kg-1.min-1) glucose infusion. After stabilization of plasma glucose levels (350 +/- 34 mg/dl, t = 120 min), beta-endorphin infusion caused an immediate and marked increase in plasma insulin level (peak response 61 +/- 9 microU/ml, P less than .01), which remained elevated even after the discontinuation of opioid infusion. Moreover, the acute insulin response to a glucose pulse (0.33 g/kg i.v.) given during beta-endorphin infusion during hyperglycemia was significantly higher than the response obtained during euglycemia (171 +/- 32 vs. 41 +/- 7 microU/ml, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

  3. High glucose-induced Ca2+ overload and oxidative stress contribute to apoptosis of cardiac cells through mitochondrial dependent and independent pathways.

    PubMed

    Kumar, Sandeep; Kain, Vasundhara; Sitasawad, Sandhya L

    2012-07-01

    Cardiac cell apoptosis is the initiating factor of cardiac complications especially diabetic cardiomyopathy. Mitochondria are susceptible to the damaging effects of elevated glucose condition. Calcium overload and oxidative insult are the two mutually non-exclusive phenomena suggested to cause cardiac dysfunction. Here, we examined the effect of high-glucose induced calcium overload in calpain-1 mediated cardiac apoptosis in an in vitro setting. H9c2, rat ventricular myoblast cell line was treated with elevated glucose condition and the cellular consequences were studied. Intracellular calcium trafficking, ROS generation, calpain-1 activation and caspase-12 and caspase-9 pathway were studied using flow cytometry, confocal microscopy and Western blot analysis. High-glucose treatment resulted in increased intracellular calcium ([Ca2+]i) which was mobilized to the mitochondria. Concomitant intra-mitochondrial calcium ([Ca2+]m) increase resulted in enhanced reactive oxygen and nitrogen species generation. These events led to mitochondrial dysfunction and apoptosis. Cardiomyocyte death exhibited several classical markers of apoptosis, including activation of caspases, appearance of annexin V on the outer plasma membrane, increased population of cells with sub-G0/G1 DNA content and nuclear condensation. Key findings include elucidation of cell signaling mechanism of high-glucose induced calcium-dependent cysteine protease calpain-1 activation, which triggers non-conventional caspases as alternate mode of cell death. This information increases the understanding of cardiac cell death under hyperglycemic condition and can possibly be extended for designing new therapeutic strategies for diabetic cardiomyopathy. The novel findings of the study reveal that high glucose induces apoptosis by both mitochondria-dependent and independent pathways via concomitant rise in intracellular calcium. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Lai; Chen, Man; Yuan, Lin

    2014-07-18

    Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and functionmore » in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.« less

  5. Acetoacetate is a more efficient energy-yielding substrate for human mesenchymal stem cells than glucose and generates fewer reactive oxygen species.

    PubMed

    Board, Mary; Lopez, Colleen; van den Bos, Christian; Callaghan, Richard; Clarke, Kieran; Carr, Carolyn

    2017-07-01

    Stem cells have been assumed to demonstrate a reliance on anaerobic energy generation, suited to their hypoxic in vivo environment. However, we found that human mesenchymal stem cells (hMSCs) have an active oxidative metabolism with a range of substrates. More ATP was consistently produced from substrate oxidation than glycolysis by cultured hMSCs. Strong substrate preferences were shown with the ketone body, acetoacetate, being oxidised at up to 35 times the rate of glucose. ROS-generation was 45-fold lower during acetoacetate oxidation compared with glucose and substrate preference may be an adaptation to reduce oxidative stress. The UCP2 inhibitor, genipin, increased ROS production with either acetoacetate or glucose by 2-fold, indicating a role for UCP2 in suppressing ROS production. Addition of pyruvate stimulated acetoacetate oxidation and this combination increased ATP production 27-fold, compared with glucose alone, which has implications for growth medium composition. Oxygen tension during culture affected metabolism by hMSCs. Between passages 2 and 5, rates of both glycolysis and substrate-oxidation increased at least 2-fold for normoxic (20% O 2 )- but not hypoxic (5% O 2 )-cultured hMSCs, despite declining growth rates and no detectable signs of differentiation. Culture of the cells with 3-hydroxybutyrate abolished the increased rates of these pathways. These findings have implications for stem cell therapy, which necessarily involves in vitro culture of cells, since low passage number normoxic cultured stem cells show metabolic adaptations without detectable changes in stem-like status. Copyright © 2017. Published by Elsevier Ltd.

  6. Glycogen Supercompensation in the Rat Brain After Acute Hypoglycemia is Independent of Glucose Levels During Recovery.

    PubMed

    Duarte, João M N; Morgenthaler, Florence D; Gruetter, Rolf

    2017-06-01

    Patients with diabetes display a progressive decay in the physiological counter-regulatory response to hypoglycemia, resulting in hypoglycemia unawareness. The mechanism through which the brain adapts to hypoglycemia may involve brain glycogen. We tested the hypothesis that brain glycogen supercompensation following hypoglycemia depends on blood glucose levels during recovery. Conscious rats were submitted to hypoglycemia of 2 mmol/L for 90 min and allowed to recover at different glycemia, controlled by means of i.v. glucose infusion. Brain glycogen concentration was elevated above control levels after 24 h of recovery in the cortex, hippocampus and striatum. This glycogen supercompensation was independent of blood glucose levels in the post-hypoglycemia period. In the absence of a preceding hypoglycemia insult, brain glycogen concentrations were unaltered after 24 h under hyperglycemia. In the hypothalamus, which controls peripheral glucose homeostasis, glycogen levels were unaltered. Overall, we conclude that post-hypoglycemia glycogen supercompensation occurs in several brain areas and its magnitude is independent of plasma glucose levels. By supporting brain metabolism during recurrent hypoglycemia periods, glycogen may have a role in the development of hypoglycemia unawareness.

  7. Glucose metabolism disorder in obese children assessed by continuous glucose monitoring system.

    PubMed

    Zou, Chao-Chun; Liang, Li; Hong, Fang; Zhao, Zheng-Yan

    2008-02-01

    Continuous glucose monitoring system (CGMS) can measure glucose levels at 5-minute intervals over a few days, and may be used to detect hypoglycemia, guide insulin therapy, and control glucose levels. This study was undertaken to assess the glucose metabolism disorder by CGMS in obese children. Eighty-four obese children were studied. Interstitial fluid (ISF) glucose levels were measured by CGMS for 24 hours covering the time for oral glucose tolerance test (OGTT). Impaired glucose tolerance (IGT), impaired fasting glucose (IFG), type 2 diabetic mellitus (T2DM) and hypoglycemia were assessed by CGMS. Five children failed to complete CGMS test. The glucose levels in ISF measured by CGMS were highly correlated with those in capillary samples (r=0.775, P<0.001). However, the correlation between ISF and capillary glucose levels was lower during the first hour than that in the later time period (r=0.722 vs r=0.830), and the ISF glucose levels in 69.62% of children were higher than baseline levels in the initial 1-3 hours. In 79 obese children who finished the CGMS, 2 children had IFG, 2 had IGT, 3 had IFG + IGT, and 2 had T2DM. Nocturnal hypoglycemia was noted during the overnight fasting in 11 children (13.92%). Our data suggest that glucose metabolism disorder including hyperglycemia and hypoglycemia is very common in obese children. Further studies are required to improve the precision of the CGMS in children.

  8. Evidence against impaired brain microtubule protein polymerization at high glucose concentrations or during diabetes mellitus.

    PubMed

    Eaker, E Y; Angelastro, J M; Purich, D L; Sninsky, C A

    1991-06-01

    Previous studies suggest that brain microtubule protein exposed to high glucose levels or isolated from diabetic rats can become glucosylated and that this impairs GTP-induced microtubule polymerization. We set out to extend that investigation to define the mechanistic basis for inhibition of microtubule assembly during diabetes or on incubation at high glucose levels. Rat and bovine brain microtubule protein was purified by cycles of polymerization/depolymerization. When microtubules were incubated for 1 h in either buffer or buffer containing glucose (up to 165 mM), there was no difference in polymerization, a finding contrary to the earlier study. Other rats were injected with vehicle or streptozotocin (90 mg/kg) to induce diabetes as evidenced by serum glucose in excess of 300 mg%, and at 4 weeks, brain microtubule protein was isolated by the polymerization cycling method. Again, there was no difference in the amount or purity of isolated microtubule protein between control or diabetic rats. We also observed no increase in microtubule glucosylation, and GTP-induced polymerization in vitro was indistinguishable for protein derived from brains of normal rats and rats with diabetes as measured by turbidity or electron microscopy. Our results suggest that in vitro incubation with glucose or in vivo elevation of glucose during diabetes fails to impair microtubule polymerization, pointing to other mechanisms for the neuropathy associated with diabetes.

  9. The liver glucose-6-phosphatase of intact microsomes is inhibited and displays sigmoid kinetics in the presence of alpha-ketoglutarate-magnesium and oxaloacetate-magnesium chelates.

    PubMed

    Mithieux, G; Vega, F V; Riou, J P

    1990-11-25

    We have recently shown that the Ca.EGTA and Mg.EDTA complexes, but not free Ca2+ or Mg2+, inhibit the liver glucose-6-phosphatase (Mithieux, G., Vega, F. V., Beylot, M., and Riou, J. P. (1990) J. Biol. Chem. 265, 7257-7259). In this work, we report that, when complexed with Mg2+, two endogenous dicarboxylic keto acids (alpha-ketoglutarate (alpha-KG) and oxaloacetate (OAA] inhibit the glucose-6-phosphatase activity at low concentrations of substrate. This phenomenon is specific for complexes of Mg2+ with alpha-KG and OAA since 1) the complexes of Mg2+ with a number of other di- or tricarboxylic acids having high structural analogy with alpha-KG and OAA (oxalate, malate, succinate, citrate, aspartate, and glutamate) do not inhibit the glucose-6-phosphatase activity and 2) the Ca.alpha-KG and Ca.OAA chelates do not inhibit the glucose-6-phosphatase activity. In the presence of Mg.alpha-KG or Mg.OAA chelates, the enzyme displays sigmoid kinetics; the Hanes plots deviate from linearity, indicating the positive cooperative dependence of the velocity upon the substrate concentration. Hill coefficients (equal to 1 in the absence of the chelates) of 1.23 and 1.33 have been determined in the presence of Mg.alpha-KG and Mg.OAA complexes, respectively. The disruption of microsomal integrity by detergents abolishes the effect of Mg.alpha-KG and Mg.OAA, suggesting that the magnesium chelates inhibit the translocase component of the glucose-6-phosphatase system.

  10. GPR142 Controls Tryptophan-Induced Insulin and Incretin Hormone Secretion to Improve Glucose Metabolism

    PubMed Central

    Efanov, Alexander M.; Fang, Xiankang; Beavers, Lisa S.; Wang, Xuesong; Wang, Jingru; Gonzalez Valcarcel, Isabel C.; Ma, Tianwei

    2016-01-01

    GPR142, a putative amino acid receptor, is expressed in pancreatic islets and the gastrointestinal tract, but the ligand affinity and physiological role of this receptor remain obscure. In this study, we show that in addition to L-Tryptophan, GPR142 signaling is also activated by L-Phenylalanine but not by other naturally occurring amino acids. Furthermore, we show that Tryptophan and a synthetic GPR142 agonist increase insulin and incretin hormones and improve glucose disposal in mice in a GPR142-dependent manner. In contrast, Phenylalanine improves in vivo glucose disposal independently of GPR142. Noteworthy, refeeding-induced elevations in insulin and glucose-dependent insulinotropic polypeptide are blunted in Gpr142 null mice. In conclusion, these findings demonstrate GPR142 is a Tryptophan receptor critically required for insulin and incretin hormone regulation and suggest GPR142 agonists may be effective therapies that leverage amino acid sensing pathways for the treatment of type 2 diabetes. PMID:27322810

  11. Evidence for the absence of cerebral glucose-6-phosphatase activity in glycogen storage disease type I (Von Gierke's disease)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Phelps, M.E.; Mazziotta, J.C.; Hawkins, R.A.

    1981-01-01

    Glycogen storage disease type I (GSD-I) is characterized by a functional deficit in glucose-6-phosphatase that normally hydrolyzes glucose-6-PO/sub 4/ to glucose. This enzyme is primarily found in liver, kidney, and muscle but it is also present in brain, where it appears to participate in the regulation of cerebral tissue glucose. Since most neurological symptoms in GSD-I patients involve systemic hypoglycemia, previous reports have not examined possible deficiencies in phosphatase activity in the brain. Positron computed tomography, F-18-labeled 2-fluorodeoxyglucose (FDG) and a tracer kinetic model for FDG were used to measure the cortical plasma/tissue forward and reverse transport, phosphorylation and dephosphorylationmore » rate constants, tissue/plasma concentration gradient, tissue concentration turnover rate for this competitive analog of glucose, and the cortical metabolic rates for glucose. Studies were carried out in age-matched normals (N = 13) and a single GSD-I patient. The dephosphorylation rate constant in the GSD-I patient was about one tenth the normal value indicating a low level of cerebral phosphatase activity. The other measured parameters were within normal limits except for the rate of glucose phosphorylation which reflected a cortical glucose metabolic rate one half the normal value. Since glucose transport and tissue glucose concentration was normal, the reduced cortical glucose metabolism probably results from the use of alternative substrates (..beta..-hydroxybutyrate and acetoacetate) which are consistently elevated in the plasma of GSD-I patients.« less

  12. FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes.

    PubMed

    Laeger, Thomas; Baumeier, Christian; Wilhelmi, Ilka; Würfel, Josefine; Kamitz, Anne; Schürmann, Annette

    2017-11-01

    Fibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes. Male NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints. FGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression. FGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice.

  13. Perinatal Exposure to Perfluorooctane Sulfonate Affects Glucose Metabolism in Adult Offspring

    PubMed Central

    Wan, Hin T.; Zhao, Yin G.; Leung, Pik Y.; Wong, Chris K. C.

    2014-01-01

    Perfluoroalkyl acids (PFAAs) are globally present in the environment and are widely distributed in human populations and wildlife. The chemicals are ubiquitous in human body fluids and have a long serum elimination half-life. The notorious member of PFAAs, perfluorooctane sulfonate (PFOS) is prioritized as a global concerning chemical at the Stockholm Convention in 2009, due to its harmful effects in mammals and aquatic organisms. PFOS is known to affect lipid metabolism in adults and was found to be able to cross human placenta. However the effects of in utero exposure to the susceptibility of metabolic disorders in offspring have not yet been elucidated. In this study, pregnant CD-1 mice (F0) were fed with 0, 0.3 or 3 mg PFOS/kg body weight/day in corn oil by oral gavage daily throughout gestational and lactation periods. We investigated the immediate effects of perinatal exposure to PFOS on glucose metabolism in both maternal and offspring after weaning (PND 21). To determine if the perinatal exposure predisposes the risk for metabolic disorder to the offspring, weaned animals without further PFOS exposure, were fed with either standard or high-fat diet until PND 63. Fasting glucose and insulin levels were measured while HOMA-IR index and glucose AUCs were reported. Our data illustrated the first time the effects of the environmental equivalent dose of PFOS exposure on the disturbance of glucose metabolism in F1 pups and F1 adults at PND 21 and 63, respectively. Although the biological effects of PFOS on the elevated levels of fasting serum glucose and insulin levels were observed in both pups and adults of F1, the phenotypes of insulin resistance and glucose intolerance were only evident in the F1 adults. The effects were exacerbated under HFD, highlighting the synergistic action at postnatal growth on the development of metabolic disorders. PMID:24498028

  14. C-myb Regulates Autophagy for Pulp Vitality in Glucose Oxidative Stress.

    PubMed

    Lee, Y H; Kim, H S; Kim, J S; Yu, M K; Cho, S D; Jeon, J G; Yi, H K

    2016-04-01

    Diabetes mellitus is closely related to oral-complicated diseases by oxidative stress. This study investigates whether cellular myeloblastosis (c-myb) could protect human dental pulp cells against glucose oxidative stress and regulate autophagy activity for pulp vitality. Diabetes mellitus was induced by streptozotocin in Sprague-Dawley rats, and their pulp tissue in teeth was analyzed in terms of pulp cavity and molecules by hematoxylin and eosin and immunohistochemistry staining. Human dental pulp cells were serially subcultured and treated with glucose oxidase in the presence of elevated glucose to generate glucose oxidative stress. The replication-deficient adenovirus c-myb and small interfering RNA c-myb were introduced for c-myb expression. The pulp tissue from the diabetic rats was structurally different from normal tissue in terms of narrow pulp capacity, reduced c-myb, and dentinogenesis molecules. Glucose oxidase treatment decreased c-myb and dentinogenesis molecules (bone morphogenetic protein 2 and 7, dentin matrix protein 1, and dentin sialophosphoprotein) in human dental pulp cells. However, overexpression of c-myb by adenovirus c-myb increased dentinogenesis, autophagy molecules (autophagy protein 5, microtubule-associated protein 1A/1B-light chain 3, and Beclin-1), and cell survival via p-AMPK/AKT signaling even with glucose oxidative stress. In contrast, the lack of c-myb decreased the above molecules and cell survival by downregulating p-AMPK/AKT signaling. The results indicate that diabetes leads to irreversible damage to dental pulp, which is related to downexpression of autophagy via the p-AMPK/AKT pathway by decline of c-myb. The findings of this study provide a new insight that c-myb could ameliorate autophagy activity and that it is applicable for monitoring complicated diseases of dental pulp. The involvement of c-myb in pulp pathology could serve a therapeutic target in oral-complicated diseases. © International & American Associations

  15. Glucose-dependent insulinotropic polypeptide directly induces glucose transport in rat skeletal muscle

    PubMed Central

    Snook, Laelie A.; Nelson, Emery M.; Dyck, David J.; Wright, David C.

    2015-01-01

    Several gastrointestinal proteins have been identified to have insulinotropic effects, including glucose-dependent insulinotropic polypeptide (GIP); however, the direct effects of incretins on skeletal muscle glucose transport remain largely unknown. Therefore, the purpose of the current study was to examine the role of GIP on skeletal muscle glucose transport and insulin signaling in rats. Relative to a glucose challenge, a mixed glucose+lipid oral challenge increased circulating GIP concentrations, skeletal muscle Akt phosphorylation, and improved glucose clearance by ∼35% (P < 0.05). These responses occurred without alterations in serum insulin concentrations. In an incubated soleus muscle preparation, GIP directly stimulated glucose transport and increased GLUT4 accumulation on the plasma membrane in the absence of insulin. Moreover, the ability of GIP to stimulate glucose transport was mitigated by the addition of the PI 3-kinase (PI3K) inhibitor wortmannin, suggesting that signaling through PI3K is required for these responses. We also provide evidence that the combined stimulatory effects of GIP and insulin on soleus muscle glucose transport are additive. However, the specific GIP receptor antagonist (Pro3)GIP did not attenuate GIP-stimulated glucose transport, suggesting that GIP is not signaling through its classical receptor. Together, the current data provide evidence that GIP regulates skeletal muscle glucose transport; however, the exact signaling mechanism(s) remain unknown. PMID:26041107

  16. Flight is the key to postprandial blood glucose balance in the fruit bats Eonycteris spelaea and Cynopterus sphinx.

    PubMed

    Peng, Xingwen; He, Xiangyang; Liu, Qi; Sun, Yunxiao; Liu, Hui; Zhang, Qin; Liang, Jie; Peng, Zhen; Liu, Zhixiao; Zhang, Libiao

    2017-11-01

    Excessive sugar consumption could lead to high blood glucose levels that are harmful to mammalian health and life. Despite consuming large amounts of sugar-rich food, fruit bats have a longer lifespan, raising the question of how these bats overcome potential hyperglycemia. We investigated the change of blood glucose level in nectar-feeding bats ( Eonycteris spelaea ) and fruit-eating bats ( Cynopterus sphinx ) via adjusting their sugar intake and time of flight. We found that the maximum blood glucose level of C. sphinx was higher than 24 mmol/L that is considered to be pathological in other mammals. After C. sphinx bats spent approximately 75% of their time to fly, their blood glucose levels dropped markedly, and the blood glucose of E. spelaea fell to the fast levels after they spent 70% time of fly. Thus, the level of blood glucose elevated with the quantity of sugar intake but declined with the time of flight. Our results indicate that high-intensive flight is a key regulator for blood glucose homeostasis during foraging. High-intensive flight may confer benefits to the fruit bats in foraging success and behavioral interactions and increases the efficiency of pollen and seed disposal mediated by bats.

  17. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium.

    PubMed

    Wu, Yu-Chieh; Buckner, Benjamin R; Zhu, Meifang; Cavanagh, H Dwight; Robertson, Danielle M

    2012-04-01

    To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real-time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (P<0.001) following culture of hTCEpi cells under elevated glucose conditions in vitro. Treatment with glucose and the mannitol control reduced IGFBP3 mRNA (P<0.001). Total IGF-1R levels were unchanged. The increase in the IGFBP3:IGF-1 ratio detected in diabetic tears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (P<0.001) when tested in vitro. Taken together, these in vivo and confirmatory in vitro findings suggest that the observed increase in IGFBP3 found in human tears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Elevated IGFBP3 levels in diabetic tears: a negative regulator of IGF-1 signaling in the corneal epithelium

    PubMed Central

    Wu, Yu-Chieh; Buckner, Benjamin R.; Zhu, Meifang; Cavanagh, H. Dwight; Robertson, Danielle M.

    2012-01-01

    Purpose To determine the ratio of IGFBP3:IGF-1 in normal and diabetic human tears, and in telomerase-immortalized human corneal epithelial cells (hTCEpi) cultured under elevated glucose conditions and to correlate these changes with total and phosphorylated levels of IGF-1R. Methods Tear samples were collected noninvasively from diabetic subjects and non-diabetic controls; corneal sensitivity was assessed using a Cochet-Bonnet Aesthesiometer. Conditioned media were collected following culture of hTCEpi cells in normal (5 mM) and elevated (25 mM) glucose conditions; mannitol was used as an osmotic control. IGFBP3, IGF-1, and phosphorylated IGF-1R levels were assessed by ELISA. IGFBP3 and IGF-1R mRNA were assessed by real time polymerase chain reaction (PCR). Total and phosphorylated IGF-1R expression in whole cell lysates was assessed by western blot. Results There was a 2.8-fold increase in IGFBP3 in diabetic tears compared to non-diabetic controls (P=0.006); IGF-1 levels were not significantly altered. No difference in corneal sensitivity was detected between groups. The concentration of IGFBP3 in tears was independent of IGF-1. Consistent with human tear measurements in vivo, IGFBP3 secretion was increased 2.2 fold (P<0.001) following culture of hTCEpi cells under elevated glucose conditions in vitro. Treatment with glucose and the mannitol control reduced IGFBP3 mRNA (P<0.001). Total IGF-1R levels were unchanged. The increase in the IGFBP3:IGF-1 ratio detected in diabetic tears compared to normal controls blocked phosphorylation of the IGF-1R by IGF-1 (P<0.001) when tested in vitro. Conclusions Taken together, these in vivo and confirmatory in vitro findings suggest that the observed increase in IGFBP3 found in human tears may attenuate IGF-1R signaling in the diabetic cornea. A long-term increase in IGFBP3 may contribute to epithelial compromise and the pathogenesis of ocular surface complications reported in diabetes. PMID:22482470

  19. Antagonism between phytohormone signalling underlies the variation in disease susceptibility of tomato plants under elevated CO2.

    PubMed

    Zhang, Shuai; Li, Xin; Sun, Zenghui; Shao, Shujun; Hu, Lingfei; Ye, Meng; Zhou, Yanhong; Xia, Xiaojian; Yu, Jingquan; Shi, Kai

    2015-04-01

    Increasing CO2 concentrations ([CO2]) have the potential to disrupt plant-pathogen interactions in natural and agricultural ecosystems, but the research in this area has often produced conflicting results. Variations in phytohormone salicylic acid (SA) and jasmonic acid (JA) signalling could be associated with variations in the responses of pathogens to plants grown under elevated [CO2]. In this study, interactions between tomato plants and three pathogens with different infection strategies were compared. Elevated [CO2] generally favoured SA biosynthesis and signalling but repressed the JA pathway. The exposure of plants to elevated [CO2] revealed a lower incidence and severity of disease caused by tobacco mosaic virus (TMV) and by Pseudomonas syringae, whereas plant susceptibility to necrotrophic Botrytis cinerea increased. The elevated [CO2]-induced and basal resistance to TMV and P. syringae were completely abolished in plants in which the SA signalling pathway nonexpressor of pathogenesis-related genes 1 (NPR1) had been silenced or in transgenic plants defective in SA biosynthesis. In contrast, under both ambient and elevated [CO2], the susceptibility to B. cinerea highly increased in plants in which the JA signalling pathway proteinase inhibitors (PI) gene had been silenced or in a mutant affected in JA biosynthesis. However, plants affected in SA signalling remained less susceptible to this disease. These findings highlight the modulated antagonistic relationship between SA and JA that contributes to the variation in disease susceptibility under elevated [CO2]. This information will be critical for investigating how elevated CO2 may affect plant defence and the dynamics between plants and pathogens in both agricultural and natural ecosystems. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  20. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo.

    PubMed

    Gautam, Dinesh; Han, Sung-Jun; Hamdan, Fadi F; Jeon, Jongrye; Li, Bo; Li, Jian Hua; Cui, Yinghong; Mears, David; Lu, Huiyan; Deng, Chuxia; Heard, Thomas; Wess, Jürgen

    2006-06-01

    One of the hallmarks of type 2 diabetes is that pancreatic beta cells fail to release sufficient amounts of insulin in the presence of elevated blood glucose levels. Insulin secretion is modulated by many hormones and neurotransmitters including acetylcholine, the major neurotransmitter of the peripheral parasympathetic nervous system. The physiological role of muscarinic acetylcholine receptors expressed by pancreatic beta cells remains unclear at present. Here, we demonstrate that mutant mice selectively lacking the M3 muscarinic acetylcholine receptor subtype in pancreatic beta cells display impaired glucose tolerance and greatly reduced insulin release. In contrast, transgenic mice selectively overexpressing M3 receptors in pancreatic beta cells show a profound increase in glucose tolerance and insulin release. Moreover, these mutant mice are resistant to diet-induced glucose intolerance and hyperglycemia. These findings indicate that beta cell M3 muscarinic receptors play a key role in maintaining proper insulin release and glucose homeostasis.

  1. Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A.

    PubMed

    Zhao, Jiejie; Xiong, Xuelian; Li, Yao; Liu, Xing; Wang, Tao; Zhang, Hong; Jiao, Yang; Jiang, Jingjing; Zhang, Huijie; Tang, Qiqun; Gao, Xin; Li, Xuejun; Lu, Yan; Liu, Bin; Hu, Cheng; Li, Xiaoying

    2018-05-01

    Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis. © 2018 by the American Diabetes Association.

  2. Association between glucose intolerance and bacterial colonisation in an adult population with cystic fibrosis, emergence of Stenotrophomonas maltophilia.

    PubMed

    Lehoux Dubois, C; Boudreau, V; Tremblay, F; Lavoie, A; Berthiaume, Y; Rabasa-Lhoret, R; Coriati, A

    2017-05-01

    Diabetes is common in cystic fibrosis (CF). Glucose can be detected in the airway when the blood glucose is elevated, which favours bacterial growth. We investigated the relationship between dysglycemia and lung pathogens in CF. Cross-sectional and prospective analysis of CF patients (N=260) who underwent a 2h-oral glucose tolerance test. Clinical data was collected. Stenotrophomonas maltophilia (S. maltophilia) was the sole bacteria increased in dysglycemic (AGT: 20.2%, CFRD: 21.6%) patients compared to normotolerants (NGT: 8.7%). S. maltophilia positive patients with dysglycemia had more pulmonary exacerbation events compared to NGTs (1.22 vs 0.63, P=0.003). The interaction between S. maltophilia colonisation and glucose tolerance status significantly increases the risk of lower lung function (P=0.003). Its growth was not affected by the evolution of the glucose tolerance after three years follow-up. Prevalence of S. maltophilia was higher in dysglycemic patients, supporting the idea that S. maltophilia is a marker of disease severity in CF. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  3. Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response

    PubMed Central

    2014-01-01

    Background Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow’s milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats. Methods We fed female rats (~2.5 to 3 months of age) CLA t10,c12 –enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions. Results There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate. Conclusions This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response. PMID:24956949

  4. Feeding butter with elevated content of trans-10, cis-12 conjugated linoleic acid to lean rats does not impair glucose tolerance or muscle insulin response.

    PubMed

    Stefanson, Amanda; Hopkins, Loren E; AlZahal, Ousama; Ritchie, Ian R; MacDonald, Tara; Wright, David C; McBride, Brian W; Dyck, David J

    2014-06-23

    Numerous studies have investigated the effects of isolated CLA supplementation on glucose homeostasis in humans and rodents. However, both the amount and relative abundance of CLA isomers in supplemental form are not representative of what is consumed from natural sources. No study to date has examined the effects of altered CLA isomer content within a natural food source. Our goal was to increase the content of the insulin desensitizing CLAt10,c12 isomer relative to the CLAc9,t11 isomer in cow's milk by inducing subacute rumenal acidosis (SARA), and subsequently investigate the effects of this milk fat on parameters related to glucose and insulin tolerance in rats. We fed female rats (~2.5 to 3 months of age) CLA t10,c12 -enriched (SARA) butter or non-SARA butter based diets for 4 weeks in either low (10% of kcal from fat; 0.18% total CLA by weight) or high (60% of kcal from fat; 0.55% total CLA by weight) amounts. In an effort to extend these findings, we then fed rats high (60% kcal) amounts of SARA or non-SARA butter for a longer duration (8 weeks) and assessed changes in whole body glucose, insulin and pyruvate tolerance in comparison to low fat and 60% lard conditions. There was a main effect for increased fasting blood glucose and insulin in SARA vs. non-SARA butter groups after 4 weeks of feeding (p < 0.05). However, blood glucose and insulin concentration, and maximal insulin-stimulated glucose uptake in skeletal muscle were similar in all groups. Following 8 weeks of feeding, insulin tolerance was impaired by the SARA butter, but not glucose or pyruvate tolerance. The non-SARA butter did not impair tolerance to glucose, insulin or pyruvate. This study suggests that increasing the consumption of a naturally enriched CLAt10,c12 source, at least in rats, has minimal impact on whole body glucose tolerance or muscle specific insulin response.

  5. FoxO1 regulates myocardial glucose oxidation rates via transcriptional control of pyruvate dehydrogenase kinase 4 expression.

    PubMed

    Gopal, Keshav; Saleme, Bruno; Al Batran, Rami; Aburasayn, Hanin; Eshreif, Amina; Ho, Kim L; Ma, Wayne K; Almutairi, Malak; Eaton, Farah; Gandhi, Manoj; Park, Edwards A; Sutendra, Gopinath; Ussher, John R

    2017-09-01

    Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of Pdk4 , the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which Pdk4 /PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the Pdk4 promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased Pdk4 /PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced Pdk4 /PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a Pdk4 promoter construct containing the FoxO1 DNA-binding element region, but not in a Pdk4 promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates Pdk4 transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates. NEW & NOTEWORTHY Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we

  6. Calculation of Glucose Dose for Intraperitoneal Glucose Tolerance Tests in Lean and Obese Mice.

    PubMed

    Jørgensen, Mikkel S; Tornqvist, Kristina S; Hvid, Henning

    2017-01-01

    Glucose tolerance tests are used frequently in nonclinical research with laboratory animals, for example during characterization of obese phenotypes. Despite published standard operating procedures for glucose tolerance tests in rodents, how glucose doses should be calculated when obese and lean animals are compared is not well documented. Typically the glucose dose is calculated as 2 g/kg body weight, regardless of body composition. With this approach, obese mice receive larger glucose doses than do lean animals, potentially leading to overestimation of glucose intolerance in obese animals. In this study, we performed intraperitoneal glucose tolerance tests in mice with diet-induced obesity and their lean controls, with glucose doses based on either the total body weight or the lean body mass of the animals. To determine glucose tolerance, we determined the blood glucose AUC during the glucose tolerance test. We found that the blood glucose AUC was increased significantly in obese mice compared with lean mice by 75% on average when glucose was dosed according to the lean body mass and by 87% when the glucose dose was calculated according to total body weight. Therefore, mice with diet-induced obesity were approximately equally glucose intolerant between the 2 dose-calculation protocols. However, we recommend calculating the glucose dose according to the lean body mass of the mice, because doing so eliminates the concern regarding overdosing of obese animals.

  7. Two Views on Discipline: What Happens When a District Abolishes Corporal Punishment? and Discipline, Disruption, and the Dilemma

    ERIC Educational Resources Information Center

    Gerhard, Victor J., Jr.; Mahoney, John T.

    1978-01-01

    Susquehanna Valley Central School abolished corporal punishment for practical reasons. At Perry Junior-Senior High School, there is a feeling on the part of parents, students, and teachers that all students are dealt with fairly and impartially since the adoption, two years ago, of the Cause-Effect Discipline Code. (Author/AM)

  8. Perifornical hypothalamic pathway to the adrenal gland: Role for glutamatergic transmission in the glucose counter-regulatory response.

    PubMed

    Sabetghadam, A; Korim, W S; Verberne, A J M

    2017-03-01

    Adrenaline is an important counter-regulatory hormone that helps restore glucose homeostasis during hypoglycaemia. However, the neurocircuitry that connects the brain glucose sensors and the adrenal sympathetic outflow to the chromaffin cells is poorly understood. We used electrical microstimulation of the perifornical hypothalamus (PeH) and the rostral ventrolateral medulla (RVLM) combined with adrenal sympathetic nerve activity (ASNA) recording to examine the relationship between the RVLM, the PeH and ASNA. In urethane-anaesthetised male Sprague-Dawley rats, intermittent single pulse electrical stimulation of the rostroventrolateral medulla (RVLM) elicited an evoked ASNA response that consisted of early (60±3ms) and late peaks (135±4ms) of preganglionic and postganglionic activity. In contrast, RVLM stimulation evoked responses in lumbar sympathetic nerve activity that were almost entirely postganglionic. PeH stimulation also produced an evoked excitatory response consisting of both preganglionic and postganglionic excitatory peaks in ASNA. Both peaks in ASNA following RVLM stimulation were reduced by intrathecal kynurenic acid (KYN) injection. In addition, the ASNA response to systemic neuroglucoprivation induced by 2-deoxy-d-glucose was abolished by bilateral microinjection of KYN into the RVLM. This suggests that a glutamatergic pathway from the perifornical hypothalamus (PeH) relays in the RVLM to activate the adrenal SPN and so modulate ASNA. The main findings of this study are that (i) adrenal premotor neurons in the RVLM may be, at least in part, glutamatergic and (ii) that the input to these neurons that is activated during neuroglucoprivation is also glutamatergic. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain.

    PubMed

    Wakabayashi, Ken T; Spekterman, Laurence; Kiyatkin, Eugene A

    2016-06-01

    Glucose, a primary metabolic substrate for cellular activity, must be delivered to the brain for normal neural functions. Glucose is also a unique reinforcer; in addition to its rewarding sensory properties and metabolic effects, which all natural sugars have, glucose crosses the blood-brain barrier and acts on glucoreceptors expressed on multiple brain cells. To clarify the role of this direct glucose action in the brain, we compared the neural and behavioural effects of glucose with those induced by fructose, a sweeter yet metabolically equivalent sugar. First, by using enzyme-based biosensors in freely moving rats, we confirmed that glucose rapidly increased in the nucleus accumbens in a dose-dependent manner after its intravenous delivery. In contrast, fructose induced a minimal response only after a large-dose injection. Second, we showed that naive rats during unrestricted access consumed larger volumes of glucose than fructose solution; the difference appeared with a definite latency during the initial exposure and strongly increased during subsequent tests. When rats with equal sugar experience were presented with either glucose or fructose in alternating order, the consumption of both substances was initially equal, but only the consumption of glucose increased during subsequent sessions. Finally, rats with equal glucose-fructose experience developed a strong preference for glucose over fructose during a two-bottle choice procedure; the effect appeared with a definite latency during the initial test and greatly amplified during subsequent tests. Our results suggest that direct entry of glucose in the brain and its subsequent effects on brain cells could be critical for the experience-dependent escalation of glucose consumption and the development of glucose preference over fructose. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  10. Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels

    PubMed Central

    Tuersunjiang, Nuermaimaiti; Odhiambo, John F.; Long, Nathan M.; Shasa, Desiree R.; Nathanielsz, Peter W.

    2013-01-01

    Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics. PMID:23921140

  11. Diet reduction to requirements in obese/overfed ewes from early gestation prevents glucose/insulin dysregulation and returns fetal adiposity and organ development to control levels.

    PubMed

    Tuersunjiang, Nuermaimaiti; Odhiambo, John F; Long, Nathan M; Shasa, Desiree R; Nathanielsz, Peter W; Ford, Stephen P

    2013-10-01

    Obesity at conception and excess gestational weight gain pose significant risks for adverse health consequences in human offspring. This study evaluated the effects of reducing dietary intake of obese/overfed ewes beginning in early gestation on fetal development. Sixty days prior to conception, ewes were assigned to a control diet [CON: 100% of National Research Council (NRC) recommendations], a diet inducing maternal obesity (MO: 150% of NRC recommendations), or a maternal obesity intervention diet (MOI: 150% of NRC recommendations to day 28 of gestation, then 100% NRC) until necropsy at midgestation (day 75) or late (day 135) gestation. Fetal size and weight, as well as fetal organ weights, were greater (P < 0.05) at midgestation in MO ewes than those of CON and MOI ewes. By late gestation, whereas fetal size and weight did not differ among dietary groups, cardiac ventricular weights and wall thicknesses as well as liver and perirenal fat weights remained elevated in fetuses from MO ewes compared with those from CON and MOI ewes. MO ewes and fetuses exhibited elevated (P < 0.05) plasma concentrations of triglycerides, cholesterol, insulin, glucose, and cortisol at midgestation compared with CON and MOI ewes and fetuses. In late gestation, whereas plasma triglycerides and cholesterol, insulin, and cortisol remained elevated in MO vs. CON and MOI ewes and fetuses, glucose concentrations were elevated in both MO and MOI fetuses compared with CON fetuses, which was associated with elevated placental GLUT3 expression in both groups. These data are consistent with the concept that reducing maternal diet of obese/overfed ewes to requirements from early gestation can prevent subsequent alterations in fetal growth, adiposity, and glucose/insulin dynamics.

  12. Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

    PubMed Central

    An, Zhibo; Johnson, Kathryn M. S.; Farmer, Tiffany; Farmer, Ben; Neal, Doss; Cherrington, Alan D.

    2013-01-01

    Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg−1·min−1, Ex-4-low; n = 5) or high (0.9 pmol·kg−1·min−1, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg−1·min−1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg−1·min−1), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. PMID:23673158

  13. The economic burden of elevated blood glucose levels in 2012: diagnosed and undiagnosed diabetes, gestational diabetes mellitus, and prediabetes.

    PubMed

    Dall, Timothy M; Yang, Wenya; Halder, Pragna; Pang, Bo; Massoudi, Marjan; Wintfeld, Neil; Semilla, April P; Franz, Jerry; Hogan, Paul F

    2014-12-01

    To update estimates of the economic burden of undiagnosed diabetes, prediabetes, and gestational diabetes mellitus in 2012 in the U.S. and to present state-level estimates. Combined with published estimates for diagnosed diabetes, these statistics provide a detailed picture of the economic costs associated with elevated glucose levels. This study estimated health care use and medical expenditures in excess of expected levels occurring in the absence of diabetes or prediabetes. Data sources that were analyzed include Optum medical claims for ∼4.9 million commercially insured patients who were continuously enrolled from 2010 to 2012, Medicare Standard Analytical Files containing medical claims for ∼2.6 million Medicare patients in 2011, and the 2010 Nationwide Inpatient Sample containing ∼7.8 million hospital discharge records. The indirect economic burden includes reduced labor force participation, missed workdays, and reduced productivity. State-level estimates reflect geographic variation in prevalence, risk factors, and prices. The economic burden associated with diagnosed diabetes (all ages) and undiagnosed diabetes, gestational diabetes, and prediabetes (adults) exceeded $322 billion in 2012, consisting of $244 billion in excess medical costs and $78 billion in reduced productivity. Combined, this amounts to an economic burden exceeding $1,000 for each American in 2012. This national estimate is 48% higher than the $218 billion estimate for 2007. The burden per case averaged $10,970 for diagnosed diabetes, $5,800 for gestational diabetes, $4,030 for undiagnosed diabetes, and $510 for prediabetes. These statistics underscore the importance of finding ways to reduce the burden of prediabetes and diabetes through prevention and treatment. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  14. The influence of elevated CO2 on non-structural carbohydrate distribution and fructan accumulation in wheat canopies

    NASA Technical Reports Server (NTRS)

    Smart, D. R.; Chatterton, N. J.; Bugbee, B.

    1994-01-01

    We grew 2.4 m2 wheat canopies in a large growth chamber under high photosynthetic photon flux (1000 micromoles m-2 s-1) and using two CO2 concentrations, 360 and 1200 micromoles mol-1. Photosynthetically active radiation (400-700 nm) was attenuated slightly faster through canopies grown in 360 micromoles mol-1 than through canopies grown in 1200 micromoles mol-1, even though high-CO2 canopies attained larger leaf area indices. Tissue fractions were sampled from each 5-cm layer of the canopies. Leaf tissue sampled from the tops of canopies grown in 1200 micromoles mol-1 accumulated significantly more total non-structural carbohydrate, starch, fructan, sucrose, and glucose (p < 0.05) than for canopies grown in 360 micromoles mol-1. Non-structural carbohydrate did not significantly increase in the lower canopy layers of the elevated CO2 treatment. Elevated CO2 induced fructan synthesis in all leaf tissue fractions, but fructan formation was greatest in the uppermost leaf area. A moderate temperature reduction of 10 degrees C over 5 d increased starch, fructan and glucose levels in canopies grown in 1200 micromoles mol-1, but concentrations of sucrose and fructose decreased slightly or remained unchanged. Those results may correspond with the use of fructosyl-residues and release of glucose when sucrose is consumed in fructan synthesis.

  15. A glucose oxidase-coupled DNAzyme sensor for glucose detection in tears and saliva.

    PubMed

    Liu, Chengcheng; Sheng, Yongjie; Sun, Yanhong; Feng, Junkui; Wang, Shijin; Zhang, Jin; Xu, Jiacui; Jiang, Dazhi

    2015-08-15

    Biosensors have been widely investigated and utilized in a variety of fields ranging from environmental monitoring to clinical diagnostics. Glucose biosensors have triggered great interest and have been widely exploited since glucose determination is essential for diabetes diagnosis. In here, we designed a novel dual-enzyme biosensor composed of glucose oxidase (GOx) and pistol-like DNAzyme (PLDz) to detect glucose levels in tears and saliva. First, GOx, as a molecular recognition element, catalyzes the oxidation of glucose forming H2O2; then PLDz recognizes the produced H2O2 as a secondary signal and performs a self-cleavage reaction promoted by Mn(2+), Co(2+) and Cu(2+). Thus, detection of glucose could be realized by monitoring the cleavage rate of PLDz. The slope of the cleavage rate of PLDz versus glucose concentration curve was fitted with a Double Boltzmann equation, with a range of glucose from 100 nM to 10mM and a detection limit of 5 μM. We further applied the GOx-PLDz 1.0 biosensor for glucose detection in tears and saliva, glucose levels in which are 720±81 μM and 405±56 μM respectively. Therefore, the GOx-PLDz 1.0 biosensor is able to determine glucose levels in tears and saliva as a noninvasive glucose biosensor, which is important for diabetic patients with frequent/continuous glucose monitoring requirements. In addition, induction of DNAzyme provides a new approach in the development of glucose biosensors. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Coping with an exogenous glucose overload: glucose kinetics of rainbow trout during graded swimming

    PubMed Central

    Choi, Kevin

    2015-01-01

    This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 μmol·kg−1·min−1 and boost glucose disposal to 40.1 ± 13 μmol·kg−1·min−1. These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise. PMID:26719305

  17. Automated UV-C mutagenesis of Kluyveromyces marxianus NRRL Y-1109 and selection for microaerophilic growth and ethanol production at elevated temperature on biomass sugars.

    PubMed

    Hughes, Stephen R; Bang, Sookie S; Cox, Elby J; Schoepke, Andrew; Ochwat, Kate; Pinkelman, Rebecca; Nelson, Danielle; Qureshi, Nasib; Gibbons, William R; Kurtzman, Cletus P; Bischoff, Kenneth M; Liu, Siqing; Cote, Gregory L; Rich, Joseph O; Jones, Marjorie A; Cedeño, David; Doran-Peterson, Joy; Riaño-Herrera, Nestor M; Rodríguez-Valencia, Nelson; López-Núñez, Juan C

    2013-08-01

    The yeast Kluyveromyces marxianus is a potential microbial catalyst for fuel ethanol production from a wide range of biomass substrates. To improve its growth and ethanol yield at elevated temperature under microaerophilic conditions, K. marxianus NRRL Y-1109 was irradiated with UV-C using automated protocols on a robotic platform for picking and spreading irradiated cultures and for processing the resulting plates. The plates were incubated under anaerobic conditions on xylose or glucose for 5 mo at 46 °C. Two K. marxianus mutant strains (designated 7-1 and 8-1) survived and were isolated from the glucose plates. Both mutant strains, but not wild type, grew aerobically on glucose at 47 °C. All strains grew anaerobically at 46 °C on glucose, galactose, galacturonic acid, and pectin; however, only 7-1 grew anaerobically on xylose at 46 °C. Saccharomyces cerevisiae NRRL Y-2403 did not grow at 46 °C on any of these substrates. With glucose as a carbon source, ethanol yield after 3 d at 46 °C was higher for 8-1 than for wild type (0.51 and 0.43 g ethanol/g glucose, respectively). With galacturonic acid as a carbon source, the ethanol yield after 7 d at 46 °C was higher for 7-1 than for wild type (0.48 and 0.34 g ethanol/g galacturonic acid, respectively). These mutant strains have potential application in fuel ethanol production at elevated temperature from sugar constituents of starch, sucrose, pectin, and cellulosic biomass.

  18. Factors associated with elevated serum alanine aminotransferase in patients with type 1 diabetes mellitus.

    PubMed

    Hatanaka, S A; Silva, N O; Colombo, B S; Correa, C G; Alcaire, B P; Coral, M H; Schiavon, L L; Narciso-Schiavon, J L

    2015-09-01

    Metabolic syndrome and type 2 diabetes are associated with insulin resistance and hepatic steatosis, which are common causes of alanine aminotransferase (ALT) elevation. This study aims to identify variables associated with altered ALT in type 1 diabetic (DM1) subjects. A cross-sectional study conducted in the outpatient endocrinology clinic of a university hospital. Patients with DM1 were seen between December 2012 and September 2013; clinical variables were collected from medical records. Fifty-six patients were included aged 27 ± 10.1 years; 60.7% were men. The study subjects exhibited an average ALT of 36.7 ± 10.3 U/L (median = 35 U/L) and their average Body Mass Index (BMI) was 23.8 ± 3.8 kg/m2. When comparing individuals with elevated ALT > 35 U/L (N. = 27) with those ALT ≤ 35 U/L (N. = 29), we found that individuals with ALT values > 35 U/L showed a higher proportion of men (77.8% vs. 44.8%, P = 0.012) and a higher mean age (30.2 ± 12.3 vs. 24.6 ± 6.9 years, P = 0.046). When new ALT reference values were applied (19 U/L for women and 30 U/L for men), five individuals had normal ALT values. Individuals with elevated ALT had higher BMI (24.3 vs. 20.9; P = 0.036), fasting glucose (194.8 ± 101.2 vs. 123.6 ± 42.0 mg/dL; P = 0.013) and higher HbA1c (9.9 ± 2.8 vs. 7.8 ± 0.7%; P < 0.001) levels. In Pearson correlation analysis, ALT values ​correlated with HbA1c (r = 0.285; P = 0.033). In patients with DM1, elevated ALT values ​​are associated with BMI, fasting glucose and HbA1c.

  19. The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

    PubMed

    Guzzardi, M A; Hodson, L; Guiducci, L; La Rosa, F; Salvadori, P A; Burchielli, S; Iozzo, P

    2017-11-01

    Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [ 18 F]fluoro-2-deoxyglucose and [ 11 C]acetate, was combined with [ 14 C]acetate and [U- 13 C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U- 13 C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U- 13 C]palmitate-TG enrichment was higher after prolonged fasting. Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and

  20. Elevated pCO2 enhances bacterioplankton removal of organic carbon

    PubMed Central

    James, Anna K.; Passow, Uta; Brzezinski, Mark A.; Parsons, Rachel J.; Trapani, Jennifer N.; Carlson, Craig A.

    2017-01-01

    Factors that affect the removal of organic carbon by heterotrophic bacterioplankton can impact the rate and magnitude of organic carbon loss in the ocean through the conversion of a portion of consumed organic carbon to CO2. Through enhanced rates of consumption, surface bacterioplankton communities can also reduce the amount of dissolved organic carbon (DOC) available for export from the surface ocean. The present study investigated the direct effects of elevated pCO2 on bacterioplankton removal of several forms of DOC ranging from glucose to complex phytoplankton exudate and lysate, and naturally occurring DOC. Elevated pCO2 (1000–1500 ppm) enhanced both the rate and magnitude of organic carbon removal by bacterioplankton communities compared to low (pre-industrial and ambient) pCO2 (250 –~400 ppm). The increased removal was largely due to enhanced respiration, rather than enhanced production of bacterioplankton biomass. The results suggest that elevated pCO2 can increase DOC consumption and decrease bacterioplankton growth efficiency, ultimately decreasing the amount of DOC available for vertical export and increasing the production of CO2 in the surface ocean. PMID:28257422

  1. Coping with an exogenous glucose overload: glucose kinetics of rainbow trout during graded swimming.

    PubMed

    Choi, Kevin; Weber, Jean-Michel

    2016-03-15

    This study examines how chronically hyperglycemic rainbow trout modulate glucose kinetics in response to graded exercise up to critical swimming speed (Ucrit), with or without exogenous glucose supply. Our goals were 1) to quantify the rates of hepatic glucose production (Ra glucose) and disposal (Rd glucose) during graded swimming, 2) to determine how exogenous glucose affects the changes in glucose fluxes caused by exercise, and 3) to establish whether exogenous glucose modifies Ucrit or the cost of transport. Results show that graded swimming causes no change in Ra and Rd glucose at speeds below 2.5 body lengths per second (BL/s), but that glucose fluxes may be stimulated at the highest speeds. Excellent glucoregulation is also achieved at all exercise intensities. When exogenous glucose is supplied during exercise, trout suppress hepatic production from 16.4 ± 1.6 to 4.1 ± 1.7 μmol·kg(-1)·min(-1) and boost glucose disposal to 40.1 ± 13 μmol·kg(-1)·min(-1). These responses limit the effects of exogenous glucose to a 2.5-fold increase in glycemia, whereas fish showing no modulation of fluxes would reach dangerous levels of 114 mM of blood glucose. Exogenous glucose reduces metabolic rate by 16% and, therefore, causes total cost of transport to decrease accordingly. High glucose availability does not improve Ucrit because the fish are unable to take advantage of this extra fuel during maximal exercise and rely on tissue glycogen instead. In conclusion, trout have a remarkable ability to adjust glucose fluxes that allows them to cope with the cumulative stresses of a glucose overload and graded exercise. Copyright © 2016 the American Physiological Society.

  2. Bats: Body mass index, forearm mass index, blood glucose levels and SLC2A2 genes for diabetes

    PubMed Central

    Meng, Fanxing; Zhu, Lei; Huang, Wenjie; Irwin, David M.; Zhang, Shuyi

    2016-01-01

    Bats have an unusually large volume of endocrine tissue, with a large population of beta cells, and an elevated sensitivity to glucose and insulin. This makes them excellent animal models for studying diabetes mellitus. We evaluated bats as models for diabetes in terms of lifestyle and genetic factors. For lifestyle factors, we generated data sets of 149 body mass index (BMI) and 860 forearm mass index (FMI) measurements for different species of bats. Both showed negative inter-species correlations with blood glucose levels in sixteen bats examined. The negative inter-species correlations may reflect adaptation of a small insectivorous ancestor to a larger frugivore. We identified an 11 bp deletion in the proximal promoter of SLC2A2 that we predicted would disrupt binding sites for the transcription repressor ZNF354C. In frugivorous bats this could explain the relatively high expression of this gene, resulting in a better capacity to absorb glucose and decrease blood glucose levels. PMID:27439361

  3. Sarcopenia is a risk factor for elevated aminotransferase in men independently of body mass index, dietary habits, and physical activity.

    PubMed

    Yoo, Ki Deok; Jun, Dae Won; Lee, Kang Nyeong; Lee, Hang Lak; Lee, Oh Young; Yoon, Byung Chul; Choi, Ho Soon

    2015-04-01

    Aminotransferase activity is a surrogate marker of liver injury showing strong correlations with obesity and metabolic syndrome. However, elevated aminotransferase activity is not uncommon in non-obese and non-alcoholic patients in clinical practice. To examine the relationship between sarcopenia and aminotransferase activity in a large population-based cohort. Data from the Korean National Health and Nutrition Examinations were used. A total of 13,431 subjects were included. A whole-body dual X-ray absorptiometry scan was performed on each patient to measure total and regional muscle mass. Appendicular skeletal muscle mass indices were also obtained. The prevalence of sarcopenia was significantly higher in the group with elevated aminotransferase levels than in the normal liver enzyme group (males: 26.5% vs. 16.9%; females: 38.3% vs. 22.1%, p<0.05). The skeletal muscle index was negatively correlated with most cardiometabolic risk factors, including fasting glucose and cholesterol levels. The frequency of elevated aminotransferase increased in male patients with sarcopenia after adjusting for potential confounding factors including age, body mass index, fasting glucose level, dietary, and exercise habits. However, the correlation was no longer observed in women after adjusting for body mass index. Sarcopenia is a risk factor for elevated aminotransferase in men, independently of body mass index, dietary habits, and physical activity. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  4. Reciprocal regulation of insulin and plasma 5'-AMP in glucose homeostasis in mice.

    PubMed

    Xia, Lin; Wang, Zhongqiu; Zhang, Ying; Yang, Xiao; Zhan, Yibei; Cheng, Rui; Wang, Shiming; Zhang, Jianfa

    2015-03-01

    A previous investigation has demonstrated that plasma 5'-AMP (pAMP) exacerbates and causes hyperglycemia in diabetic mice. However, the crosstalk between pAMP and insulin signaling to regulate glucose homeostasis has not been investigated in depth. In this study, we showed that the blood glucose level was more dependent on the ratio of insulin to pAMP than on the absolute level of these two factors. Administration of 5'-AMP significantly attenuated the insulin-stimulated insulin receptor (IR) autophosphorylation in the liver and muscle tissues, resulting in the inhibition of downstream AKT phosphorylation. A docking analysis indicated that adenosine was a potential inhibitor of IR tyrosine kinase. Moreover, the 5'-AMP treatment elevated the ATP level in the pancreas and in the isolated islets, stimulating insulin secretion and increasing the plasma level of insulin. The insulin administration decreased the 5'-AMP-induced hyper-adenosine level by the up-regulation of adenosine kinase activities. Our results indicate that blood glucose homeostasis is reciprocally regulated by pAMP and insulin. © 2015 Society for Endocrinology.

  5. Glucose turnover and defense of blood glucose levels in Arctic fox (Alopex lagopus).

    PubMed

    Tallas, P G; White, R G

    1988-01-01

    1. Glucose utilization was assessed in fed and fasted arctic fox, maintained on a diet similar in composition to food available in the wild. 2. Fasted (24 hr) glucose concentration was not significantly different from the fed level (134 mg/dl). 3. Fasting was associated with a significant reduction in glucose space, pool size, total entry rate, and irreversible loss which suggests a decline in gluconeogenesis. 4. Glucose recycling was not significantly different between the fed and fasted states. 5. We suggest that, in the arctic fox, the mechanism for defending blood glucose levels during fasting is based on restricting blood glucose to tissues with a high glucose dependency.

  6. The Role of Incretins in Glucose Homeostasis and Diabetes Treatment

    PubMed Central

    Kim, Wook; Egan, Josephine M.

    2009-01-01

    Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, as well as others to be described in this review, their final common raison d’être is to aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4). A lack of secretion of incretins or an increase in their clearance are not pathogenic factors in diabetes. However, in type 2 diabetes (T2DM), GIP no longer modulates glucose-dependent insulin secretion, even at supraphysiological (pharmacological) plasma levels, and therefore GIP incompetence is detrimental to β-cell function, especially after eating. GLP-1, on the other hand, is still insulinotropic in T2DM, and this has led to the development of compounds that activate the GLP-1 receptor with a view to improving insulin secretion. Since 2005, two new classes of drugs based on incretin action have been approved for lowering blood glucose levels in T2DM: an incretin mimetic (exenatide, which is a potent long-acting agonist of the GLP-1 receptor) and an incretin enhancer (sitagliptin, which is a DPP4 inhibitor). Exenatide is injected subcutaneously twice daily and its use leads to lower blood glucose and higher insulin levels, especially in the fed state. There is glucose-dependency to its insulin secretory capacity, making it unlikely to cause low blood sugars (hypoglycemia). DPP4 inhibitors are orally active and they increase endogenous blood levels of active incretins, thus leading to prolonged incretin action. The elevated levels of GLP-1 are thought to be the mechanism underlying their

  7. [Biochemical measurements of glucose metabolism in relation to cause of death and postmortem effects].

    PubMed

    Kernbach, G; Püschel, K; Brinkmann, B

    1986-01-01

    This study was performed to examine the relationship between postmortem biochemical values and cause of death. The follow samples were taken from 399 corpses: cerebrospinal fluid (CSF; n = 376, suboccipital), blood (n = 158, femoral vein), and urine (n = 101, at autopsy). (See Table 1 for causes of death) All samples were stored at -80 degrees C. A further 100 samples of blood were later taken and stored at +4 degrees C before testing. Biochemical determinations made were: glucose in CSF, blood, and urine (hexokinase method); lactate (LDH/GPT) and free acetone (HS-gas chromatography) in CSF; hemoglobin A1 in blood (microcolumn technique). In 34 cases fatal diabetic coma was considered verified by morphological and chemical findings. One hundred cases of sudden cardiac death were chosen as the main control group. In 32 of the 34 cases defined above, the value of the formula of Traub (glucose + lactate in CSF) exceeded 415 mg/dl. It is not influenced significantly by hyperglycemia or hyperlactatemia due to factors other than diabetes (i.e., carbon monoxide, asphyxia). After death the value rose till the 30th hpm, then remained stable for at least 1 week. Fatal coma was defined as the ketoacidotic form if free acetone in CSF ranged above 21 mg/l. In these cases, CSF glucose and free acetone correlated positively. Hemoglobin A1 remained stable after death. Its amount was independent from postmortem blood glucose, postmortem interval and total hemoglobin. Furthermore, the manner of storage (-80 degrees or +4 degrees C) had no significant influence on its values. In 29 of 34 cases of fatal coma, Hb A1 exceeded 12.1%. Analysis of urine glucose showed elevated levels (over 500 mg/dl) in diabetic comas. On conclusion, fatal diabetic coma seems indicated as the cause of death if measured values of postmortem biochemistry exceed the following limits: CSF-Traub 415 mg/dl, free acetone (CSF) 21 mg/l; Hb A1 12.1%; urine glucose 500 mg/dl. Most important are the Traub formula and

  8. Ectopic expression of ABSCISIC ACID 2/GLUCOSE INSENSITIVE 1 in Arabidopsis promotes seed dormancy and stress tolerance.

    PubMed

    Lin, Pei-Chi; Hwang, San-Gwang; Endo, Akira; Okamoto, Masanori; Koshiba, Tomokazu; Cheng, Wan-Hsing

    2007-02-01

    Abscisic acid (ABA) is an important phytohormone that plays a critical role in seed development, dormancy, and stress tolerance. 9-cis-Epoxycarotenoid dioxygenase is the key enzyme controlling ABA biosynthesis and stress tolerance. In this study, we investigated the effect of ectopic expression of another ABA biosynthesis gene, ABA2 (or GLUCOSE INSENSITIVE 1 [GIN1]) encoding a short-chain dehydrogenase/reductase in Arabidopsis (Arabidopsis thaliana). We show that ABA2-overexpressing transgenic plants with elevated ABA levels exhibited seed germination delay and more tolerance to salinity than wild type when grown on agar plates and/or in soil. However, the germination delay was abolished in transgenic plants showing ABA levels over 2-fold higher than that of wild type grown on 250 mm NaCl. The data suggest that there are distinct mechanisms underlying ABA-mediated inhibition of seed germination under diverse stress. The ABA-deficient mutant aba2, with a shorter primary root, can be restored to normal root growth by exogenous application of ABA, whereas transgenic plants overexpressing ABA2 showed normal root growth. The data reflect that the basal levels of ABA are essential for maintaining normal primary root elongation. Furthermore, analysis of ABA2 promoter activity with ABA2::beta-glucuronidase transgenic plants revealed that the promoter activity was enhanced by multiple prolonged stresses, such as drought, salinity, cold, and flooding, but not by short-term stress treatments. Coincidently, prolonged drought stress treatment led to the up-regulation of ABA biosynthetic and sugar-related genes. Thus, the data support ABA2 as a late expression gene that might have a fine-tuning function in mediating ABA biosynthesis through primary metabolic changes in response to stress.

  9. Genetic and Functional Assessment of the Role of the rs13431652-A and rs573225-A Alleles in the G6PC2 Promoter That Are Strongly Associated With Elevated Fasting Glucose Levels

    PubMed Central

    Bouatia-Naji, Nabila; Bonnefond, Amélie; Baerenwald, Devin A.; Marchand, Marion; Bugliani, Marco; Marchetti, Piero; Pattou, François; Printz, Richard L.; Flemming, Brian P.; Umunakwe, Obi C.; Conley, Nicholas L.; Vaxillaire, Martine; Lantieri, Olivier; Balkau, Beverley; Marre, Michel; Lévy-Marchal, Claire; Elliott, Paul; Jarvelin, Marjo-Riitta; Meyre, David; Dina, Christian; Oeser, James K.; Froguel, Philippe; O'Brien, Richard M.

    2010-01-01

    OBJECTIVE Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: β = 0.075, P = 3.6 × 10−35; rs573225 β = 0.073 P = 3.6 × 10−34), in addition to rs560887 (β = 0.071, P = 1.2 × 10−31). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out. PMID:20622168

  10. Dietary ribonucleic acid suppresses inflammation of adipose tissue and improves glucose intolerance that is mediated by immune cells in C57BL/6 mice fed a high-fat diet.

    PubMed

    Sakai, Tohru; Taki, Tomoyo; Nakamoto, Akiko; Tazaki, Shiho; Arakawa, Mai; Nakamoto, Mariko; Tsutsumi, Rie; Shuto, Emi

    2015-01-01

    Recent evidence suggests that immune cells play an important role in differentiation of inflammatory macrophages in adipose tissue, which contributes to systemic chronic inflammation. Dietary ribonucleic acid (RNA) has been shown to modulate immune function. We hypothesized that RNA affects immune cell function in adipose tissue and then improves inflammatory response in adipose tissue. C57/BL6 mice and recombination activating gene-1 (RAG-1) knockout mice on a C57BL/6 mice background were fed a high-fat diet containing 1% RNA for 12 wk. An oral glucose tolerance test was performed. Supplementation of dietary RNA in C57BL/6 mice fed a high-fat diet resulted in a smaller area under the curve (AUC) after oral glucose administration than that for control mice. The mRNA expression levels of inflammation-related cytokines in adipose tissue and serum interleukin-6 levels were reduced by dietary RNA supplementation. Interestingly, reduction of the AUC value by RNA supplementation was abolished in T and B cell-deficient RAG-1 knockout mice. These results indicate that RNA improves inflammation in adipose tissue and reduces the AUC value following oral glucose administration in a T and B cell-dependent manner.

  11. Continuous Glucose Monitoring

    PubMed Central

    van Beers, Cornelis A. J.; DeVries, J. Hans

    2016-01-01

    The necessity of strict glycemic control is unquestionable. However, hypoglycemia remains a major limiting factor in achieving satisfactory glucose control, and evidence is mounting to show that hypoglycemia is not benign. Over the past decade, evidence has consistently shown that real-time continuous glucose monitoring improves glycemic control in terms of lowering glycated hemoglobin levels. However, real-time continuous glucose monitoring has not met the expectations of the diabetes community with regard to hypoglycemia prevention. The earlier trials did not demonstrate any effect on either mild or severe hypoglycemia and the effect of real-time continuous glucose monitoring on nocturnal hypoglycemia was often not reported. However, trials specifically designed to reduce hypoglycemia in patients with a high hypoglycemia risk have demonstrated a reduction in hypoglycemia, suggesting that real-time continuous glucose monitoring can prevent hypoglycemia when it is specifically used for that purpose. Moreover, the newest generation of diabetes technology currently available commercially, namely sensor-augmented pump therapy with a (predictive) low glucose suspend feature, has provided more convincing evidence for hypoglycemia prevention. This article provides an overview of the hypoglycemia outcomes of randomized controlled trials that investigate the effect of real-time continuous glucose monitoring alone or sensor-augmented pump therapy with a (predictive) low glucose suspend feature. Furthermore, several possible explanations are provided why trials have not shown a reduction in severe hypoglycemia. In addition, existing evidence is presented of real-time continuous glucose monitoring in patients with impaired awareness of hypoglycemia who have the highest risk of severe hypoglycemia. PMID:27257169

  12. Perspectives on the metabolic management of epilepsy through dietary reduction of glucose and elevation of ketone bodies.

    PubMed

    Greene, Amanda E; Todorova, Mariana T; Seyfried, Thomas N

    2003-08-01

    Brain cells are metabolically flexible because they can derive energy from both glucose and ketone bodies (acetoacetate and beta-hydroxybutyrate). Metabolic control theory applies principles of bioenergetics and genome flexibility to the management of complex phenotypic traits. Epilepsy is a complex brain disorder involving excessive, synchronous, abnormal electrical firing patterns of neurons. We propose that many epilepsies with varied etiologies may ultimately involve disruptions of brain energy homeostasis and are potentially manageable through principles of metabolic control theory. This control involves moderate shifts in the availability of brain energy metabolites (glucose and ketone bodies) that alter energy metabolism through glycolysis and the tricarboxylic acid cycle, respectively. These shifts produce adjustments in gene-linked metabolic networks that manage or control the seizure disorder despite the continued presence of the inherited or acquired factors responsible for the epilepsy. This hypothesis is supported by information on the management of seizures with diets including fasting, the ketogenic diet and caloric restriction. A better understanding of the compensatory genetic and neurochemical networks of brain energy metabolism may produce novel antiepileptic therapies that are more effective and biologically friendly than those currently available.

  13. Berberine enhances the AMPK activation and autophagy and mitigates high glucose-induced apoptosis of mouse podocytes.

    PubMed

    Jin, Yingli; Liu, Shuping; Ma, Qingshan; Xiao, Dong; Chen, Li

    2017-01-05

    High glucose concentration can induce injury of podocytes and berberine has a potent activity against diabetic nephropathy. However, whether and how berberine can inhibit high glucose-mediated injury of podocytes have not been clarified. This study tested the effect of berberine on high glucose-mediated apoptosis and the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) activation and autophagy in podocytes. The results indicated that berberine significantly mitigated high glucose-decreased cell viability, and nephrin and podocin expression as well as apoptosis in mouse podocytes. Berberine significantly increased the AMPK activation and mitigated high glucose and/or the AMPK inhibitor, compound C-mediated mTOR activation and apoptosis in podocytes. Berberine significantly enhanced the AMPK activation and protected from high glucose-induced apoptosis in the AMPK-silencing podocytes. Furthermore, berberine significantly increased the high glucose-elevated Unc-51-like autophagy-activating kinase 1 (ULK1) S317/S555 phosphorylation, Beclin-1 expression, the ratios of LC3II to LC3I expression and the numbers of autophagosomes, but reduced ULK1 S757 phosphorylation in podocytes. In addition, berberine significantly attenuated compound C-mediated inhibition of autophagy in podocytes. The protective effect of berberine on high glucose-induced podocyte apoptosis was significantly mitigated by pre-treatment with 3-methyladenine or bafilomycin A1. Collectively, berberine enhanced autophagy and protected from high glucose-induced injury in podocytes by promoting the AMPK activation. Our findings may provide new insights into the molecular mechanisms underlying the anti-diabetic nephropathy effect of berberine and may aid in design of new therapies for intervention of diabetic nephropathy. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Glucose, Lactate and Glutamine but not Glutamate Support Depolarization-Induced Increased Respiration in Isolated Nerve Terminals.

    PubMed

    Hohnholt, Michaela C; Andersen, Vibe H; Bak, Lasse K; Waagepetersen, Helle S

    2017-01-01

    Synaptosomes prepared from various aged and gene modified experimental animals constitute a valuable model system to study pre-synaptic mechanisms. Synaptosomes were isolated from whole brain and the XFe96 extracellular flux analyzer (Seahorse Bioscience) was used to study mitochondrial respiration and glycolytic rate in presence of different substrates. Mitochondrial function was tested by sequentially exposure of the synaptosomes to the ATP synthase inhibitor, oligomycin, the uncoupler FCCP (carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone) and the electron transport chain inhibitors rotenone and antimycin A. The synaptosomes exhibited intense respiratory activity using glucose as substrate. The FCCP-dependent respiration was significantly higher with 10 mM glucose compared to 1 mM glucose. Synaptosomes also readily used pyruvate as substrate, which elevated basal respiration, activity-dependent respiration induced by veratridine and the respiratory response to uncoupling compared to that obtained with glucose as substrate. Also lactate was used as substrate by synaptosomes but in contrast to pyruvate, mitochondrial lactate mediated respiration was comparable to respiration using glucose as substrate. Synaptosomal respiration using glutamate and glutamine as substrates was significantly higher compared to basal respiration, whereas oligomycin-dependent and FCCP-induced respiration was lower compared to the responses obtained in the presence of glucose as substrate. We provide evidence that synaptosomes are able to use besides glucose and pyruvate also the substrates lactate, glutamate and glutamine to support their basal respiration. Veratridine was found to increase respiration supported by glucose, pyruvate, lactate and glutamine and FCCP was found to increase respiration supported by glucose, pyruvate and lactate. This was not the case when glutamate was the only energy substrate.

  15. Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis.

    PubMed

    Armata, Heather L; Golebiowski, Diane; Jung, Dae Young; Ko, Hwi Jin; Kim, Jason K; Sluss, Hayla K

    2010-12-01

    Ataxia telangiectasia (A-T) patients can develop multiple clinical pathologies, including neuronal degeneration, an elevated risk of cancer, telangiectasias, and growth retardation. Patients with A-T can also exhibit an increased risk of insulin resistance and type 2 diabetes. The ATM protein kinase, the product of the gene mutated in A-T patients (Atm), has been implicated in metabolic disease, which is characterized by insulin resistance and increased cholesterol and lipid levels, blood pressure, and atherosclerosis. ATM phosphorylates the p53 tumor suppressor on a site (Ser15) that regulates transcription activity. To test whether the ATM pathway that regulates insulin resistance is mediated by p53 phosphorylation, we examined insulin sensitivity in mice with a germ line mutation that replaces the p53 phosphorylation site with alanine. The loss of p53 Ser18 (murine Ser15) led to increased metabolic stress, including severe defects in glucose homeostasis. The mice developed glucose intolerance and insulin resistance. The insulin resistance correlated with the loss of antioxidant gene expression and decreased insulin signaling. N-Acetyl cysteine (NAC) treatment restored insulin signaling in late-passage primary fibroblasts. The addition of an antioxidant in the diet rendered the p53 Ser18-deficient mice glucose tolerant. This analysis demonstrates that p53 phosphorylation on an ATM site is an important mechanism in the physiological regulation of glucose homeostasis.

  16. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

    PubMed Central

    Brereton, Melissa F.; Iberl, Michaela; Shimomura, Kenju; Zhang, Quan; Adriaenssens, Alice E.; Proks, Peter; Spiliotis, Ioannis I.; Dace, William; Mattis, Katia K.; Ramracheya, Reshma; Gribble, Fiona M.; Reimann, Frank; Clark, Anne; Rorsman, Patrik; Ashcroft, Frances M.

    2014-01-01

    Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized. PMID:25145789

  17. The effects of bisphosphonates on taurine transport in retinal capillary endothelial cells under high glucose conditions.

    PubMed

    Lee, Na-Young; Kang, Young-Sook

    2013-01-01

    Diabetic retinopathy (DR) is a major cause of blindness in diabetic patients. Elevated glucose and vascular endothelial growth factor (VEGF) in retina can trigger many of the retinal vascular changes caused by diabetes and DR. Recently, bisphosphonates, antiosteoporosis drugs, have been reported to have anti-angiogenic effect by decreasing VEGF. Taurine has several biological processes such as osmoregulation and antioxidation in retina. Therefore, the purpose of this study is to clarify the regulation of taurine transport activity by high glucose concentration and the effect of inhibitors for VEGF function, bisphosphonates, on taurine transport under high glucose condition using TR-iBRB cell lines as an in vitro model of inner blood-retinal barrier (iBRB). As a result, by exposing TR-iBRB cells to high glucose for 48 h, [(3)H]taurine uptake was decreased continuously. [(3)H]Taurine uptake was increased significantly by pretreatment of alendronate and pamidronate compared with the values for high glucose. Increased [(3)H]taurine uptake by pretreatment of alendronate and pamidronate was significantly reduced by mevalonate pathway intermediates, geranylgeraniol (GGOH). In conclusion, taurine transport through the iBRB under high glucose condition can be regulated by bisphosphonates via mevalonate pathway. Therefore, we suggest that bisphosphonates could have the beneficial effects on DR by regulation of taurine contents in retina.

  18. Agmatine abolishes restraint stress-induced depressive-like behavior and hippocampal antioxidant imbalance in mice.

    PubMed

    Freitas, Andiara E; Bettio, Luis E B; Neis, Vivian B; Santos, Danúbia B; Ribeiro, Camille M; Rosa, Priscila B; Farina, Marcelo; Rodrigues, Ana Lúcia S

    2014-04-03

    Agmatine has been recently emerged as a novel candidate to assist the conventional pharmacotherapy of depression. The acute restraint stress (ARS) is an unavoidable stress situation that may cause depressive-like behavior in rodents. In this study, we investigated the potential antidepressant-like effect of agmatine (10mg/kg, administered acutely by oral route) in the forced swimming test (FST) in non-stressed mice, as well as its ability to abolish the depressive-like behavior and hippocampal antioxidant imbalance induced by ARS. Agmatine reduced the immobility time in the mouse FST (1-100mg/kg) in non-stressed mice. ARS caused an increase in the immobility time in the FST, indicative of a depressive-like behavior, as well as hippocampal lipid peroxidation, and an increase in the activity of hippocampal superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities, reduced catalase (CAT) activity and increased SOD/CAT ratio, an index of pro-oxidative conditions. Agmatine was effective to abolish the depressive-like behavior induced by ARS and to prevent the ARS-induced lipid peroxidation and changes in SOD, GR and CAT activities and in SOD/CAT activity ratio. Hippocampal levels of reduced glutathione (GSH) were not altered by any experimental condition. In conclusion, the present study shows that agmatine was able to abrogate the ARS-induced depressive-like behavior and the associated redox hippocampal imbalance observed in stressed restraint mice, suggesting that its antidepressant-like effect may be dependent on its ability to maintain the pro-/anti-oxidative homeostasis in the hippocampus. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. DISCOVERY OF NOVEL GLUCOSE-REGULATED PROTEINS IN ISOLATED HUMAN PANCREATIC ISLETS USING LC-MS/MS-BASED PROTEOMICS

    PubMed Central

    Schrimpe-Rutledge, Alexandra C.; Fontès, Ghislaine; Gritsenko, Marina A.; Norbeck, Angela D.; Anderson, David J.; Waters, Katrina M.; Adkins, Joshua N.; Smith, Richard D.; Poitout, Vincent; Metz, Thomas O.

    2012-01-01

    The prevalence of diabetes mellitus is increasing dramatically throughout the world, and the disease has become a major public health issue. The most common form of the disease, type 2 diabetes, is characterized by insulin resistance and insufficient insulin production from the pancreatic beta-cell. Since glucose is the most potent regulator of beta-cell function under physiological conditions, identification of the insulin secretory defect underlying type 2 diabetes requires a better understanding of glucose regulation of human beta-cell function. To this aim, a bottom-up LC-MS/MS-based proteomics approach was used to profile pooled islets from multiple donors under basal (5 mM) or high (15 mM) glucose conditions. Our analysis discovered 256 differentially abundant proteins (~p<0.05) after 24 h of high glucose exposure from more than 4500 identified in total. Several novel glucose-regulated proteins were elevated under high glucose conditions, including regulators of mRNA splicing (Pleiotropic regulator 1), processing (Retinoblastoma binding protein 6), and function (Nuclear RNA export factor 1), in addition to Neuron navigator 1 and Plasminogen activator inhibitor 1. Proteins whose abundances markedly decreased during incubation at 15 mM glucose included Bax inhibitor 1 and Synaptotagmin-17. Up-regulation of Dicer 1 and SLC27A2 and down-regulation of Phospholipase Cβ4 were confirmed by Western blots. Many proteins found to be differentially abundant after high glucose stimulation are annotated as uncharacterized or hypothetical. These findings expand our knowledge of glucose regulation of the human islet proteome and suggest many hitherto unknown responses to glucose that require additional studies to explore novel functional roles. PMID:22578083

  20. Single-cell imaging of bioenergetic responses to neuronal excitotoxicity and oxygen and glucose deprivation.

    PubMed

    Connolly, Niamh M C; Düssmann, Heiko; Anilkumar, Ujval; Huber, Heinrich J; Prehn, Jochen H M

    2014-07-30

    Excitotoxicity is a condition occurring during cerebral ischemia, seizures, and chronic neurodegeneration. It is characterized by overactivation of glutamate receptors, leading to excessive Ca(2+)/Na(+) influx into neurons, energetic stress, and subsequent neuronal injury. We and others have previously investigated neuronal populations to study how bioenergetic parameters determine neuronal injury; however, such experiments are often confounded by population-based heterogeneity and the contribution of effects of non-neuronal cells. Hence, we here characterized bioenergetics during transient excitotoxicity in rat and mouse primary neurons at the single-cell level using fluorescent sensors for intracellular glucose, ATP, and activation of the energy sensor AMP-activated protein kinase (AMPK). We identified ATP depletion and recovery to energetic homeostasis, along with AMPK activation, as surprisingly rapid and plastic responses in two excitotoxic injury paradigms. We observed rapid recovery of neuronal ATP levels also in the absence of extracellular glucose, or when glycolytic ATP production was inhibited, but found mitochondria to be critical for fast and complete energetic recovery. Using an injury model of oxygen and glucose deprivation, we identified a similarly rapid bioenergetics response, yet with incomplete ATP recovery and decreased AMPK activity. Interestingly, excitotoxicity also induced an accumulation of intracellular glucose, providing an additional source of energy during and after excitotoxicity-induced energy depletion. We identified this to originate from extracellular, AMPK-dependent glucose uptake and from intracellular glucose mobilization. Surprisingly, cells recovering their elevated glucose levels faster to baseline survived longer, indicating that the plasticity of neurons to adapt to bioenergetic challenges is a key indicator of neuronal viability. Copyright © 2014 the authors 0270-6474/14/3410192-14$15.00/0.

  1. Susceptibility of interstitial continuous glucose monitor performance to sleeping position.

    PubMed

    Mensh, Brett D; Wisniewski, Natalie A; Neil, Brian M; Burnett, Daniel R

    2013-07-01

    Developing a round-the-clock artificial pancreas requires accurate and stable continuous glucose monitoring. The most widely used continuous glucose monitors (CGMs) are percutaneous, with the sensor residing in the interstitial space. Inaccuracies in percutaneous CGM readings during periods of lying on the devices (e.g., in various sleeping positions) have been anecdotally reported but not systematically studied. In order to assess the impact of sleep and sleep position on CGM performance, we conducted a study in human subjects in which we measured the variability of interstitial CGM data at night as a function of sleeping position. Commercially available sensors were placed for 4 days in the abdominal subcutaneous tissue in healthy, nondiabetic volunteers (four sensors per person, two per side). Nocturnal sleeping position was determined from video recordings and correlated to sensor data. We observed that, although the median of the four sensor readings was typically 70-110 mg/dl during sleep, individual sensors intermittently exhibited aberrant glucose readings (>25 mg/dl away from median) and that these aberrant readings were strongly correlated with subjects lying on the sensors. We expected and observed that most of these aberrant sleep-position-related CGM readings were sudden decreases in reported glucose values, presumably due to local blood-flow decreases caused by tissue compression. Curiously, in rare cases, the aberrant CGM readings were elevated values. These findings highlight limitations in our understanding of interstitial fluid physiology in the subcutaneous space and have significant implications for the utilization of sensors in the construction of an artificial pancreas. © 2013 Diabetes Technology Society.

  2. Oocyte aging-induced Neuronatin (NNAT) hypermethylation affects oocyte quality by impairing glucose transport in porcine.

    PubMed

    Gao, Ying-Ying; Chen, Li; Wang, Tao; Nie, Zheng-Wen; Zhang, Xia; Miao, Yi-Liang

    2016-10-26

    DNA methylation plays important roles in regulating many physiological behaviors; however, few studies were focused on the changes of DNA methylation during oocyte aging. Early studies showed that some imprinted genes' DNA methylation had been changed in aged mouse oocytes. In this study, we used porcine oocytes to test the hypothesis that oocyte aging would alter DNA methylation pattern of genes and disturb their expression in age oocytes, which affected the developmental potential of oocytes. We compared several different types of genes and found that the expression and DNA methylation of Neuronatin (NNAT) were disturbed in aged oocytes significantly. Additional experiments demonstrated that glucose transport was impaired in aged oocytes and injection of NNAT antibody into fresh oocytes led to the same effects on glucose transport. These results suggest that the expression of NNAT was declined by elevating DNA methylation, which affected oocyte quality by decreasing the ability of glucose transport in aged oocytes.

  3. The reducing agent dithiothreitol (DTT) does not abolish the inhibitory nicotinic response recorded from rat dorsolateral septal neurons

    NASA Technical Reports Server (NTRS)

    Sorenson, E. M.; Gallagher, J. P.

    1993-01-01

    Previous intracellular recordings have demonstrated that dorsolateral septal nucleus (DLSN) neurons express a novel nicotinic receptor which produces a direct membrane hyperpolarization when activated by nicotinic agonists. Activation of the classical excitatory nicotinic receptors has been shown to require a disulfide bond involving the cysteines at positions 192 and 193 of the alpha subunits of the receptor. Reduction of this cystine bond with dithiothreitol (DTT) abolishes agonist activation of excitatory nicotinic receptors. We have now examined whether DTT treatment of the inhibitory nicotinic receptor on DLSN neurons also abolishes the inhibitory nicotinic response. We find that the inhibitory response persists after treatment of the neurons with 1 mM DTT, even if the reduction is followed by alkylation of the receptor with bromoacetylcholine to prevent possible reformation of disulfide bonds. This result suggests that the agonist binding site on the inhibitory nicotinic receptor does not require an intact disulfide bond, similar to the bond on the alpha subunit of the excitatory nicotinic receptor, for agonist activation of the receptor. Some of these results have been previously reported in abstract form.

  4. Glucose oxidase probe as a surface-enhanced Raman scattering sensor for glucose.

    PubMed

    Qi, Guohua; Wang, Yi; Zhang, Biying; Sun, Dan; Fu, Cuicui; Xu, Weiqing; Xu, Shuping

    2016-10-01

    Glucose oxidase (GOx) possessing a Raman-active chromophore (flavin adenine dinucleotide) is used as a signal reporter for constructing a highly specific "turn off" surface-enhanced Raman scattering (SERS) sensor for glucose. This sensing chip is made by the electrostatic assembly of GOx over silver nanoparticle (Ag NP)-functionalized SERS substrate through a positively charged polyelectrolyte linker under the pH of 6.86. To trace glucose in blood serum, owing to the reduced pH value caused by the production of gluconic acid in the GOx-catalyzed oxidation reaction, the bonding force between GOx and polyelectrolyte weakens, making GOx drop off from the sensing chip. As a result, the SERS intensity of GOx on the chip decreases along with the concentration of glucose. This glucose SERS sensor exhibits excellent selectivity based on the specific GOx/glucose catalysis reaction and high sensitivity to 1.0 μM. The linear sensing range is 2.0-14.0 mM, which also meets the requirement on the working range of the human blood glucose detection. Using GOx as a probe shows superiority over other organic probes because GOx almost has no toxicity to the biological system. This sensing mechanism can be applied for intracellular in vivo SERS monitoring of glucose in the future. Graphical abstract Glucose oxidase is used as a Raman signal reporter for constructing a highly specific glucose surface-enhanced Raman scattering (SERS) sensor.

  5. The amine oxidase inhibitor phenelzine limits lipogenesis in adipocytes without inhibiting insulin action on glucose uptake.

    PubMed

    Carpéné, Christian; Grès, Sandra; Rascalou, Simon

    2013-06-01

    The antidepressant phenelzine is a monoamine oxidase inhibitor known to inhibit various other enzymes, among them semicarbazide-sensitive amine oxidase (currently named primary amine oxidase: SSAO/PrAO), absent from neurones but abundant in adipocytes. It has been reported that phenelzine inhibits adipocyte differentiation of cultured preadipocytes. To further explore the involved mechanisms, our aim was to study in vitro the acute effects of phenelzine on de novo lipogenesis in mature fat cells. Therefore, glucose uptake and incorporation into lipid were measured in mouse adipocytes in response to phenelzine, other hydrazine-based SSAO/PrAO-inhibitors, and reference agents. None of the inhibitors was able to impair the sevenfold activation of 2-deoxyglucose uptake induced by insulin. Phenelzine did not hamper the effect of lower doses of insulin. However, insulin-stimulated glucose incorporation into lipids was dose-dependently inhibited by phenelzine and pentamidine, but not by semicarbazide or BTT2052. In contrast, all these SSAO/PrAO inhibitors abolished the transport and lipogenesis stimulation induced by benzylamine. These data indicate that phenelzine does not inhibit glucose transport, the first step of lipogenesis, but inhibits at 100 μM the intracellular triacylglycerol assembly, consistently with its long-term anti-adipogenic effect and such rapid action was not found with all the hydrazine derivatives tested. Therefore, the alterations of body weight control consecutive to the use of this antidepressant drug might be not only related to central effects on food intake/energy expenditure, but could also depend on its direct action in adipocytes. Nonetheless, phenelzine antilipogenic action is not merely dependent on SSAO/PrAO inhibition.

  6. Blood glucose concentrations of arm and finger during dynamic glucose conditions.

    PubMed

    Szuts, Ete Z; Lock, J Paul; Malomo, Kenneth J; Anagnostopoulos, Althea

    2002-01-01

    We set out to determine the physiological difference between the capillary blood of the arm and finger with the greatest possible accuracy using the HemoCue B-glucose analyzer on subjects undergoing a meal tolerance test (MTT) or oral glucose tolerance test (OGTT). MTT study was performed on 50 subjects who drank a liquid meal (Ensure, 40 g of carbohydrates) and who were tested on the arm and finger every 30 min for up to 4 h. OGTT study was performed on 12 subjects who drank a 100-g glucose solution (Glucola) and were tested on the arm and finger every 15 min during the first hour and thereafter every 30 min for up to 3 h. Average percent glucose difference between arm and finger reached a maximal value about 1 h following glucose load, with arm glucose being about 5% lower than that of finger. At other times, average differences were less than this. At the greatest rate of glucose change (>2 mg/dL-min), mean percent bias was found to be about 6%. Despite these measurable differences, when arm results were plotted on the Clarke error grid against finger values, >97% of the data were within zone A (rest in zone B). Thus, physiological differences between arm and finger were clinically insignificant. Our studies with HemoCue confirmed the existence of measurable physiological glucose differences between arm and finger following a glucose challenge, but these differences were found to be clinically insignificant even in those subjects in whom they were measurable.

  7. Regulation of ATP-binding cassette transporters and cholesterol efflux by glucose in primary human monocytes and murine bone marrow-derived macrophages

    USDA-ARS?s Scientific Manuscript database

    Individuals with type 2 diabetes mellitus are at increased risk of developing atherosclerosis. This may be partially attributable to suppression of macrophage ATP-binding cassette (ABC) transporter mediated cholesterol efflux by sustained elevated blood glucose concentrations. Two models were used...

  8. Parsing glucose entry into the brain: novel findings obtained with enzyme-based glucose biosensors.

    PubMed

    Kiyatkin, Eugene A; Wakabayashi, Ken T

    2015-01-21

    Extracellular levels of glucose in brain tissue reflect dynamic balance between its gradient-dependent entry from arterial blood and its use for cellular metabolism. In this work, we present several sets of previously published and unpublished data obtained by using enzyme-based glucose biosensors coupled with constant-potential high-speed amperometry in freely moving rats. First, we consider basic methodological issues related to the reliability of electrochemical measurements of extracellular glucose levels in rats under physiologically relevant conditions. Second, we present data on glucose responses induced in the nucleus accumbens (NAc) by salient environmental stimuli and discuss the relationships between local neuronal activation and rapid glucose entry into brain tissue. Third, by presenting data on changes in NAc glucose induced by intravenous and intragastric glucose delivery, we discuss other mechanisms of glucose entry into the extracellular domain following changes in glucose blood concentrations. Lastly, by showing the pattern of NAc glucose fluctuations during glucose-drinking behavior, we discuss the relationships between "active" and "passive" glucose entry to the brain, its connection to behavior-related metabolic activation, and the possible functional significance of these changes in behavioral regulation. These data provide solid experimental support for the "neuronal" hypothesis of neurovascular coupling, which postulates the critical role of neuronal activity in rapid regulation of vascular tone, local blood flow, and entry of glucose and oxygen to brain tissue to maintain active cellular metabolism.

  9. Glucose rapidly decreases plasma membrane GLUT4 content in rat skeletal muscle.

    PubMed

    Marette, A; Dimitrakoudis, D; Shi, Q; Rodgers, C D; Klip, A; Vranic, M

    1999-02-01

    We have previously demonstrated that chronic hyperglycemia per se decreases GLUT4 glucose transporter expression and plasma membrane content in mildly streptozotocin- (STZ) diabetic rats (Biochem. J. 284, 341-348, 1992). In the present study, we investigated the effect of an acute rise in glycemia on muscle GLUT4 and GLUT1 protein contents in the plasma membrane, in the absence of insulin elevation. Four experimental groups of rats were analyzed in the postabsorptive state: 1. Control rats. 2. Hyperglycemic STZ-diabetic rats with moderately reduced fasting insulin levels. 3. STZ-diabetic rats made normoglycemic with phlorizin treatment. 4. Phlorizin-treated (normoglycemic) STZ-diabetic rats infused with glucose for 40 min. The uniqueness of the latter model is that glycemia can be rapidly raised without any concomitant increase in plasma insulin levels. Plasma membranes were isolated from hindlimb muscle and GLUT1 and GLUT4 proteins amounts determined by Western blot analysis. As predicted, STZ-diabetes caused a significant decrease in the abundance of GLUT4 in the isolated plasma membranes. Normalization of glycemia for 3 d with phlorizin treatment restored plasma membrane GLUT4 content in muscle of STZ-diabetic rats. A sudden rise in glycemia over a period of 40 min caused the GLUT4 levels in the plasma membrane fraction to decrease to those of nontreated STZ-diabetic rats. In contrast to the GLUT4 transporter, plasma membrane GLUT1 abundance was not changed by the acute glucose challenge. It is concluded that glucose can have regulatory effect by acutely reducing plasma membrane GLUT4 protein contents in rat skeletal muscle. We hypothesize that this glucose-induced downregulation of plasma membrane GLUT4 could represent a protective mechanism against excessive glucose uptake under hyperglycemic conditions accompanied by insulin resistance.

  10. Insertion sequence 1515 in the ply gene of a type 1 clinical isolate of Streptococcus pneumoniae abolishes pneumolysin expression.

    PubMed

    Garnier, Fabien; Janapatla, Rajendra Prasad; Charpentier, Emmanuelle; Masson, Geoffrey; Grélaud, Carole; Stach, Jean François; Denis, François; Ploy, Marie-Cécile

    2007-07-01

    A serotype 1 Streptococcus pneumoniae strain isolated by blood culture from a woman with pneumonia was found to harbor insertion sequence (IS) 1515 in the pneumolysin gene, abolishing pneumolysin expression. To our knowledge, this is the first report of an IS in the pneumolysin gene of S. pneumoniae.

  11. Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women

    PubMed Central

    Nair, K. Sreekumaran; Daniels, Janice K.; Basal, Eati; Schimke, Jill M.

    2012-01-01

    Hyperandrogenism and chronic low-grade inflammation are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate inflammation. We determined the effect of oral androgen administration on fasting and glucose-stimulated nuclear factor-κB (NF-κB) activation and expression and related markers of inflammation in mononuclear cells (MNC) of lean reproductive-age women. Sixteen lean, ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n = 8 each) for 5 days in a randomized, controlled, double-blind fashion. Nuclear activation of NF-κB, p65 and p105 NF-κB subunit RNA, TNFα and IL-1β mRNA, and NF-κB p65 and inhibitory-κB (IκB) protein were quantified from MNC obtained while fasting and 2 h after glucose ingestion, before and after DHEA or placebo administration. Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any inflammatory markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-S, increased the percent change in fasting and glucose-challenged activated NF-κB, p65, p105, TNFα, and IL-1β RNA and p65 protein, and decreased the percent change in fasting and glucose-challenged IκB protein. We conclude that elevation of circulating androgens to the range observed in PCOS upregulates the NF-κB inflammation pathway in lean reproductive-age women. Thus, hyperandrogenemia activates and sensitizes MNC to glucose in this population. PMID:22045316

  12. Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women.

    PubMed

    González, Frank; Nair, K Sreekumaran; Daniels, Janice K; Basal, Eati; Schimke, Jill M

    2012-02-01

    Hyperandrogenism and chronic low-grade inflammation are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate inflammation. We determined the effect of oral androgen administration on fasting and glucose-stimulated nuclear factor-κB (NF-κB) activation and expression and related markers of inflammation in mononuclear cells (MNC) of lean reproductive-age women. Sixteen lean, ovulatory reproductive-age women were treated with 130 mg of DHEA or placebo (n = 8 each) for 5 days in a randomized, controlled, double-blind fashion. Nuclear activation of NF-κB, p65 and p105 NF-κB subunit RNA, TNFα and IL-1β mRNA, and NF-κB p65 and inhibitory-κB (IκB) protein were quantified from MNC obtained while fasting and 2 h after glucose ingestion, before and after DHEA or placebo administration. Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any inflammatory markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-S, increased the percent change in fasting and glucose-challenged activated NF-κB, p65, p105, TNFα, and IL-1β RNA and p65 protein, and decreased the percent change in fasting and glucose-challenged IκB protein. We conclude that elevation of circulating androgens to the range observed in PCOS upregulates the NF-κB inflammation pathway in lean reproductive-age women. Thus, hyperandrogenemia activates and sensitizes MNC to glucose in this population.

  13. Rapid quantitative detection of glucose content in glucose injection by reaction headspace gas chromatography.

    PubMed

    Xie, Wei-Qi; Gong, Yi-Xian; Yu, Kong-Xian

    2017-10-20

    This work investigates an automated technique for rapid detecting the glucose content in glucose injection by reaction headspace gas chromatography (HS-GC). This method is based on the oxidation reaction of glucose in glucose injection with potassium dichromate. The carbon dioxide (CO 2 ) formed from the oxidation reaction can be quantitatively detected by GC. The results show that the relative standard deviation (RSD) of the present method was within 2.91%, and the measured glucose contents in glucose injection closely match those quantified by the reference method (relative differences <6.45%). The new HS-GC technique is rapid, practical and can be used to the batch detection of the glucose content in glucose injection related applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Parsing Glucose Entry into the Brain: Novel Findings Obtained with Enzyme-Based Glucose Biosensors

    PubMed Central

    2015-01-01

    Extracellular levels of glucose in brain tissue reflect dynamic balance between its gradient-dependent entry from arterial blood and its use for cellular metabolism. In this work, we present several sets of previously published and unpublished data obtained by using enzyme-based glucose biosensors coupled with constant-potential high-speed amperometry in freely moving rats. First, we consider basic methodological issues related to the reliability of electrochemical measurements of extracellular glucose levels in rats under physiologically relevant conditions. Second, we present data on glucose responses induced in the nucleus accumbens (NAc) by salient environmental stimuli and discuss the relationships between local neuronal activation and rapid glucose entry into brain tissue. Third, by presenting data on changes in NAc glucose induced by intravenous and intragastric glucose delivery, we discuss other mechanisms of glucose entry into the extracellular domain following changes in glucose blood concentrations. Lastly, by showing the pattern of NAc glucose fluctuations during glucose-drinking behavior, we discuss the relationships between “active” and “passive” glucose entry to the brain, its connection to behavior-related metabolic activation, and the possible functional significance of these changes in behavioral regulation. These data provide solid experimental support for the “neuronal” hypothesis of neurovascular coupling, which postulates the critical role of neuronal activity in rapid regulation of vascular tone, local blood flow, and entry of glucose and oxygen to brain tissue to maintain active cellular metabolism. PMID:25490002

  15. Gestational glucocorticoid exposure disrupts glucose homeostasis that is accompanied by increased endoglin and DPP-4 activity instead of GSK-3 in rats.

    PubMed

    Badmus, Olufunto O; Michael, Olugbenga S; Rabiu, Saheed; Olatunji, Lawrence A

    2018-04-13

    Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offspring's in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0.2 mg/kg; po) between gestational days 14 and 19. Gestational GC exposure resulted in impaired glucose homeostasis that is accompanied with elevated circulating levels of inflammatory biomarkers (endoglin, uric acid, and platelet/lymphocyte ratio), oxidative stress (malondialdehyde), blood viscosity, reduced NO level and increased DPP-4 activity. However, these effects were associated with atherogenic dyslipidemia and reduced GSK-3.We conclude that plasma endoglin, a marker of vascular inflammation, and plasma DPP-4 activity are increased in pregnant rats treated with GC during late gestation. Therefore, glucose deregulation associated with gestational GC exposure is through endoglin-/DPP-4-dependent but GSK-3-independent pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Glucose tolerance test - non-pregnant

    MedlinePlus

    Oral glucose tolerance test - non-pregnant; OGTT - non-pregnant; Diabetes - glucose tolerance test; Diabetic - glucose tolerance test ... The most common glucose tolerance test is the oral glucose ... the test begins, a sample of blood will be taken. You will then ...

  17. Role of various indices derived from an oral glucose tolerance test in the prediction of conversion from prediabetes to type 2 diabetes.

    PubMed

    Kim, Ye An; Ku, Eu Jeong; Khang, Ah Reum; Hong, Eun Shil; Kim, Kyoung Min; Moon, Jae Hoon; Choi, Sung Hee; Park, Kyong Soo; Jang, Hak Chul; Lim, Soo

    2014-11-01

    The clinical implications of prediabetes for development of type 2 diabetes may differ for Asian ethnicity. We investigated various indices derived from a 2-h oral glucose tolerance test (OGTT) in people with prediabetes to predict their future risk of diabetes. We recruited 406 consecutive subjects with prediabetes from 2005 to 2006 and followed them up every 3-6 months for up to 9 years. Prediabetes was defined as isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), combined glucose intolerance (CGI), or isolated elevated HbA1c (5.7-6.4%, 39-46 mmol/mol) without IFG or IGT. The rate of diabetes conversion was compared between prediabetes categories. The association of glycemic indices with development of diabetes was also investigated. Eighty-one patients were diagnosed with diabetes during the 9-year follow-up (median 46.0 months). The rate of diabetes conversion was higher in subjects with CGI (31.9%), or isolated IGT (18.5%) than in those with isolated IFG (15.2%) or isolated elevated HbA1c (10.9%). Surrogate markers reflecting β-cell dysfunction were more closely associated with diabetes conversion than insulin resistance indices. Subjects with a 30-min postload glucose ≥ 165 mg/dL and a 30-min C-peptide < 5 ng/mL had 8.83 times greater risk (95% confidence interval 2.98-26.16) of developing diabetes than other prediabetic subjects. In Asians, at least Koreans, β-cell dysfunction seems to be the major determinant for diabetes conversion. A combination of high glucose and low C-peptide levels at 30 min after OGTT may be a good predictor for diabetes conversion in this population. Copyright © 2014. Published by Elsevier Ireland Ltd.

  18. Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism.

    PubMed

    Gu, Yuan; Qi, Chunting; Sun, Xiaoxiao; Ma, Xiuquan; Zhang, Haohao; Hu, Lihong; Yuan, Junying; Yu, Qiang

    2012-08-15

    Selectively eradicating cancer cells with minimum adverse effects on normal cells is a major challenge in the development of anticancer therapy. We hypothesize that nutrient-limiting conditions frequently encountered by cancer cells in poorly vascularized solid tumors might provide an opportunity for developing selective therapy. In this study, we investigated the function and molecular mechanisms of a natural compound, arctigenin, in regulating tumor cell growth. We demonstrated that arctigenin selectively promoted glucose-starved A549 tumor cells to undergo necrosis by inhibiting mitochondrial respiration. In doing so, arctigenin elevated cellular level of reactive oxygen species (ROS) and blocked cellular energy metabolism in the glucose-starved tumor cells. We also demonstrated that cellular ROS generation was caused by intracellular ATP depletion and played an essential role in the arctigenin-induced tumor cell death under the glucose-limiting condition. Furthermore, we combined arctigenin with the glucose analogue 2-deoxyglucose (2DG) and examined their effects on tumor cell growth. Interestingly, this combination displayed preferential cell-death inducing activity against tumor cells compared to normal cells. Hence, we propose that the combination of arctigenin and 2DG may represent a promising new cancer therapy with minimal normal tissue toxicity. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  19. High glucose increases the formation and pro-oxidative activity of endothelial microparticles.

    PubMed

    Burger, Dylan; Turner, Maddison; Xiao, Fengxia; Munkonda, Mercedes N; Akbari, Shareef; Burns, Kevin D

    2017-09-01

    Individuals with diabetes exhibit increases in circulating endothelial microparticles (eMPs, also referred to as endothelial microvesicles), which are associated with endothelial dysfunction and a heightened risk of cardiovascular complications. We have shown that eMPs are markers and mediators of vascular injury although their role in diabetes is unclear. We hypothesised that the composition and biological activity of eMPs are altered in response to high glucose exposure. We assessed the effects of high glucose on eMP formation, composition and signalling in cultured HUVECs. eMPs were isolated from the media of HUVECs cultured under conditions of normal glucose (eMP NG ), high glucose (eMP HG ) or osmotic control of L-glucose (eMP LG ). eMP size, concentration and surface charge were assessed by nanoparticle tracking analysis and flow cytometry. eMP protein composition was assessed by liquid chromatography-tandem mass spectrometry, and eMP-mediated effects on coagulation, reactive oxygen species (ROS) production and vessel function were assessed. Exposure of HUVECs to high glucose for 24 h caused a threefold increase in eMP formation, increased mean particle size (269 ± 18 nm vs 226 ± 11 nm) and decreased surface charge. Compared with eMP NG or eMP LG , eMP HG possessed approximately threefold greater pro-coagulant activity, stimulated HUVEC ROS production to a greater extent (~250% of eMP NG ) and were more potent inhibitors of endothelial-dependent relaxation. Proteomic analysis of eMPs identified 1212 independent proteins of which 68 were exclusively found in eMP HG . Gene ontology analysis revealed that eMP HG -exclusive proteins were associated with signalling pathways related to blood coagulation, cell signalling and immune cell activation. Our results indicate that elevated glucose is a potent stimulus for eMP formation that also alters their molecular composition leading to increased bioactivity. Such effects may contribute to progressive

  20. The effect of endurance training and subsequent physical inactivity on glycaemic control after oral glucose load and physical exercise in healthy men

    NASA Astrophysics Data System (ADS)

    Radikova, Zofia; Ksinantova, Lucia; Kaciuba-Uscilko, Hanna; Nazar, Krystyna; Vigas, Milan; Koska, Juraj

    2007-02-01

    Physical inactivity during space flight has a profound effect on glucose metabolism. The aim of this study was to test whether endurance training (ET) may improve a negative effect of subsequent -6∘ head-down bed rest (HDBR) on glucose metabolism. Fourteen healthy males completed the study consisting of 6 weeks lasting ET followed by 6 days HDBR. Treadmill exercise at 80% of pre-training VO2max and 75 g oral glucose tolerance test (OGTT) were performed before and after ET as well as after HDBR. ET increased VO2max by 11%. ET significantly lowered while HDBR had no effect on fasting and OGTT plasma glucose levels. ET had no effect while HDBR was followed by an augmentation of insulin and C-peptide response to OGTT. Insulin sensitivity tended to increase after ET and to decrease during HDBR, however, mostly without statistical significance. Plasma glucose, insulin and C-peptide response to exercise were elevated after HDBR only. Our study shows that antecedent physical training could ameliorate a negative effect of simulated microgravity on insulin-mediated glucose metabolism.