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Sample records for insulin-dependent glucose uptake

  1. Maximum Oxygen Uptake Determination in Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Fremion, Amy S.; And Others

    1987-01-01

    A study of 10 children with insulin-dependent diabetes mellitus performing a maximum-effort cycling test indicated blood glucose levels did not change appreciably during test, while maximal oxygen uptake was substandard for their age groups. Findings suggest patients in fair to poor metabolic control can tolerate stress testing without…

  2. Bavachin from Psoralea corylifolia Improves Insulin-Dependent Glucose Uptake through Insulin Signaling and AMPK Activation in 3T3-L1 Adipocytes.

    PubMed

    Lee, Hyejin; Li, Hua; Noh, Minsoo; Ryu, Jae-Ha

    2016-01-01

    The fruit of Psoralea corylifolia L. (Fabaceae) (PC), known as "Bo-Gol-Zhee" in Korea has been used as traditional medicine. Ethanol and aqueous extracts of PC have an anti-hyperglycemic effect by increasing plasma insulin levels and decreasing blood glucose and total plasma cholesterol levels in type 2 diabetic rats. In this study, we purified six compounds from PC and investigated their anti-diabetic effect. Among the purified compounds, bavachin most potently accumulated lipids during adipocyte differentiation. Intracellular lipid accumulation was measured by Oil Red-O (ORO) cell staining to investigate the effect of compounds on adipogenesis. Consistently, bavachin activated gene expression of adipogenic transcriptional factors, proliferator-activated receptorγ (PPARγ) and CCAAT/enhancer binding protein-α (C/EBPα). Bavachin also increased adiponectin expression and secretion in adipocytes. Moreover, bavachin increased insulin-induced glucose uptake by differentiated adipocytes and myoblasts. In differentiated adipocytes, we found that bavachin enhanced glucose uptake via glucose transporter 4 (GLUT4) translocation by activating the Akt and 5'AMP-activated protein kinase (AMPK) pathway in the presence or absence of insulin. These results suggest that bavachin from Psoralea corylifolia might have therapeutic potential for type 2 diabetes by activating insulin signaling pathways. PMID:27070585

  3. Bavachin from Psoralea corylifolia Improves Insulin-Dependent Glucose Uptake through Insulin Signaling and AMPK Activation in 3T3-L1 Adipocytes

    PubMed Central

    Lee, Hyejin; Li, Hua; Noh, Minsoo; Ryu, Jae-Ha

    2016-01-01

    The fruit of Psoralea corylifolia L. (Fabaceae) (PC), known as “Bo-Gol-Zhee” in Korea has been used as traditional medicine. Ethanol and aqueous extracts of PC have an anti-hyperglycemic effect by increasing plasma insulin levels and decreasing blood glucose and total plasma cholesterol levels in type 2 diabetic rats. In this study, we purified six compounds from PC and investigated their anti-diabetic effect. Among the purified compounds, bavachin most potently accumulated lipids during adipocyte differentiation. Intracellular lipid accumulation was measured by Oil Red-O (ORO) cell staining to investigate the effect of compounds on adipogenesis. Consistently, bavachin activated gene expression of adipogenic transcriptional factors, proliferator-activated receptorγ (PPARγ) and CCAAT/enhancer binding protein-α (C/EBPα). Bavachin also increased adiponectin expression and secretion in adipocytes. Moreover, bavachin increased insulin-induced glucose uptake by differentiated adipocytes and myoblasts. In differentiated adipocytes, we found that bavachin enhanced glucose uptake via glucose transporter 4 (GLUT4) translocation by activating the Akt and 5′AMP-activated protein kinase (AMPK) pathway in the presence or absence of insulin. These results suggest that bavachin from Psoralea corylifolia might have therapeutic potential for type 2 diabetes by activating insulin signaling pathways. PMID:27070585

  4. PEDF attenuates insulin-dependent molecular pathways of glucose homeostasis in skeletal myocytes.

    PubMed

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2016-02-15

    Pigment epithelium-derived factor (PEDF) is an anti-angiogenic serpin associated with insulin resistance in metabolic disorders such as diabetes, metabolic syndrome, obesity and polycystic ovarian syndrome. While the mechanism of PEDF induced-insulin resistance of metabolic disorders has been attributed to its inflammatory and lipolytic effects, little evidence exists to support a direct role of PEDF in mediating insulin resistance. Here, we seminally provide evidence that PEDF can inhibit insulin signal transduction governing glucose homeostasis from the receptor to the effector phosphorylation through Akt/PKB-dependent and -independent pathways in mouse and human skeletal muscle cell lines. PEDF attenuates the insulin-dependent molecular axes of glucose metabolism. Exposure of skeletal myocytes to PEDF attenuates insulin-dependent insulin receptor autophosphorylation, tyrosine phosphorylation of insulin receptor substrate 1, and dual loop phosphorylation-activation of Akt. PEDF significantly inhibits the downstream effector - glycogen synthase kinase (and thereby the glycogenic axis of insulin signalling). PEDF turned off both the molecular switches of GLUT4 translocation: IRS-Akt/PKB-AS160 mediated and IR-pCbl-dependent GLUT4 translocation (the molecular axis of glucose uptake). These findings implicate a direct effect of PEDF on multiple insulin-dependent molecular mechanisms of glucose homeostasis in skeletal muscle cells, thereby enabling it to contribute to peripheral insulin resistance at the cellular level.

  5. Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects.

    PubMed

    Thorburn, A; Litchfield, A; Fabris, S; Proietto, J

    1995-05-01

    A transient rise in hepatic glucose production (HGP) after an oral glucosa load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic 'control' subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 +/- 0.52 to 12.58 +/- 1.86 mumol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40-50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects. PMID:7587920

  6. Mechanisms of insulin-dependent glucose transport into porcine and bovine skeletal muscle.

    PubMed

    Duhlmeier, Reinhard; Hacker, Anja; Widdel, Andrea; von Engelhardt, Wolfgang; Sallmann, Hans-Peter

    2005-07-01

    Euglycemic, hyperinsulinemic clamp tests have shown that adult ruminants are less insulin-sensitive than monogastric omnivores. The present study was carried out to elucidate possible cellular mechanisms contributing to this impaired insulin sensitivity of ruminants. Western blotting was used to measure glucose transporters 1 and 4 (GLUT1, GLUT4) in oxidative (musculus masseter and diaphragm) and glycolytic (musculus longissimus dorsi and semitendinosus) skeletal muscle in the crude membranes of pigs and cows. Muscles were characterized biochemically. To determine insulin-stimulated 3-O-D-[(3)H]-methylglucose (3-O-MG) uptake and GLUT4 translocation, porcine and bovine musculus semitendinosus strips were removed by open muscle biopsy and incubated without and with 0.1 or 20 mIU insulin/ml. GLUT4 translocation was analyzed using subcellular fractionation techniques to isolate partially purified plasma membranes and cytoplasmic vesicles and using Western blotting. GLUT4 protein contents were significantly higher in oxidative than in glycolytic muscles in pigs and cows. GLUT1 protein contents were significantly higher in glycolytic than in oxidative muscles in bovines but not in porcines. The 3-O-MG uptake into musculus semitendinosus was similar in both species. Maximum insulin-induced GLUT4 translocation into musculus semitendinosus plasma membrane was significantly lower in bovines than in porcines. These results indicate that GLUT1 is the predominant glucose transporter in bovine glycolytic muscles and that a reinforced insulin-independent glucose uptake via GLUT1 may compensate for the impaired insulin-stimulated GLUT4 translocation, resulting in a similar 3-O-MG uptake in bovine and porcine musculus semitendinosus. These findings may explain at least in part the impaired in vivo insulin sensitivity of adult ruminants compared with that of omnivorous monogastric animals.

  7. Recombinant glucose uptake system

    DOEpatents

    Ingrahm, Lonnie O.; Snoep, Jacob L.; Arfman, Nico

    1997-01-01

    Recombinant organisms are disclosed that contain a pathway for glucose uptake other than the pathway normally utilized by the host cell. In particular, the host cell is one in which glucose transport into the cell normally is coupled to PEP production. This host cell is transformed so that it uses an alternative pathway for glucose transport that is not coupled to PEP production. In a preferred embodiment, the host cell is a bacterium other than Z. mobilis that has been transformed to contain the glf and glk genes of Z. mobilis. By uncoupling glucose transport into the cell from PEP utilization, more PEP is produced for synthesis of products of commercial importance from a given quantity of biomass supplied to the host cells.

  8. The effects of targeting improvements in urine glucose on metabolic control in children with insulin dependent diabetes.

    PubMed

    Epstein, L H; Beck, S; Figueroa, J; Farkas, G; Kazdin, A E; Daneman, D; Becker, D

    1981-01-01

    A treatment program designed to increase the percentage of negative urine tests was implemented using a multiple-baseline across groups design in a sample of 19 families of children with insulin dependent diabetes. The treatment involved instruction in insulin adjustment, decrease in intake of simple sugars and saturated fats, and increase in exercise, along with teaching the parents to support improvements in children's self-regulatory behaviors using a point economy and praise. New procedures designed to measure and reinforce adherence to the urine testing regimen were developed. Results showed significant increases in percentage of negative urines consistent with implementation of treatment across the three treatment groups, which were maintained over the follow-up period. Metabolic measures of control, including glycosylated hemoglobin and serum glucose did not show improvements even though the relationship between the percentage of negative urine tests and glycosylated hemoglobin was very high during treatment.

  9. Nuclear magnetic resonance studies of glucose metabolism in non-insulin-dependent diabetes mellitus subjects.

    PubMed

    Shulman, R G

    1996-09-01

    In this review, the results of a series of NMR experiments investigating glucose storage and synthesis in NIDDM patients and normal controls have been summarized. These have shown: 1. The deficit in nonoxidative glucose disposal in NIDDM subjects results from a defect in the muscle glycogen synthesis pathway. 2. Reduced activity of glucose transporter/hexokinase step in this pathway accounts for the reduced rate of glycogen synthesis in NIDDM patients. 3. This reduced activity of GT/Hk is a genetic defect present before the clinical onset of disease in prediabetic descendants of diabetic parents. 4. In muscle from normal, healthy subjects the rate of glycogen synthesis is controlled by the glucose transport/hexokinase activity step and not by the activity of the muscle glycogen synthase enzyme. 5. Hepatic gluconeogenesis is responsible for most hepatic glucose production during an overnight fast in both normal and NIDDM subjects, and increases in gluconeogenic flux are responsible for the increased rate of hepatic glucose production in NIDDM subjects. 6. In contrast to human muscle, where glycogenesis ceases at rest, in the liver gluconeogenesis and glycogenolysis are always active. Numerous previous studies were considered prior to embarking in each of these NMR experiments. In the original research articles we published, the earlier studies were discussed in terms of the relevant literature. Here, however, I have chosen to present the NMR data as simply as possible, in the hope of exposing the significance of these studies by disentangling the results from the complexities of NMR methodology.

  10. Age dependence of glucose tolerance in adult KK-Ay mice, a model of non-insulin dependent diabetes mellitus.

    PubMed

    Chakraborty, Goutam; Thumpayil, Sherin; Lafontant, David-Erick; Woubneh, Wolde; Toney, Jeffrey H

    2009-11-01

    Yellow KK mice carrying the 'yellow obese' gene Ay are a well established polygenic model for human non-insulin dependent diabetes mellitus. These animals develop marked adiposity and decreased glucose tolerance relative to their control littermates, KK mice. The authors monitored glucose tolerance in KK-Ay mice over time and observed a significant (Pglucose tolerance when maintained on a normal diet for 25 weeks or longer, due in part to increases in plasma levels of insulin and amylin.

  11. Insulin-dependent glucose metabolism in dairy cows with variable fat mobilization around calving.

    PubMed

    Weber, C; Schäff, C T; Kautzsch, U; Börner, S; Erdmann, S; Görs, S; Röntgen, M; Sauerwein, H; Bruckmaier, R M; Metges, C C; Kuhla, B; Hammon, H M

    2016-08-01

    Dairy cows undergo significant metabolic and endocrine changes during the transition from pregnancy to lactation, and impaired insulin action influences nutrient partitioning toward the fetus and the mammary gland. Because impaired insulin action during transition is thought to be related to elevated body condition and body fat mobilization, we hypothesized that over-conditioned cows with excessive body fat mobilization around calving may have impaired insulin metabolism compared with cows with low fat mobilization. Nineteen dairy cows were grouped according to their average concentration of total liver fat (LFC) after calving in low [LLFC; LFC <24% total fat/dry matter (DM); n=9] and high (HLFC; LFC >24.4% total fat/DM; n=10) fat-mobilizing cows. Blood samples were taken from wk 7 antepartum (ap) to wk 5 postpartum (pp) to determine plasma concentrations of glucose, insulin, glucagon, and adiponectin. We applied euglycemic-hyperinsulinemic (EGHIC) and hyperglycemic clamps (HGC) in wk 5 ap and wk 3 pp to measure insulin responsiveness in peripheral tissue and pancreatic insulin secretion during the transition period. Before and during the pp EGHIC, [(13)C6] glucose was infused to determine the rate of glucose appearance (GlucRa) and glucose oxidation (GOx). Body condition, back fat thickness, and energy-corrected milk were greater, but energy balance was lower in HLFC than in LLFC. Plasma concentrations of glucose, insulin, glucagon, and adiponectin decreased at calving, and this was followed by an immediate increase of glucagon and adiponectin after calving. Insulin concentrations ap were higher in HLFC than in LLFC cows, but the EGHIC indicated no differences in peripheral insulin responsiveness among cows ap and pp. However, GlucRa and GOx:GlucRa during the pp EGHIC were greater in HLFC than in LLFC cows. During HGC, pancreatic insulin secretion was lower, but the glucose infusion rate was higher pp than ap in both groups. Plasma concentrations of nonesterified

  12. Prevalence of non-insulin-dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec.

    PubMed Central

    Delisle, H F; Ekoé, J M

    1993-01-01

    OBJECTIVE: To assess and compare the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in two native Indian communities. DESIGN: Population-based study. SETTING: Two Algonquin communities in Quebec: River Desert and Lac Simon. PARTICIPANTS: All native Indian residents aged at least 15 years were eligible; 621 (59%) of them volunteered to enroll in the study. The participation rate was 49% in River Desert and 76% in Lac Simon. MAIN OUTCOME MEASURES: Fasting blood glucose level and serum glucose level 2 hours after 75-g oral glucose tolerance test, as described by the World Health Organization, in all subjects except those with confirmed diabetes. Other measures included body mass index (BMI), fat distribution and blood pressure. MAIN RESULTS: The age-sex standardized prevalence rate of NIDDM was 19% in Lac Simon (95% confidence interval [CI] 16% to 21%); this was more than twice the rate of 9% in River Desert (95% CI 7% to 11%). The IGT rates were comparable in the two communities (River Desert 5%, Lac Simon 6%). NIDDM and IGT were uncommon under the age of 35 years. Only in Lac Simon was the NIDDM prevalence rate significantly higher among the women than among the men (23% v. 14%); almost half of the women aged 35 years or more had diabetes. In Lac Simon the rate of marked obesity (BMI greater than 30) was significantly higher among the women than among the men (37% v. 19%; p < 0.001); this sex-related difference was not found in River Desert (rates 31% and 23% respectively). Previously undiagnosed NIDDM accounted for 25% of all the cases. NIDDM and IGT were significantly associated with high BMI, sum of skinfold thicknesses and waist:hip circumference ratio (p < 0.001). The subscapular:triceps skinfold ratio, however, did not display such an association, nor did the age-adjusted systolic blood pressure. CONCLUSIONS: The prevalence of NIDDM is high in Algonquin communities and may vary markedly between communities

  13. The serum insulin and plasma glucose responses to milk and fruit products in type 2 (non-insulin-dependent) diabetic patients.

    PubMed

    Gannon, M C; Nuttall, F Q; Krezowski, P A; Billington, C J; Parker, S

    1986-11-01

    The plasma glucose and serum insulin responses were determined in untreated Type 2 (non-insulin-dependent) diabetic patients following the ingestion of foods containing sucrose, glucose, fructose or lactose in portions that contained 50 g of carbohydrate. The results were compared to those obtained following the ingestion of pure fructose, sucrose, glucose + fructose and lactose. The objectives were to determine 1) if the glucose response to naturally occurring foods could be explained by the known carbohydrate content, and 2) whether the insulin response could be explained by the glucose response. The glucose response was essentially the same whether the carbohydrate was given as a pure substance, or in the form of a naturally occurring food. The glucose response to each type of carbohydrate was that expected from the known metabolism of the constituent monosaccharides. The glucose areas following the ingestion of the foods were: Study 1: glucose 11.7, orange juice 7.3, sucrose 5.2, glucose + fructose 6.3, and fructose 0.7 mmol X h/l; Study 2: glucose 14.6, orange juice 7.3, apples 5.5, and apple juice 4.7 mmol X h/l; Study 3: glucose 12.6, ice cream 8.1, milk 3.7, and lactose 4.1 mmol X h/l. The insulin response was greater than could be explained by the glucose response for all meals except apples. Milk was a particularly potent insulin secretagogue; the observed insulin response was approximately 5-fold greater than would be anticipated from the glucose response. In summary, the plasma glucose response to ingestion of fruits and milk products can be predicted from the constituent carbohydrate present. The serum insulin response cannot.

  14. Influence of diazepam on blood glucose levels in nondiabetic and non-insulin-dependent diabetic subjects under dental treatment with local anesthesia.

    PubMed Central

    Schaira, Vanessa Rocha Lima; Ranali, José; Saad, Mário José Abdalla; de Oliveira, Patrícia Cristine; Ambrosano, Glaúcia Maria Bovi; Volpato, Maria Cristina

    2004-01-01

    The effect of diazepam on blood glucose concentration (BGC) was investigated in a double-blind cross-over study in 10 healthy and 10 non-insulin-dependent diabetic subjects taking oral hypoglycemic drugs. In the first session, fasting blood samples were taken for blood glucose and glycosylated hemoglobin estimation and at 60, 80, 95, 125, and 155 minutes thereafter for glucose estimation. In another 2 sessions, a venous sample was taken immediately before premedication (5 mg diazepam or placebo randomly given during breakfast). One hour later a blood sample was taken, and the volunteers were submitted to periodontal treatment after injection of 1.8 mL of 2% mepivacaine with 1:100,000 adrenaline. Venous blood samples were taken at 15, 30, 60, and 90 minutes after injection. The changes in BGC were analyzed using analysis of variance (ANOVA) for repeated measures; the means were compared using Tukey test (P = .05). Statistically significant differences in the BGC were observed between diabetic and nondiabetic groups (P = .00003). However, there were no significant differences among the sessions of the same group (P = .29). The results of this study show that a single dose of 5 mg diazepam before dental treatment does not influence BGC in nondiabetic and non-insulin-dependent diabetic subjects. PMID:15106685

  15. Measurement of Glucose Uptake in Cultured Cells.

    PubMed

    Yamamoto, Norio; Ueda-Wakagi, Manabu; Sato, Takuya; Kawasaki, Kengo; Sawada, Keisuke; Kawabata, Kyuichi; Akagawa, Mitsugu; Ashida, Hitoshi

    2015-12-08

    Facilitative glucose uptake transport systems are ubiquitous in animal cells and are responsible for transporting glucose across cell surface membranes. Evaluation of glucose uptake is crucial in the study of numerous diseases and metabolic disorders such as myocardial ischemia, diabetes mellitus, and cancer. Detailed in this unit are laboratory methods for assessing glucose uptake into mammalian cells. The unit is divided into five sections: (1) a brief overview of glucose uptake assays in cultured cells; (2) a method for measuring glucose uptake using radiolabeled 3-O-methylglucose; (3) a method for measuring glucose uptake using radiolabeled 2-deoxyglucose (2DG); (4) a microplate method for measuring 2DG-uptake using an enzymatic, fluorometric assay; and (5) a microplate-based method using a fluorescent analog of 2DG.

  16. Screening for bioactive metabolites in plant extracts modulating glucose uptake and fat accumulation.

    PubMed

    El-Houri, Rime B; Kotowska, Dorota; Olsen, Louise C B; Bhattacharya, Sumangala; Christensen, Lars P; Grevsen, Kai; Oksbjerg, Niels; Færgeman, Nils; Kristiansen, Karsten; Christensen, Kathrine B

    2014-01-01

    Dichloromethane and methanol extracts of seven different food and medicinal plants were tested in a screening platform for identification of extracts with potential bioactivity related to insulin-dependent glucose uptake and fat accumulation. The screening platform included a series of in vitro bioassays, peroxisome proliferator-activated receptor (PPAR) γ-mediated transactivation, adipocyte differentiation of 3T3-L1 cell cultures, and glucose uptake in both 3T3-L1 adipocytes and primary porcine myotubes, as well as one in vivo bioassay, fat accumulation in the nematode Caenorhabditis elegans. We found that dichloromethane extracts of aerial parts of golden root (Rhodiola rosea) and common elder (Sambucus nigra) as well as the dichloromethane extracts of thyme (Thymus vulgaris) and carrot (Daucus carota) were able to stimulate insulin-dependent glucose uptake in both adipocytes and myotubes while weekly activating PPARγ without promoting adipocyte differentiation. In addition, these extracts were able to decrease fat accumulation in C. elegans. Methanol extracts of summer savory (Satureja hortensis), common elder, and broccoli (Brassica oleracea) enhanced glucose uptake in myotubes but were not able to activate PPARγ, indicating a PPARγ-independent effect on glucose uptake. PMID:25254050

  17. Evidence that down-regulation of. beta. -cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia

    SciTech Connect

    Orci, L.; Ravazzola, M.; Baetens, D.; Amherdt, M. ); Inman, L.; Johnson, J.H.; Unger, R.H. Dept. of Veterans Affairs Medical Center, Dallas, TX ); Peterson, R.G. ); Newgard, C.B. )

    1990-12-01

    Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic {beta} cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat, a model of NIDDM that closely resembles the human syndrome, the authors have previously reported profound underexpression of GLUT-2, the high-K{sub m} facilitative glucose transporter expressed by {beta} cells of normal animals. Here they report that islets of diabetic rats exhibit a marked decrease in the volume density of GLUT-2-positive {beta} cells and a reduction at the electron-microscopic level in the number of GLUT-2-immunoreactive sites per unit of {beta}-cell plasma membrane. The deficiency of GLUT-2 cannot be induced in normal {beta} cells by in vivo or in vitro exposure to high levels of glucose nor can it be prevented in {beta} cells of prediabetic ZDF rats by elimination of hyperglycemia. They conclude that this dearth of immunodetectable GLUT-2 in NIDDM is not secondary to hyperglycemia and therefore that it may well play a causal role in the development of hyperglycemia.

  18. General aspects of muscle glucose uptake.

    PubMed

    Alvim, Rafael O; Cheuhen, Marcel R; Machado, Silmara R; Sousa, André Gustavo P; Santos, Paulo C J L

    2015-03-01

    Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.

  19. Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle.

    PubMed

    Sylow, Lykke; Jensen, Thomas E; Kleinert, Maximilian; Mouatt, Joshua R; Maarbjerg, Stine J; Jeppesen, Jacob; Prats, Clara; Chiu, Tim T; Boguslavsky, Shlomit; Klip, Amira; Schjerling, Peter; Richter, Erik A

    2013-04-01

    In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contraction-induced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice (~60-100%) and humans (~40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of muscle-specific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

  20. Down-regulation of lipoprotein lipase increases glucose uptake in L6 muscle cells

    SciTech Connect

    Lopez, Veronica; Saraff, Kumuda; Medh, Jheem D.

    2009-11-06

    Thiazolidinediones (TZDs) are synthetic hypoglycemic agents used to treat type 2 diabetes. TZDs target the peroxisome proliferator activated receptor-gamma (PPAR-{gamma}) and improve systemic insulin sensitivity. The contributions of specific tissues to TZD action, or the downstream effects of PPAR-{gamma} activation, are not very clear. We have used a rat skeletal muscle cell line (L6 cells) to demonstrate that TZDs directly target PPAR-{gamma} in muscle cells. TZD treatment resulted in a significant repression of lipoprotein lipase (LPL) expression in L6 cells. This repression correlated with an increase in glucose uptake. Down-regulation of LPL message and protein levels using siRNA resulted in a similar increase in insulin-dependent glucose uptake. Thus, LPL down-regulation improved insulin sensitivity independent of TZDs. This finding provides a novel method for the management of insulin resistance.

  1. Lack of CD2AP disrupts Glut4 trafficking and attenuates glucose uptake in podocytes.

    PubMed

    Tolvanen, Tuomas A; Dash, Surjya Narayan; Polianskyte-Prause, Zydrune; Dumont, Vincent; Lehtonen, Sanna

    2015-12-15

    The adapter protein CD2-associated protein (CD2AP) functions in various signaling and vesicle trafficking pathways, including endosomal sorting and/or trafficking and degradation pathways. Here, we investigated the role of CD2AP in insulin-dependent glucose transporter 4 (Glut4, also known as SLC2A4) trafficking and glucose uptake. Glucose uptake was attenuated in CD2AP(-/-) podocytes compared with wild-type podocytes in the basal state, and CD2AP(-/-) podocytes failed to increase glucose uptake in response to insulin. Live-cell imaging revealed dynamic trafficking of HA-Glut4-GFP in wild-type podocytes, whereas in CD2AP(-/-) podocytes, HA-Glut4-GFP clustered perinuclearly. In subcellular membrane fractionations, CD2AP co-fractionated with Glut4, IRAP (also known as LNPEP) and sortilin, constituents of Glut4 storage vesicles (GSVs). We further found that CD2AP forms a complex with GGA2, a clathrin adaptor, which sorts Glut4 to GSVs, suggesting a role for CD2AP in this process. We also found that CD2AP forms a complex with clathrin and connects clathrin to actin in the perinuclear region. Furthermore, clathrin recycling back to trans-Golgi membranes from the vesicular fraction containing GSVs was defective in the absence of CD2AP. This leads to reduced insulin-stimulated trafficking of GSVs and attenuated glucose uptake into CD2AP(-/-) podocytes.

  2. Comparison of glycosylated hemoglobin with the oral glucose tolerance test. A study in subjects with normoglycemia, glucose intolerance and non-insulin-dependent diabetes mellitus.

    PubMed

    Cederholm, J; Ronquist, G; Wibell, L

    1984-10-01

    At a health survey of 819 subjects, 47-54 years old, the rate of glucose intolerance (GI) was 6.2% (51 subjects) according to 75 g oral glucose tolerance tests (OGTT) and WHO criteria. In GI-subjects, the mean HbA1 was 7.3% (10th-90th percentile range 6.2-8.3%), and significantly higher than the mean HbA1 in 150 subjects with normal OGTT, which was 6.5% (10th-90th percentile range 5.7-7.4%). With an upper normal limit of 7.8% (mean + 2 SD) only 20% of all GI-subjects had a raised HbA1. The differences between 31 GI-subjects, with low HbA1 (mean 6.9%), and 20 GI-subjects, with relatively high HbA1 (mean 7.9%), were not significant with respect to fasting and 2-hour blood glucose, area under glucose curve, body mass index, index of physical activity, rate of hypertension or rate of first degree relatives with diabetes. In an unselected group of 157 subjects, sampled consecutively during the first part of the survey, the mean HbA1 was 6.6% (10th-90th percentile range 5.8-7.5 %) 150 subjects were those with normal OGTT, 6 subjects had GI and only one subject had previously unknown diabetes. No distinct correlations between HbA1 and OGTT fasting or 2 hour values were found in this sample. No correlation was found within the separate groups of 51 GI-subjects and 150 normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Zinc transporter 7 deficiency affects lipid synthesis in adipocytes by inhibiting insulin-dependent Akt activity and glucose uptake

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice deficient for zinc transporter 7 (Znt7) are mildly zinc deficient, accompanied with low body weight gain and body fat accumulation. To investigate the underlying mechanism of Znt7 deficiency in body adiposity, we investigated fatty acid composition and insulin sensitivity in visceral (epididyma...

  4. Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells via multipathway mechanisms.

    PubMed

    Kang, Changkeun; Lee, Hyunkyoung; Jung, Eun-Sun; Seyedian, Ramin; Jo, MiNa; Kim, Jehein; Kim, Jong-Shu; Kim, Euikyung

    2012-12-15

    Saffron (Crocus sativus Linn.) has been an important subject of research in the past two decades because of its various biological properties, including anti-cancer, anti-inflammatory, and anti-atherosclerotic activities. On the other hand, the molecular bases of its actions have been scarcely understood. Here, we elucidated the mechanism of the hypoglycemic actions of saffron through investigating its signaling pathways associated with glucose metabolism in C(2)C(12) skeletal muscle cells. Saffron strongly enhanced glucose uptake and the phosphorylation of AMPK (AMP-activated protein kinase)/ACC (acetyl-CoA carboxylase) and MAPKs (mitogen-activated protein kinases), but not PI 3-kinase (Phosphatidylinositol 3-kinase)/Akt. Interestingly, the co-treatment of saffron and insulin further improved the insulin sensitivity via both insulin-independent (AMPK/ACC and MAPKs) and insulin-dependent (PI 3-kinase/Akt and mTOR) pathways. It also suggested that there is a crosstalk between the two signaling pathways of glucose metabolism in skeletal muscle cells. These results could be confirmed from the findings of GLUT4 translocation. Taken together, AMPK plays a major role in the effects of saffron on glucose uptake and insulin sensitivity in skeletal muscle cells. Our study provides important insights for the possible mechanism of action of saffron and its potential as a therapeutic agent in diabetic patients.

  5. Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes.

    PubMed

    El-Houri, Rime B; Kotowska, Dorota; Christensen, Kathrine B; Bhattacharya, Sumangala; Oksbjerg, Niels; Wolber, Gerhard; Kristiansen, Karsten; Christensen, Lars P

    2015-07-01

    A dichloromethane (DCM) extract of carrot roots was found to stimulate insulin-dependent glucose uptake (GU) in adipocytes in a dose dependent manner. Bioassay-guided fractionation of the DCM extract resulted in the isolation of the polyacetylenes falcarinol and falcarindiol. Both polyacetylenes were able to significantly stimulate basal and/or insulin-dependent GU in 3T3-L1 adipocytes and porcine myotube cell cultures in a dose-dependent manner. Falcarindiol increased peroxisome proliferator-activated receptor (PPAR)γ-mediated transactivation significantly at concentrations of 3, 10 and 30 μM, while PPARγ-mediated transactivation by falcarinol was only observed at 10 μM. Docking studies accordingly indicated that falcarindiol binds to the ligand binding domain of PPARγ with higher affinity than falcarinol and that both polyacetylenes exhibit characteristics of PPARγ partial agonists. Falcarinol was shown to inhibit adipocyte differentiation as evident by gene expression studies and Oil Red O staining, whereas falcarindiol did not inhibit adipocyte differentiation, which indicates that these polyacetylenes have distinct modes of action. The results of the present study suggest that falcarinol and falcarindiol may represent scaffolds for novel partial PPARγ agonists with possible antidiabetic properties.

  6. Polyacetylenes from carrots (Daucus carota) improve glucose uptake in vitro in adipocytes and myotubes.

    PubMed

    El-Houri, Rime B; Kotowska, Dorota; Christensen, Kathrine B; Bhattacharya, Sumangala; Oksbjerg, Niels; Wolber, Gerhard; Kristiansen, Karsten; Christensen, Lars P

    2015-07-01

    A dichloromethane (DCM) extract of carrot roots was found to stimulate insulin-dependent glucose uptake (GU) in adipocytes in a dose dependent manner. Bioassay-guided fractionation of the DCM extract resulted in the isolation of the polyacetylenes falcarinol and falcarindiol. Both polyacetylenes were able to significantly stimulate basal and/or insulin-dependent GU in 3T3-L1 adipocytes and porcine myotube cell cultures in a dose-dependent manner. Falcarindiol increased peroxisome proliferator-activated receptor (PPAR)γ-mediated transactivation significantly at concentrations of 3, 10 and 30 μM, while PPARγ-mediated transactivation by falcarinol was only observed at 10 μM. Docking studies accordingly indicated that falcarindiol binds to the ligand binding domain of PPARγ with higher affinity than falcarinol and that both polyacetylenes exhibit characteristics of PPARγ partial agonists. Falcarinol was shown to inhibit adipocyte differentiation as evident by gene expression studies and Oil Red O staining, whereas falcarindiol did not inhibit adipocyte differentiation, which indicates that these polyacetylenes have distinct modes of action. The results of the present study suggest that falcarinol and falcarindiol may represent scaffolds for novel partial PPARγ agonists with possible antidiabetic properties. PMID:25970571

  7. Contraction stimulates muscle glucose uptake independent of atypical PKC.

    PubMed

    Yu, Haiyan; Fujii, Nobuharu L; Toyoda, Taro; An, Ding; Farese, Robert V; Leitges, Michael; Hirshman, Michael F; Mul, Joram D; Goodyear, Laurie J

    2015-11-01

    Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζ(WT)), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζ(T410A)). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζ(WT), and PKC-ζ(T410A) tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζ(T410A) tibialis anterior muscles compared to WT or PKC-ζ(WT) tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λζ activity is not necessary for contraction-stimulated glucose uptake.

  8. ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells.

    PubMed

    Izawa, Yuki; Yoshizumi, Masanori; Fujita, Yoshiko; Ali, Nermin; Kanematsu, Yasuhisa; Ishizawa, Keisuke; Tsuchiya, Koichiro; Obata, Toshiyuki; Ebina, Yousuke; Tomita, Shuhei; Tamaki, Toshiaki

    2005-08-15

    Clinical evidence suggests a relationship between hypertension and insulin resistance, and cross-talk between angiotensin II (Ang II) and insulin signaling pathways may take place. We now report the effect of Ang II on insulin-induced glucose uptake and its intracellular mechanisms in vascular smooth muscle cells (VSMC). We examined the translocation of glucose transporter-4 (GLUT-4) and glucose uptake in rat aortic smooth muscle cells (RASMC). Mitogen-activated protein (MAP) kinases and Akt activities, and phosphorylation of insulin receptor substrate-1 (IRS-1) at the serine and tyrosine residues were measured by immunoprecipitation and immunoblotting. As a result, Ang II inhibited insulin-induced GLUT-4 translocation from cytoplasm to the plasma membrane in RASMC. Ang II induced extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation and IRS-1 phosphorylation at Ser307 and Ser616. Ang II-induced Ser307 and Ser616 phophorylation of IRS-1 was inhibited by a MEK inhibitor, PD98059, and a JNK inhibitor, SP600125. Ang II inhibition of insulin-stimulated IRS-1 tyrosyl phophorylation and Akt activation were reversed by PD98059 but not by SP600125. Ang II inhibited insulin-induced glucose uptake, which was also reversed by PD98059 but not by SP600125. It is shown that Ang II-induced ERK1/2 activation inhibits insulin-dependent glucose uptake through serine phophorylation of IRS-1 in RASMC.

  9. Glucose uptake in Oesophagostomum dentatum and the effect of oxfendazole.

    PubMed

    Petersen, M B; Friis, C

    1998-12-31

    The uptake of 14C-glucose by adult Oesophagostomum dentatum was characterised. The uptake was a non-linear function of external glucose concentration. The maximum velocity of uptake (Vmax) was 0.964 nmol/100 mg dry weight (dw)/5 min, and the transport constant (Kt) was 10.02 microM. When phlorizin, phloretin and 3-O-methylglucose were tested for their effects on the uptake of 14C-glucose, phloretin and 3-O-methylglucose produced significant inhibitions, indicating that the uptake was mediated and occurred by facilitated diffusion. Exposure of the worms to oxfendazole prior to incubation with 14C-glucose did not affect the uptake of glucose. In another experiment worms were incubated with unlabelled glucose and the external glucose concentration was measured enzymatically. During a 7 h incubation period, the quantity of glucose remaining in the incubation medium of oxfendazole exposed worms was significantly greater than in the control group. It was concluded that oxfendazole did not influence the process of 14C-glucose uptake, but might induce changes in the parasite leading to a reduced ability to deplete the incubation medium of glucose.

  10. In vitro effect of fenugreek extracts on intestinal sodium-dependent glucose uptake and hepatic glycogen phosphorylase A.

    PubMed

    Al-Habori, M; Raman, A; Lawrence, M J; Skett, P

    2001-01-01

    Fenugreek (Trigonella foenum-graecum L. seed) is a food with traditional medicinal use in diabetes. Beneficial effects have been demonstrated in diabetic animals and both insulin-dependent and non-insulin-dependent diabetic subjects. Effects of a lipid extract A, crude ethanolic extract B, further sub-fractions of B (saponin-free C, saponin D and sapogenin E) and a gum fibre fraction F on intestinal sodium-dependent glucose uptake were investigated in vitro using rabbit intestinal brush border membrane vesicles. All fractions except A inhibited glucose-uptake at 0.33 and/or 3.3 mg/mL (p < 0.001). Greatest inhibition was observed with fractions D and E. Diosgenin and trigonelline (compounds reported in fenugreek) also inhibited glucose-uptake (IC50 values approximately 3 mg/ml, equivalent to 8 mM and 19 mM respectively) but did not account for the activity of the crude extracts. Fenugreek extracts had no effect on basal levels of glycogen phosphorylase a (HGPa) activity in rat hepatocyte suspensions. However fractions C and E caused a marginal but statistically significant inhibition (18.9 and 15.1% respectively, p < 0.05) of glucagon induction of this enzyme suggesting a glucagon-antagonist effect. Diosgenin (1.65 mg/ml; 4 mM) inhibited glucagon-induced HGPa activity by 20% (p < 0.05), and was more effective than trigonelline (non significant inhibition of 9.4% at 1.65 mg/ml, 10 mM). PMID:12369721

  11. Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism.

    PubMed Central

    Tessari, P; Nosadini, R; Trevisan, R; De Kreutzenberg, S V; Inchiostro, S; Duner, E; Biolo, G; Marescotti, M C; Tiengo, A; Crepaldi, G

    1986-01-01

    To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present. PMID:3519679

  12. High intensity exercise decreases global brain glucose uptake in humans

    PubMed Central

    Kemppainen, Jukka; Aalto, Sargo; Fujimoto, Toshihiko; Kalliokoski, Kari K; Långsjö, Jaakko; Oikonen, Vesa; Rinne, Juha; Nuutila, Pirjo; Knuuti, Juhani

    2005-01-01

    Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of V˙O2max on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6 ± 4.6 versus 26.1 ± 5.0 μmol (100 g)−1 min−1, P < 0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P < 0.05 between 30% and 75% of V˙O2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions. PMID:16037089

  13. Polymethoxyflavonoids tangeretin and nobiletin increase glucose uptake in murine adipocytes.

    PubMed

    Onda, Kenji; Horike, Natsumi; Suzuki, Tai-ichi; Hirano, Toshihiko

    2013-02-01

    Tangeretin and nobiletin are polymethoxyflavonoids that are contained in citrus fruits. Polymethoxyflavonoids are reported to have several biological functions including anti-inflammatory, anti-atherogenic, or anti-diabetic effects. However, whether polymethoxyflavonoids directly affect glucose uptake in tissues is not well understood. In the current study, we investigated whether tangeretin and nobiletin affect glucose uptake in insulin target cells such as adipocytes. We observed that treatment with tangeretin or nobiletin significantly increased the uptake of [(3) H]-deoxyglucose in differentiated 3T3-F442A adipocytes in a concentration-dependent manner. Data showed that phosphatidyl inositol 3 kinase, Akt1/2, and the protein kinase A pathways were involved in the increase in glucose uptake induced by polymethoxyflavonoids. These data suggest that the anti-diabetic action of polymethoxyflavonoids is partly exerted via these signaling pathways in insulin target tissues.

  14. Insulin-dependent (type I) diabetes mellitus.

    PubMed Central

    Rodger, W

    1991-01-01

    Insulin-dependent (type I) diabetes mellitus is a chronic disease characterized by hyperglycemia, impaired metabolism and storage of important nutrients, evidence of autoimmunity, and long-term vascular and neurologic complications. Insulin secretory function is limited. Cell membrane binding is not primarily involved. The goal of treatment is to relieve symptoms and to achieve blood glucose levels as close to normal as possible without severe hypoglycemia. However, even with education and self-monitoring of the blood glucose level, attaining recommended target values (plasma glucose level less than 8.0 mmol/L before main meals for adults) remains difficult. Human insulin offers no advantage in glycemic control but is important in the management and prevention of immune-related clinical problems (e.g., injection-site lipoatrophy, insulin resistance and allergy) associated with the use of beef or pork insulin. Therapy with one or two injections per day of mixed short-acting or intermediate-acting insulin preparations is a compromise between convenience and the potential for achieving target plasma glucose levels. Intensive insulin therapy with multiple daily injections or continuous infusion with an insulin pump improves mean glycated hemoglobin levels; however, it increases rates of severe hypoglycemia and has not been shown to decrease the incidence of clinically significant renal, retinal or neurologic dysfunction. Future prospects include automated techniques of insulin delivery, immunosuppression to preserve endogenous insulin secretion and islet transplantation. PMID:1933705

  15. Ceramide 1-phosphate stimulates glucose uptake in macrophages

    PubMed Central

    Ouro, Alberto; Arana, Lide; Gangoiti, Patricia; Rivera, Io-Guané; Ordoñez, Marta; Trueba, Miguel; Lankalapalli, Ravi S.; Bittman, Robert; Gomez-Muñoz, Antonio

    2014-01-01

    It is well established that ceramide 1-phosphate (C1P) is mitogenic and antiapoptotic, and that it is implicated in the regulation of macrophage migration. These activities require high energy levels to be available in cells. Macrophages obtain most of their energy from glucose. In this work, we demonstrate that C1P enhances glucose uptake in RAW264.7 macrophages. The major glucose transporter involved in this action was found to be GLUT 3, as determined by measuring its translocation from the cytosol to the plasma membrane. C1P-stimulated glucose uptake was blocked by selective inhibitors of phosphatidylinositol 3-kinase (PI3K) or Akt, also known as protein kinase B (PKB), and by specific siRNAs to silence the genes encoding for these kinases. C1P-stimulated glucose uptake was also inhibited by pertussis toxin (PTX) and by the siRNA that inhibited GLUT 3 expression. C1P increased the affinity of the glucose transporter for its substrate, and enhanced glucose metabolism to produce ATP. The latter action was also inhibited by PI3K- and Akt-selective inhibitors, PTX, or by specific siRNAs to inhibit GLUT 3 expression. PMID:23333242

  16. An inositol 1,4,5-triphosphate (IP3)-IP3 receptor pathway is required for insulin-stimulated glucose transporter 4 translocation and glucose uptake in cardiomyocytes.

    PubMed

    Contreras-Ferrat, A E; Toro, B; Bravo, R; Parra, V; Vásquez, C; Ibarra, C; Mears, D; Chiong, M; Jaimovich, E; Klip, A; Lavandero, S

    2010-10-01

    Intracellular calcium levels ([Ca2+]i) and glucose uptake are central to cardiomyocyte physiology, yet connections between them have not been studied. We investigated whether insulin regulates [Ca2+]i in cultured cardiomyocytes, the participating mechanisms, and their influence on glucose uptake via SLC2 family of facilitative glucose transporter 4 (GLUT4). Primary neonatal rat cardiomyocytes were preloaded with the Ca2+ fluorescent dye fluo3-acetoxymethyl ester compound (AM) and visualized by confocal microscopy. Ca2+ transport pathways were selectively targeted by chemical and molecular inhibition. Glucose uptake was assessed using [3H]2-deoxyglucose, and surface GLUT4 levels were quantified in nonpermeabilized cardiomyocytes transfected with GLUT4-myc-enhanced green fluorescent protein. Insulin elicited a fast, two-component, transient increase in [Ca2+]i. Nifedipine and ryanodine prevented only the first component. The second one was reduced by inositol-1,4,5-trisphosphate (IP3)-receptor-selective inhibitors (xestospongin C, 2 amino-ethoxydiphenylborate), by type 2 IP3 receptor knockdown via small interfering RNA or by transfected Gβγ peptidic inhibitor βARKct. Insulin-stimulated glucose uptake was prevented by bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid-AM, 2-amino-ethoxydiphenylborate, and βARK-ct but not by nifedipine or ryanodine. Similarly, insulin-dependent exofacial exposure of GLUT4-myc-enhanced green fluorescent protein was inhibited by bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid-AM and xestospongin C but not by nifedipine. Phosphatidylinositol 3-kinase and Akt were also required for the second phase of Ca2+ release and GLUT4 translocation. Transfected dominant-negative phosphatidylinositol 3-kinase γ inhibited the latter. In conclusion, in primary neonatal cardiomyocytes, insulin induces an important component of Ca2+ release via IP3 receptor. This component signals to glucose uptake via GLUT4, revealing a so-far unrealized

  17. An inositol 1,4,5-triphosphate (IP3)-IP3 receptor pathway is required for insulin-stimulated glucose transporter 4 translocation and glucose uptake in cardiomyocytes.

    PubMed

    Contreras-Ferrat, A E; Toro, B; Bravo, R; Parra, V; Vásquez, C; Ibarra, C; Mears, D; Chiong, M; Jaimovich, E; Klip, A; Lavandero, S

    2010-10-01

    Intracellular calcium levels ([Ca2+]i) and glucose uptake are central to cardiomyocyte physiology, yet connections between them have not been studied. We investigated whether insulin regulates [Ca2+]i in cultured cardiomyocytes, the participating mechanisms, and their influence on glucose uptake via SLC2 family of facilitative glucose transporter 4 (GLUT4). Primary neonatal rat cardiomyocytes were preloaded with the Ca2+ fluorescent dye fluo3-acetoxymethyl ester compound (AM) and visualized by confocal microscopy. Ca2+ transport pathways were selectively targeted by chemical and molecular inhibition. Glucose uptake was assessed using [3H]2-deoxyglucose, and surface GLUT4 levels were quantified in nonpermeabilized cardiomyocytes transfected with GLUT4-myc-enhanced green fluorescent protein. Insulin elicited a fast, two-component, transient increase in [Ca2+]i. Nifedipine and ryanodine prevented only the first component. The second one was reduced by inositol-1,4,5-trisphosphate (IP3)-receptor-selective inhibitors (xestospongin C, 2 amino-ethoxydiphenylborate), by type 2 IP3 receptor knockdown via small interfering RNA or by transfected Gβγ peptidic inhibitor βARKct. Insulin-stimulated glucose uptake was prevented by bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid-AM, 2-amino-ethoxydiphenylborate, and βARK-ct but not by nifedipine or ryanodine. Similarly, insulin-dependent exofacial exposure of GLUT4-myc-enhanced green fluorescent protein was inhibited by bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid-AM and xestospongin C but not by nifedipine. Phosphatidylinositol 3-kinase and Akt were also required for the second phase of Ca2+ release and GLUT4 translocation. Transfected dominant-negative phosphatidylinositol 3-kinase γ inhibited the latter. In conclusion, in primary neonatal cardiomyocytes, insulin induces an important component of Ca2+ release via IP3 receptor. This component signals to glucose uptake via GLUT4, revealing a so-far unrealized

  18. Glucose uptake and glycogen synthesis in muscles from immobilized limbs

    NASA Technical Reports Server (NTRS)

    Nicholson, W. F.; Watson, P. A.; Booth, F. W.

    1984-01-01

    Defects in glucose metabolism in muscles of immobilized limbs of mice were related to alterations in insulin binding, insulin responsiveness, glucose supply, and insulin activation of glycogen synthase. These were tested by in vitro methodology. A significant lessening in the insulin-induced maximal response of 2-deoxyglucose uptake into the mouse soleus muscle occurred between the 3rd and 8th h of limb immobilization, suggesting a decreased insulin responsiveness. Lack of change in the specific binding of insulin to muscles of 24-h immobilized limbs indicates that a change in insulin receptor number did not play a role in the failure of insulin to stimulate glucose metabolism. Its inability to stimulate glycogen synthesis in muscle from immobilized limbs is due, in part, to a lack of glucose supply to glycogen synthesis and also to the ineffectiveness of insulin to increase the percentage of glycogen synthase in its active form in muscles from 24-h immobilized limbs.

  19. Actin filaments participate in the relocalization of phosphatidylinositol3-kinase to glucose transporter-containing compartments and in the stimulation of glucose uptake in 3T3-L1 adipocytes.

    PubMed Central

    Wang, Q; Bilan, P J; Tsakiridis, T; Hinek, A; Klip, A

    1998-01-01

    Insulin stimulates the rate of glucose uptake into muscle and adipose cells by translocation of glucose transporters from an intracellular storage pool to the plasma membrane. This event requires the prior activation of phosphatidylinositol 3-kinase (PI 3-kinase). Here we report that insulin causes an increase in wortmannin-sensitive PI 3-kinase activity and a gain in the enzyme's regulatory and catalytic subunits p85alpha and p110beta (but not p110alpha) in the intracellular compartments containing glucose transporters. The hormone also caused a marked reorganization of actin filaments, which was prevented by cytochalasin D. Cytochalasin D also decreased significantly the insulin-dependent association of PI 3-kinase activity and the levels of insulin receptor substrate (IRS)-1, p85alpha and p110beta with immunopurified GLUT4-containing compartments. In contrast, the drug did not alter the insulin-induced tyrosine phosphorylation of IRS-1, the association of PI 3-kinase with IRS-1, or the stimulation of PI 3-kinase by insulin in anti-(IRS-1) or anti-p85 immunoprecipitates from whole cell lysates. Cytochalasin D, and the chemically unrelated latrunculin B, which also inhibits actin filament reassembly, prevented the insulin stimulation of glucose transport by approx. 50%. Cytochalasin D decreased by about one-half the insulin-dependent translocation to the plasma membrane of the GLUT1 and GLUT4 glucose transporters. The results suggest that the existence of intact actin filament is correlated with the full recruitment of glucose transporters by insulin. The underlying function of the actin filaments might be to facilitate the insulin-mediated association of the p85-p110 PI 3-kinase with glucose-transporter-containing compartments. PMID:9560323

  20. FADD is essential for glucose uptake and survival of thymocytes.

    PubMed

    Zhang, Xiang-Yu; Yang, Bing-Ya; Wang, Jia-Yu; Mo, Xuan; Zhang, Jing; Hua, Zi-Chun

    2014-08-22

    Fas-associated protein with death domain (FADD) has been implicated in T lymphocytes, but the nature of FADD-dependent mechanism in early T cell development has not been completely elucidated. In this study, using T-cell specific deletion mice, we observed that FADD deficiency in thymocytes led to increased apoptosis and reduced cell numbers, which may be attributed to the reduction of Glut1 expression and correspondingly decreased glucose uptake. Furthermore, an abnormal transduction of Akt signaling was discovered in FADD(-/-) thymocytes, which may be responsible for the declined Glut1 expression. Collectively, our results demonstrate the new function of FADD in glucose metabolism and survival of early T cells.

  1. Effects of iriflophenone 3-C-β-glucoside on fasting blood glucose level and glucose uptake

    PubMed Central

    Pranakhon, Ratree; Aromdee, Chantana; Pannangpetch, Patchareewan

    2015-01-01

    Background: One of the biological activities of agar wood (Aquilaria sinensis Lour., Thymelaeaceae), is anti-hyperglycemic activity. The methanolic extract (ME) was proven to possess the fasting blood glucose activity in rat and glucose uptake transportation by rat adipocytes. Objective: To determine the decreasing fasting blood glucose level of constituents affordable for in vivo test. If the test was positive, the mechanism which is positive to the ME, glucose transportation, will be performed. Materials and Methods: The ME was separated by column chromatography and identified by spectroscopic methods. Mice was used as an animal model (in vivo), and rat adipocytes were used for the glucose transportation activity (in vitro). Result: Iriflophenone 3-C-β-glucoside (IPG) was the main constituent, 3.17%, and tested for the activities. Insulin and the ME were used as positive controls. The ME, IPG and insulin lowered blood glucose levels by 40.3, 46.4 and 41.5%, respectively, and enhanced glucose uptake by 152, 153, and 183%, respectively. Conclusion: These findings suggest that IPG is active in lowering fasting blood glucose with potency comparable to that of insulin. PMID:25709215

  2. Regulation of exercise-stimulated glucose uptake in skeletal muscle

    PubMed Central

    2016-01-01

    AMP-activated protein kinase (AMPK) is a Ser/Thr kinase that has been thought to be an important mediator for exercise-stimulated glucose uptake in skeletal muscle. Liver kinase B1 (LKB1) is an upstream kinase for AMPK and AMPK-related protein kinases, of which the function in skeletal muscle has not been well documented. Our group and others have generated mice lacking AMPK activity in skeletal muscle, as well as muscle-specific LKB1 knockout mice. In this review, we discuss the potential role of AMPK and LKB1 in regulating exercise-stimulated glucose uptake in skeletal muscle. We also discuss our recent study, demonstrating the molecular mechanism of obesity-induced development of skeletal muscle insulin resistance. PMID:27462580

  3. Influence of Acute and Chronic Exercise on Glucose Uptake

    PubMed Central

    Röhling, Martin; Herder, Christian; Stemper, Theodor; Müssig, Karsten

    2016-01-01

    Insulin resistance plays a key role in the development of type 2 diabetes. It arises from a combination of genetic predisposition and environmental and lifestyle factors including lack of physical exercise and poor nutrition habits. The increased risk of type 2 diabetes is molecularly based on defects in insulin signaling, insulin secretion, and inflammation. The present review aims to give an overview on the molecular mechanisms underlying the uptake of glucose and related signaling pathways after acute and chronic exercise. Physical exercise, as crucial part in the prevention and treatment of diabetes, has marked acute and chronic effects on glucose disposal and related inflammatory signaling pathways. Exercise can stimulate molecular signaling pathways leading to glucose transport into the cell. Furthermore, physical exercise has the potential to modulate inflammatory processes by affecting specific inflammatory signaling pathways which can interfere with signaling pathways of the glucose uptake. The intensity of physical training appears to be the primary determinant of the degree of metabolic improvement modulating the molecular signaling pathways in a dose-response pattern, whereas training modality seems to have a secondary role. PMID:27069930

  4. An overview of muscle glucose uptake during exercise. Sites of regulation.

    PubMed

    Wasserman, D H; Halseth, A E

    1998-01-01

    The uptake of blood glucose by skeletal muscle is a complex process. In order to be metabolized, glucose must travel the path from blood to interstitium to intracellular space and then be phosphorylated to glucose 6-phosphate (G6P). Movement of glucose from blood to interstitium is determined by skeletal muscle blood flow, capillary recruitment and the endothelial permeability to glucose. The influx of glucose from the interstitium to intracellular space is determined by the number of glucose transporters in the sarcolemma and the glucose gradient across the sarcolemma. The capacity to phosphorylate glucose is determined by the amount of skeletal muscle hexokinase II, hexokinase II compartmentalization within the cell, and the concentration of the hexokinase II inhibitor G6P. Any change in glucose uptake occurs due to an alteration in one or more of these steps. Based on the low calculated intracellular glucose levels and the higher affinity of glucose for phosphorylation relative to transport, glucose transport is generally considered rate-determining for basal muscle glucose uptake. Exercise increases both the movement of glucose from blood to sarcolemma and the permeability of the sarcolemma to glucose. Whether the ability to phosphorylate glucose is increased in the working muscle remains to be clearly shown. It is possible that the accelerated glucose delivery and transport rates during exercise bias regulation so that muscle glucose phosphorylation exerts more control on muscle glucose uptake. Conditions that alter glucose uptake during exercise, such as increased NEFA concentrations, decreased oxygen availability and adrenergic stimulation, must work by altering one or more of the three steps involved in glucose uptake. This review describes the regulation of glucose uptake during exercise at each of these sites under a number of conditions, as well as describing muscle glucose uptake in the post-exercise state.

  5. The effect of catecholamines on intestinal glucose and oxygen uptake in the dog.

    PubMed Central

    Grayson, J; Oyebola, D D

    1983-01-01

    Using the anaesthetized dog, continuous recording was made of the oxygen and glucose contents of the artery and the vein draining the upper jejunum. Flow was also measured and results expressed as differences in oxygen and glucose between the aorta and the jejunal vein (a-v), also as oxygen consumption and glucose uptake. Resting glucose uptake was greater than could be accounted for on the basis of oxidation. When adrenaline (1 microgram/kg. min) or noradrenaline (2 micrograms/kg. min) was infused intravenously, oxygen uptake rose by about 50% whereas glucose uptake rose by 300-500%; moreover, the rise in glucose uptake was apparent before the rise in oxygen uptake. The beta-blocking agent, propranolol (0 X 5 mg/kg. min) had no effect on oxygen uptake but caused a three-fold rise in glucose uptake. Subsequently infusion of adrenaline had no effect on oxygen uptake and no effect on glucose uptake. However, on stopping the infusion there was a marked drop in glucose uptake, which was not maintained. It is suggested that the effects of catecholamines may be due to altered arterial blood glucose levels and that the jejunum may play a role in glucose homeostasis which requires the action of beta receptors. PMID:6644618

  6. Management of the pregnant, insulin-dependent diabetic woman.

    PubMed

    Jovanovic, L; Peterson, C M

    1980-01-01

    An intensive care program was offered to all insulin-dependent, pregnant diabetic women who presented to The New York Hospital Obstetrical Clinic in their eighth week or less of gestation. The patients were hospitalized for 1 wk to normalize their blood glucose and to teach the technique of self-monitored glucose determination, diet and exchange lists, and the method to titrate insulin according to the blood glucose determination. The mean blood glucose for the first 10 patients accepted to the program was 169 mg/dl at the start of the program with a mean hemoglobin A1c of 9.4% for the group (normal < 5.5%) and glucosuria up to 50 g/24 h. After discharge, mean glucose was 91 mg/dl, and urinary glucose excretion was 1.4 g/24 h. HbA1c fell into the normal range 5 wk after normoglycemia was achieved (3.4%) (nl < 5.5%). Normoglycemia was maintained as outpatients until 3 wk before delivery when the patients were readmitted for tests of fetal well-being. Mean weight gain for the mothers was 12.2 kg. Mean glucose at delivery was 87 mg/dl and HbA1c was 3%. Hormonal profiles (hCG, hPRL, estrogens, progesterone, hPL) normalized after normoglycemia was achieved and remained normal until delivery. Mean gestational age at time of delivery was 38.8 wk with a mean infant birth weight of 2988 g. No infant manifested hypoglycemia, hypocalcemia, erythremia, or respiratory disease. The use of self-monitored blood glucose allows for optimal care of the insulin-dependent, pregnant diabetic woman while she remains at home with her family. PMID:6996970

  7. 4-Hydroxyderricin, as a PPARγ Agonist, Promotes Adipogenesis, Adiponectin Secretion, and Glucose Uptake in 3T3-L1 Cells.

    PubMed

    Li, Yongjia; Goto, Tsuyoshi; Yamakuni, Kanae; Takahashi, Haruya; Takahashi, Nobuyuki; Jheng, Huei-Fen; Nomura, Wataru; Taniguchi, Masahiko; Baba, Kimiye; Murakami, Shigeru; Kawada, Teruo

    2016-07-01

    Adipocyte differentiation plays a pivotal role in maintaining the production of small-size adipocytes with insulin sensitivity, and impaired adipogenesis is implicated in insulin resistance. 4-Hydroxyderricin (4-HD), a phytochemical component of Angelica keiskei, possesses diverse biological properties such as anti-inflammatory, antidiabetic, and antitumor. In the present study, we investigated the effects of 4-HD on adipocyte differentiation. 4-HD promoted lipid accumulation in 3T3-L1 cells, upregulated both peroxisome proliferator-activated receptor (PPAR)-γ mRNA and protein expression, and acted as a ligand for PPARγ in the luciferase assay. Moreover, 4-HD increased the mRNA and protein expression levels of adiponectin. Additionally, it promoted insulin-dependent glucose uptake into 3T3-L1 adipocytes and increased Akt phosphorylation and glucose transporter (GLUT) 4 mRNA expression. In summary, these findings suggest that 4-HD, which promoted adipogenesis and insulin sensitivity in 3T3-L1 cells, might be a phytochemical with potent insulin-sensitizing effects. PMID:27098252

  8. Role of Adrenergic Receptors in Glucose, Fructose and Galactose-Induced Increases in Intestinal Glucose Uptake in Dogs.

    PubMed

    Salman, T M; Alada, A R A; Oyebola, D D O

    2014-12-29

    The study investigated the role of adrenergic receptors in glucose, fructose-, and galactose- induced increases in intestinal glucose uptake. Experiments were carried out on fasted male anaesthetized Nigerian local dogs divided into seven groups (with five dogs per group). Group I dogs were administered normal saline and served as control. Dogs in groups II, III and IV were intravenously infused with glucose (1.1 mg/kg/min), fructose (1.1 mg/kg/min) and galactose (1.1 mg/kg/min) respectively. Another three groups, V, VI and VII were pretreated with prazosin (0.2mg/kg), propranolol (0.5mg/kg) or a combination of prazosin (0.2mg/kg) and propranolol (0.5mg/kg) followed by glucose infusion, frutose infusion or galactose infusion respectively. Through a midline laparatomy, the upper jejunum was cannulated for blood flow measurement and blood samples were obtained for measurement of glucose content of the arterial blood and venous blood from the upper jejunal segment. Glucose uptake was calculated as the product of jejunal blood flow and the difference between arterial and venous glucose levels (A-V glucose). The results showed that pretreatment of the animal with prazosin had no effect on glucose and galactose induced increases in glucose uptake. However, pretreatment with propranolol completely abolished glucose, fructose and galactose-induced increases in intestinal glucose uptake. Prazosin also significantly reduced galactose-induced increase in intestinal glucose uptake. The results suggest that the increases in intestinal glucose uptake induced by glucose and fructose are mediated mostly by beta adrenergic receptors while that of galactose is mediated by both alpha and beta adrenergic receptors.

  9. Glucose metabolism in sediments of a eutrophic lake: tracer analysis of uptake and product formation.

    PubMed

    King, G M; Klug, M J

    1982-12-01

    The uptake of glucose and the formation of end products from glucose catabolism have been measured for sediments of eutrophic Wintergreen Lake with a combination of tritiated and C-labeled tracers. Time course analyses of the loss of [H]glucose from sediments were used to establish rate constants for glucose uptake at natural substrate concentrations. Turnover times from these analyses were about 1 min for littoral and profundal sediments. No seasonal or site differences were noted in turnover times. Time course analyses of [U-C]glucose uptake and C-labeled end product formation indicated that glucose mass flow could not be calculated from end product formation since the specific activity of added [C]glucose was significantly diluted by pools of intracellular glucose and glucose metabolites. Mass flow could only be accurately estimated by use of rates of uptake from tracer studies. Intermediate fermentation end products included acetate (71%), propionate (15%), lactate (9%), and only minor amounts of butyrates or valerates. Addition of H(2) to sediments resulted in greater production of lactate (28%) and decreased formation of acetate (50%), but did not affect glucose turnover. Depth profiles of glucose uptake indicated that rates of uptake decreased with depth over the 0- to 18-cm interval and that glucose uptake accounted for 30 to 40% of methanogenesis in profundal sediments.

  10. GnRH increases glucose transporter-1 expression and stimulates glucose uptake in the gonadotroph.

    PubMed

    Harris, Valerie M; Bendre, Sachin V; Gonzalez De Los Santos, Francina; Fite, Alemu; El-Yaman El-Dandachli, Ahmad; Kurenbekova, Lyazat; Abou-Samra, Abdul B; Buggs-Saxton, Colleen

    2012-02-01

    GnRH is the main regulator of the hypothalamic-pituitary-gonadal (H-P-G) axis. GnRH stimulates the pituitary gonadotroph to synthesize and secrete gonadotrophins (LH and FSH), and this effect of GnRH is dependent on the availability of glucose and other nutrients. Little is known about whether GnRH regulates glucose metabolism in the gonadotroph. This study examined the regulation of glucose transporters (Gluts) by GnRH in the LβT2 gonadotroph cell line. Using real-time PCR analysis, the expression of Glut1, -2, -4, and -8 was detected, but Glut1 mRNA expression level was more abundant than the mRNA expression levels of Glut2, -4, and -8. After the treatment of LβT2 cells with GnRH, Glut1 mRNA expression was markedly induced, but there was no GnRH-induction of Glut2, -4, or -8 mRNA expression in LβT2 cells. The effect of GnRH on Glut1 mRNA expression is partly mediated by ERK activation. GnRH increased GLUT1 protein and stimulated GLUT1 translocation to the cell surface of LβT2 cells. Glucose uptake assays were performed in LβT2 cells and showed that GnRH stimulates glucose uptake in the gonadotroph. Finally, exogenous treatment of mice with GnRH increased the expression of Glut1 but not the expression of Glut2, -4, or -8 in the pituitary. Therefore, regulation of glucose metabolism by GnRH via changes in Gluts expression and subcellular location in the pituitary gonadotroph reveals a novel response of the gonadotroph to GnRH.

  11. The Effects of Capillary Transit Time Heterogeneity (CTH) on the Cerebral Uptake of Glucose and Glucose Analogs: Application to FDG and Comparison to Oxygen Uptake

    PubMed Central

    Angleys, Hugo; Jespersen, Sune N.; Østergaard, Leif

    2016-01-01

    Glucose is the brain's principal source of ATP, but the extent to which cerebral glucose consumption (CMRglc) is coupled with its oxygen consumption (CMRO2) remains unclear. Measurements of the brain's oxygen-glucose index OGI = CMRO2/CMRglc suggest that its oxygen uptake largely suffices for oxidative phosphorylation. Nevertheless, during functional activation and in some disease states, brain tissue seemingly produces lactate although cerebral blood flow (CBF) delivers sufficient oxygen, so-called aerobic glycolysis. OGI measurements, in turn, are method-dependent in that estimates based on glucose analog uptake depend on the so-called lumped constant (LC) to arrive at CMRglc. Capillary transit time heterogeneity (CTH), which is believed to change during functional activation and in some disease states, affects the extraction efficacy of oxygen from blood. We developed a three-compartment model of glucose extraction to examine whether CTH also affects glucose extraction into brain tissue. We then combined this model with our previous model of oxygen extraction to examine whether differential glucose and oxygen extraction might favor non-oxidative glucose metabolism under certain conditions. Our model predicts that glucose uptake is largely unaffected by changes in its plasma concentration, while changes in CBF and CTH affect glucose and oxygen uptake to different extents. Accordingly, functional hyperemia facilitates glucose uptake more than oxygen uptake, favoring aerobic glycolysis during enhanced energy demands. Applying our model to glucose analogs, we observe that LC depends on physiological state, with a risk of overestimating relative increases in CMRglc during functional activation by as much as 50%. PMID:27790110

  12. Aprotinin induced lipohypertrophy and glomerulonephritis in an insulin dependent diabetic.

    PubMed

    Dandona, P; Mier, A; Boag, F; Chappell, M; Beckett, A G

    1985-07-01

    In an insulin dependent diabetic who was hyperglycaemic and ketotic despite 3,000 u of insulin injected subcutaneously in 2 divided doses daily, 50 u of intravenous insulin infused over 24 hr restored normal glucose homeostasis. A combination of insulin (800 u) and aprotinin (10,000 u) given twice daily also produced adequate glucose homeostasis for a period of 12 months. The patient then developed local hypertrophy of subcutaneous tissue at the injection site and her diabetic control deteriorated. Non-selective proteinuria followed and she developed nephrotic syndrome. Renal biopsy revealed a membraneous glomerulonephritis with subepithelial immune complexes, appearances consistent with a drug-induced glomerulonephritis. Withdrawal of aprotinin led to a gradual remission of nephrotic syndrome and proteinuria over several months. During this period, her diabetes was well controlled with continuous subcutaneous infusion of insulin at a dose of 500 u/24 hr. This case report demonstrates: the effective use of aprotinin for prolonged periods in insulin dependent diabetics with abnormal absorption of subcutaneously injected insulin; aprotinin induced lipohypertrophy which was not observed when insulin was injected alone; aprotinin-associated glomerulonephritis and nephrotic syndrome; the effective use of CSII--at higher insulin doses--in such patients with subcutaneous malabsorption of insulin.

  13. Hydrogen Improves Glycemic Control in Type1 Diabetic Animal Model by Promoting Glucose Uptake into Skeletal Muscle

    PubMed Central

    Amitani, Haruka; Asakawa, Akihiro; Cheng, Kaichun; Amitani, Marie; Kaimoto, Kaori; Nakano, Masako; Ushikai, Miharu; Li, Yingxiao; Tsai, Minglun; Li, Jiang-Bo; Terashi, Mutsumi; Chaolu, Huhe; Kamimura, Ryozo; Inui, Akio

    2013-01-01

    Hydrogen (H2) acts as a therapeutic antioxidant. However, there are few reports on H2 function in other capacities in diabetes mellitus (DM). Therefore, in this study, we investigated the role of H2 in glucose transport by studying cultured mouse C2C12 cells and human hepatoma Hep-G2 cells in vitro, in addition to three types of diabetic mice [Streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet-induced type 2 diabetic mice, and genetically diabetic db/db mice] in vivo. The results show that H2 promoted 2-[14C]-deoxy-d-glucose (2-DG) uptake into C2C12 cells via the translocation of glucose transporter Glut4 through activation of phosphatidylinositol-3-OH kinase (PI3K), protein kinase C (PKC), and AMP-activated protein kinase (AMPK), although it did not stimulate the translocation of Glut2 in Hep G2 cells. H2 significantly increased skeletal muscle membrane Glut4 expression and markedly improved glycemic control in STZ-induced type 1 diabetic mice after chronic intraperitoneal (i.p.) and oral (p.o.) administration. However, long-term p.o. administration of H2 had least effect on the obese and non-insulin-dependent type 2 diabetes mouse models. Our study demonstrates that H2 exerts metabolic effects similar to those of insulin and may be a novel therapeutic alternative to insulin in type 1 diabetes mellitus that can be administered orally. PMID:23326534

  14. Review of insulin-dependent and insulin-independent agents for treating patients with type 2 diabetes mellitus and potential role for sodium-glucose co-transporter 2 inhibitors.

    PubMed

    Freeman, Jeffrey S

    2013-05-01

    Diabetes, especially type 2 diabetes mellitus (T2DM), continues to be a global health care problem. Although the beneficial effects of glycemic control are well established, in the United States, > 40% of adults with diabetes fail to achieve target glycated hemoglobin levels. Antidiabetic drug classes vary with respect to their mechanisms of action, glucose-lowering potential, and safety and tolerability profiles. Antidiabetic drug classes include some agents that depend on the presence or action of insulin for their therapeutic effect. As the disease state of T2DM progresses, patient pancreatic β-cell function declines, and therapies that stimulate insulin secretion or improve insulin sensitivity become less effective for this population. Therefore, the development of additional antidiabetic agents with novel mechanisms of action that can be used alone or in combination with currently approved medications may help patients achieve glycemic control. Agents that have comparable glucose-lowering capabilities but different mechanisms of action may fill treatment gaps or meet the needs of patient subpopulations. For example, inhibitors of sodium-glucose co-transporter 2 (SGLT2) represent an emerging class of glucose-lowering agents. The SGLT2 inhibitors reduce glucose reabsorption by the kidney, leading to increased urinary glucose excretion and caloric loss. In clinical trials, these agents have been shown to improve glycemic control and to reduce body weight in patients with T2DM. Additionally, SGLT2 inhibitors pose a low risk for hypoglycemia and are generally well tolerated; however, their use has been associated with an increase in the frequency of genital infections and, in some studies, urinary tract infections. Sodium-glucose co-transporter 2 inhibitors may provide an alternative or an addition to existing therapies for the treatment of patients with T2DM.

  15. Lactation outcome in insulin-dependent diabetic women.

    PubMed

    Ferris, A M; Dalidowitz, C K; Ingardia, C M; Reece, E A; Fumia, F D; Jensen, R G; Allen, L H

    1988-03-01

    To document the incidence and management of breast feeding among women with insulin-dependent diabetes mellitus (IDDM), 30 IDDM mothers and 30 controls were followed from birth of their infants to 6 weeks postpartum. The researchers interviewed the mothers in the hospital and by telephone at 1, 2, and 6 weeks postpartum. Fifty-three percent of the IDDM women and 57% of the general hospital population intended to breast feed. Because of the need for neonatal observation for hypoglycemia, most IDDM mothers were separated from their infants for the first 2 days. After 1 week, as many IDDM mothers as controls nursed. Initially, no differences in breast-feeding problems were found between the groups, but between 2 and 6 weeks postpartum, two IDDM nursing mothers but none of the controls experienced clinically diagnosed mastitis. A daily diet prescription of 31 kcal per kilogram of maternal body weight was associated with IDDM mothers' ability to sustain lactation, in contrast with 25 kcal per kilogram of maternal weight for IDDM mothers who stopped nursing. Six-week postpartum fasting plasma glucose levels of IDDM mothers who exclusively breast fed were significantly lower (4.6 +/- 2.2 mmol/L [82 +/- 40 mg/dl]) than the glucose levels of the women who stopped nursing (8.1 +/- 2.1 mmol/L [145 +/- 37 mg/dl]) or the glucose levels of the IDDM mothers who chose to bottle feed (6.7 +/- 1.7 mmol/L [120 +/- 30 mg/dl]). It appears that adequate maternal calories, blood sugar control, early breast stimulation, and mastitis monitoring are necessary for optimal lactation outcome in insulin-dependent diabetic women.

  16. Myristic Acid Enhances Diacylglycerol Kinase δ-Dependent Glucose Uptake in Myotubes.

    PubMed

    Wada, Yuko; Sakiyama, Shizuka; Sakai, Hiromichi; Sakane, Fumio

    2016-08-01

    Decreased expression of diacylglycerol kinase (DGK) δ in skeletal muscles attenuates glucose uptake and is closely related to the pathogenesis of type 2 diabetes. Therefore, up-regulation of DGKδ expression is thought to protect and improve glucose homoeostasis in type 2 diabetes. We recently determined that myristic acid (14:0), but not palmitic (16:0) or stearic (18:0) acid, significantly increased DGKδ2 protein expression in mouse C2C12 myotubes. In the current study, we analyzed whether myristic acid indeed enhances glucose uptake in C2C12 myotubes. We observed that myristic acid caused ~1.4-fold increase in insulin-independent glucose uptake. However, palmitic and stearic acids failed to enhance glucose uptake. DGKδ-specific siRNA decreased myristic acid-dependent increase of glucose uptake. Moreover, overexpression of DGKδ2 enhanced glucose uptake in C2C12 cells in the absence of myristic acid treatment. Taken together, these results strongly suggest that myristic acid enhances basal glucose uptake in myotubes in a DGKδ2 expression-dependent manner.

  17. Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine

    PubMed Central

    Szlachetka, Adam M.; Haorah, James

    2011-01-01

    Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers. PMID:21556365

  18. Effects of xylitol on carbohydrate digesting enzymes activity, intestinal glucose absorption and muscle glucose uptake: a multi-mode study.

    PubMed

    Chukwuma, Chika Ifeanyi; Islam, Md Shahidul

    2015-03-01

    The present study investigated the possible mechanism(s) behind the effects of xylitol on carbohydrate digesting enzymes activity, muscle glucose uptake and intestinal glucose absorption using in vitro, ex vivo and in vivo experimental models. The effects of increasing concentrations of xylitol (2.5%-40% or 164.31 mM-2628.99 mM) on alpha amylase and alpha glucosidase activity in vitro and intestinal glucose absorption and muscle glucose uptake were investigated under ex vivo conditions. Additionally, the effects of an oral bolus dose of xylitol (1 g per kg BW) on gastric emptying and intestinal glucose absorption and digesta transit in the different segments of the intestinal tract were investigated in normal and type 2 diabetic rats at 1 hour after dose administration, when phenol red was used as a recovery marker. Xylitol exhibited concentration-dependent inhibition of alpha amylase (IC₅₀ = 1364.04 mM) and alpha glucosidase (IC₅₀ = 1127.52 mM) activity in vitro and small intestinal glucose absorption under ex vivo condition. Xylitol also increased dose dependent muscle glucose uptake with and without insulin, although the uptake was not significantly affected by the addition of insulin. Oral single bolus dose of xylitol significantly delayed gastric emptying, inhibited intestinal glucose absorption but increased the intestinal digesta transit rate in both normal and diabetic rats compared to their respective controls. The data of this study suggest that xylitol reduces intestinal glucose absorption via inhibiting major carbohydrate digesting enzymes, slowing gastric emptying and fastening the intestinal transit rate, but increases muscle glucose uptake in normal and type 2 diabetic rats.

  19. A Simple Flow Cytometric Method to Measure Glucose Uptake and Glucose Transporter Expression for Monocyte Subpopulations in Whole Blood.

    PubMed

    Palmer, Clovis S; Anzinger, Joshua J; Butterfield, Tiffany R; McCune, Joseph M; Crowe, Suzanne M

    2016-01-01

    Monocytes are innate immune cells that can be activated by pathogens and inflammation associated with certain chronic inflammatory diseases. Activation of monocytes induces effector functions and a concomitant shift from oxidative to glycolytic metabolism that is accompanied by increased glucose transporter expression. This increased glycolytic metabolism is also observed for trained immunity of monocytes, a form of innate immunological memory. Although in vitro protocols examining glucose transporter expression and glucose uptake by monocytes have been described, none have been examined by multi-parametric flow cytometry in whole blood. We describe a multi-parametric flow cytometric protocol for the measurement of fluorescent glucose analog 2-NBDG uptake in whole blood by total monocytes and the classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)) and non-classical (CD14(+)CD16(++)) monocyte subpopulations. This method can be used to examine glucose transporter expression and glucose uptake for total monocytes and monocyte subpopulations during homeostasis and inflammatory disease, and can be easily modified to examine glucose uptake for other leukocytes and leukocyte subpopulations within blood. PMID:27584036

  20. Nanomolar Caffeic Acid Decreases Glucose Uptake and the Effects of High Glucose in Endothelial Cells

    PubMed Central

    Natarelli, Lucia; Ranaldi, Giulia; Leoni, Guido; Roselli, Marianna; Guantario, Barbara; Comitato, Raffaella; Ambra, Roberto; Cimino, Francesco; Speciale, Antonio; Virgili, Fabio; Canali, Raffaella

    2015-01-01

    Epidemiological studies suggest that moderate and prolonged consumption of coffee is associated with a reduced risk of developing type 2 diabetes but the molecular mechanisms underlying this effect are not known. In this study, we report the effects of physiological concentrations of caffeic acid, easily achievable by normal dietary habits, in endothelial cells cultured in 25 mM of glucose (high glucose, HG). In HG, the presence of 10 nM caffeic acid was associated with a decrease of glucose uptake but not to changes of GLUT-1 membrane localization or mRNA levels. Moreover, caffeic acid countered HG-induced loss of barrier integrity, reducing actin rearrangement and FITC-dextran passage. The decreased flux of glucose associated to caffeic acid affected HG induced apoptosis by down-regulating the expression of initiator (caspase 8 and 9) and effector caspases (caspase 7 and 3) and by increasing the levels of phosphorylated Bcl-2. We also observed that caffeic acid in HG condition was associated to a reduction of p65 subunit nuclear levels with respect to HG alone. NF-κB activation has been shown to lead to apoptosis in HG treated cells and the analysis of the expression of a panel of about 90 genes related to NF-κB signaling pathway revealed that caffeic acid significantly influenced gene expression changes induced by HG. In conclusion, our results suggest that caffeic acid, decreasing the metabolic stress induced by HG, allows the activation of survival mechanisms mediated by a different modulation of NF-κB-related signaling pathways and to the activation of anti-apoptotic proteins. PMID:26544184

  1. Assessing Glucose Uptake through the Yeast Hexose Transporter 1 (Hxt1)

    PubMed Central

    Roy, Adhiraj; Dement, Angela D.; Cho, Kyu Hong; Kim, Jeong-Ho

    2015-01-01

    The transport of glucose across the plasma membrane is mediated by members of the glucose transporter family. In this study, we investigated glucose uptake through the yeast hexose transporter 1 (Hxt1) by measuring incorporation of 2-NBDG, a non-metabolizable, fluorescent glucose analog, into the yeast Saccharomyces cerevisiae. We find that 2-NBDG is not incorporated into the hxt null strain lacking all glucose transporter genes and that this defect is rescued by expression of wild type Hxt1, but not of Hxt1 with mutations at the putative glucose-binding residues, inferred from the alignment of yeast and human glucose transporter sequences. Similarly, the growth defect of the hxt null strain on glucose is fully complemented by expression of wild type Hxt1, but not of the mutant Hxt1 proteins. Thus, 2-NBDG, like glucose, is likely to be transported into the yeast cells through the glucose transport system. Hxt1 is internalized and targeted to the vacuole for degradation in response to glucose starvation. Among the mutant Hxt1 proteins, Hxt1N370A and HXT1W473A are resistant to such degradation. Hxt1N370A, in particular, is able to neither uptake 2-NBDG nor restore the growth defect of the hxt null strain on glucose. These results demonstrate 2-NBDG as a fluorescent probe for glucose uptake in the yeast cells and identify N370 as a critical residue for the stability and function of Hxt1. PMID:25816250

  2. Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice.

    PubMed

    Hong, Yet Hoi; Frugier, Tony; Zhang, Xinmei; Murphy, Robyn M; Lynch, Gordon S; Betik, Andrew C; Rattigan, Stephen; McConell, Glenn K

    2015-05-01

    Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ(-/-) and nNOSμ(+/+) mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor N(G)-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ(-/-) and nNOSμ(+/+) mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (~4%) were detected in muscles from nNOSμ(-/-) mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.

  3. Different alterations in the insulin-stimulated glucose uptake in the athlete's heart and skeletal muscle.

    PubMed Central

    Nuutila, P; Knuuti, M J; Heinonen, O J; Ruotsalainen, U; Teräs, M; Bergman, J; Solin, O; Yki-Järvinen, H; Voipio-Pulkki, L M; Wegelius, U

    1994-01-01

    Physical training increases skeletal muscle insulin sensitivity. Since training also causes functional and structural changes in the myocardium, we compared glucose uptake rates in the heart and skeletal muscles of trained and untrained individuals. Seven male endurance athletes (VO2max 72 +/- 2 ml/kg/min) and seven sedentary subjects matched for characteristics other than VO2max (43 +/- 2 ml/kg/min) were studied. Whole body glucose uptake was determined with a 2-h euglycemic hyperinsulinemic clamp, and regional glucose uptake in femoral and arm muscles, and myocardium using 18F-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose uptake in the athletes was increased by 68% in whole body (P < 0.0001), by 99% in the femoral muscles (P < 0.01), and by 62% in arm muscles (P = 0.06), but it was decreased by 33% in the heart muscle (P < 0.05) as compared with the sedentary subjects. The total glucose uptake rate in the heart was similar in the athletes and control subjects. Left ventricular mass in the athletes was 79% greater (P < 0.001) and the meridional wall stress smaller (P < 0.001) as estimated by echocardiography. VO2max correlated directly with left ventricular mass (r = 0.87, P < 0.001) and inversely with left ventricular wall stress (r = -0.86, P < 0.001). Myocardial glucose uptake correlated directly with the rate-pressure product (r = 0.75, P < 0.02) and inversely with left ventricular mass (r = -0.60, P < 0.05) or with the whole body glucose disposal (r = -0.68, P < 0.01). Thus, in athletes, (a) insulin-stimulated glucose uptake is enhanced in the whole body and skeletal muscles, (b) whereas myocardial glucose uptake per muscle mass is reduced possibly due to decreased wall stress and energy requirements or the use of alternative fuels, or both. Images PMID:8182160

  4. Renal scintigraphy in insulin-dependent diabetes mellitus: Early glomerular and urologic dysfunction

    SciTech Connect

    Poirier, J.Y.; Moisan, A.; Le Cloirec, J.; Siemen, C.; Yaouanq, J.; Edan, G.; Herry, J.Y. )

    1990-07-01

    Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by intravenous injection of 99mTc-diethylenetriaminepentaacetic acid (DTPA) and 131I-Hippuran in 115 insulin-dependent diabetic patients with albumin excretion rates (AER) less than 200 micrograms/min, and in 45 normal subjects. Separate kidney function and urinary elimination were estimated by renography. GFR was increased in the diabetic patients (152 +/- 24 ml/min/1.73 m2 vs. 128 +/- 15) and correlated significantly with RPF (r = 0.5; p less than 10(-9)). No relationship was found between GFR and the duration of diabetes, blood glucose, HbA1c, or AER. Fifty patients were hyperfiltering with RPF and filtration fraction higher than those in the normofiltering group. Slow intrarenal or pyeloureteral elimination, either unilateral or bilateral, was observed in 3 controls and 60 diabetic subjects (24 hyperfiltering; 36 normofiltering) and did not disappear with the patient in the standing position. In these 60 patients, mean age, duration of diabetes, blood glucose, HbA1c, 24 h albumin excretion rate, and frequency of peripheral or autonomic neuropathy did not differ from patients with normal scintigraphy; GFR was lower in the group with slow elimination, but not significantly so. 99mTc-DTPA renal uptake was symmetric in all the controls; asymmetric renal uptake with asymmetric GFR was observed in 13 patients (7 hyperfiltering; 6 normofiltering) and often associated with slower elimination. No evidence for renal stenotic atheroma or parenchymatous disease was found on the angiopyleoureterography. The results suggest that incipient uropathy is a very common phenomenon that occurs irrespective of glomerular dysfunction.

  5. A Case of Insulin-dependent Diabetes.

    PubMed

    Gonzalez, Nicholas

    2016-07-01

    Background • There is a paucity of information on alternative, nutrition-based treatments for insulin-dependent diabetes. Primary Study Objective • This case report provides detailed information on the nutrition-based treatment of a man with insulin-dependent diabetes. Methods/Design • This is a single case report taken from the author's private practice. Setting • The treatment was provided at a private office in New York, NY, USA. Participants • A single patient in the author's practice is reported. Intervention • The patient was treated with a combination of pancreatic enzymes, supplements and nutrients, and cleansing and detoxification procedures, plus amber lenses for severe insomnia. Primary Outcome Measures • The outcome measures were patient self-report of symptoms, overall well-being, and function at work and in leisure time; observation of the patient by the physician; and blood work. Results • The patient described dramatic, sustained improvement in terms of symptoms, function, well-being, and life satisfaction. Improvement in blood sugar control was documented by blood work. Conclusion • The complex, tailored nutritional protocol combined with detoxification procedures, resulted in marked improvement in a patient who had been treated by numerous different physicians without benefit prior to his consulting with the author. PMID:27548490

  6. Insulin-dependent diabetes and HLA.

    PubMed

    Dausset, J; Hors, J; Contu, L; Busson, M; Schmid, M; Cathelineau, G; Lestradet, H; Baron, D

    1979-12-01

    The study of a hundred and fifteen unrelated insulin-dependent diabetes and eight families with at least two insulin-dependent diabetes members made it possible to confirm the higher frequency of HLA-B8 and B18 (p less than 0.001) among patients, producing a RR of 2.24 and 2.47 respectively. The increased B15 frequency did not achieve statistical significance. B18 whose gametic association (delta = 0.0438) was significant only in diabetic patients was often related to Aw19-2 (Aw30 + Aw31). The B8/B18 genotype gave a relative risk (RR = 4.98) which was significantly higher than that of B8, B18 and B15 heterozygotes (1.50, 1.24 and 1.39 respectively). Pairs of diabetic siblings were more frequently HLA identical than would be expected by chance, and distribution of the pairs of affected sibs into the three categories, identical, semi-identical and different, was closer to the recessive model than to the dominant one. The fact that the B8/B18 individuals had a RR slightly higher than the B8 and B18 homozygotes and distinctly higher than the heterozygotes for only one of these genes, favours the hypothesis of two dominant genes, giving the appearance of recessivity. The gene associated with B18 in Southern Europe seems to play the same part as that of the gene associated with B15 in Northern Europe. PMID:398300

  7. Increasing Exercise Intensity Reduces Heterogeneity of Glucose Uptake in Human Skeletal Muscles

    PubMed Central

    Kemppainen, Jukka; Fujimoto, Toshihiko; Knuuti, Juhani; Kalliokoski, Kari K.

    2012-01-01

    Proper muscle activation is a key feature of survival in different tasks in daily life as well as sports performance, but can be impaired in elderly and in diseases. Therefore it is also clinically important to better understand the phenomenon that can be elucidated in humans non-invasively by positron emission tomography (PET) with measurements of spatial heterogeneity of glucose uptake within and among muscles during exercise. We studied six healthy young men during 35 minutes of cycling at relative intensities of 30% (low), 55% (moderate), and 75% (high) of maximal oxygen consumption on three separate days. Glucose uptake in the quadriceps femoris muscle group (QF), the main force producing muscle group in recreational cycling, and its four individual muscles, was directly measured using PET and 18F-fluoro-deoxy-glucose. Within-muscle heterogeneity was determined by calculating the coefficient of variance (CV) of glucose uptake in PET image voxels within the muscle of interest, and among-muscles heterogeneity of glucose uptake in QF was expressed as CV of the mean glucose uptake values of its separate muscles. With increasing intensity, within-muscle heterogeneity decreased in the entire QF as well as within its all four individual parts. Among-muscles glucose uptake heterogeneity also decreased with increasing intensity. However, mean glucose uptake was consistently lower and heterogeneity higher in rectus femoris muscle that is known to consist of the highest percentage of fast twitch type II fibers, compared to the other three QF muscles. In conclusion, these results show that in addition to increased contribution of distinct muscle parts, with increases in exercise intensity there is also an enhanced recruitment of muscle fibers within all of the four heads of QF, despite established differences in muscle-part specific fiber type distributions. Glucose uptake heterogeneity may serve as a useful non-invasive tool to elucidate muscle activation in aging and

  8. Uncoupler-Resistant Glucose Uptake by the Thermophilic Glycolytic Anaerobe Thermoanaerobacter thermosulfuricus (Clostridium thermohydrosulfuricum)

    PubMed Central

    Cook, Gregory M.; Janssen, Peter H.; Morgan, Hugh W.

    1993-01-01

    The transport of glucose across the bacterial cell membrane of Thermoanaerobacter thermosulfuricus (Clostridium thermohydrosulfuricum) Rt8.B1 was governed by a permease which did not catalyze concomitant substrate transport and phosphorylation and thus was not a phosphoenolpyruvate-dependent phosphotransferase. Glucose uptake was carrier mediated, could not be driven by an artificial membrane potential (Δψ) in the presence or absence of sodium, and was not sensitive to inhibitors which dissipate the proton motive force (Δp; tetrachlorosalicylanilide, N,N-dicyclohexylcarboiimide, and 2,4-dinitrophenol), and no uptake of the nonmetabolizable analog 2-deoxyglucose could be demonstrated. The glucokinase apparent Km for glucose (0.21 mM) was similar to the Kt (affinity constant) for glucose uptake (0.15 mM), suggesting that glucokinase controls the rate of glucose uptake. Inhibitors of ATP synthesis (iodoacetate and sodium fluoride) also inhibited glucose uptake, and this effect was due to a reduction in the level of ATP available to glucokinase for glucose phosphorylation. These results indicated that T. thermosulfuricus Rt8.B1 lacks a concentrative uptake system for glucose and that uptake is via facilitated diffusion, followed by ATP-dependent phosphorylation by glucokinase. In T. thermosulfuricus Rt8.B1, glucose is metabolized by the Embden-Meyerhof-Parnas pathway, which yields 2 mol of ATP (G. M. Cook, unpublished data). Since only 1 mol of ATP is used to transport 1 mol of glucose, the energetics of this system are therefore similar to those found in bacteria which possess a phosphotransferase. PMID:16349043

  9. Glucose uptake in rat soleus - Effect of acute unloading and subsequent reloading

    NASA Technical Reports Server (NTRS)

    Henriksen, Eric J.; Tischler, Marc E.

    1988-01-01

    The effect of acutely reduced weight bearing (unloading) on the in vitro uptake of 2-1,2-H-3-deoxy-D-glucose was studied in the soleus muscle by tail casting and suspending rats. After just 4 h, the uptake of 2-deoxy-D-glucose fell (-19 percent) and declined further after an additional 20 h of unloading. This diminution at 24 h was associated with slower oxidation of C-14-glucose and incorporation of C-14-glucose into glycogen. At 3 days of unloading, basal uptake of 2-deoxy-D-glucose did not differ from control. Reloading of the soleus after 1 or 3 days of unloading increased uptake of 2-deoxy-D-glucose above control and returned it to normal within 6 h and 4 days, respectively. These effects of unloading and recovery were caused by local changes in the soleus, because the extensor digitorum longus from the same hindlimbs did not display any alterations in uptake of 2-deoxy-D-glucose or metabolism of glucose.

  10. HLA antigens and insulin dependent diabetes mellitus. A family study.

    PubMed

    Savi, M; Neri, T M; Zavaroni, I; Coscelli, I

    1977-12-01

    Sixteen insulin dependent diabetic patients (age at onset less than 35 years) and their families were tissue typed for HLA antigens. Glucose tolerance of relatives was also tested. Among diabetic patients two HLA antigens were found with increased frequency: B8 (31 percent, control 15 percent) and Bw35 (38 percent, control 23 percent). Among normal relatives B8 and Bw35 had the same frequency as the control group. Bw15 frequency was not increased in either group. In relatives, no correlation between HLA antigens (B8 or Bw35) and abnormal glucose tolerance, obesity and over-weight at birth was found. Present data confirm previous reports of high B8 frequency in early onset diabetic patients, but fail to demonstrate a raised frequency of abnormal glucose tolerance among relatives bearing B8 (or, in our cases, Bw35). B8 may be considered a genetic indicator for susceptibility to juvenile diabetes. On the basis of present results in families, however non genetic factors clearly also play a determinant role. Furthermore, that diabetogenesis arises from a link between Ir-genes and HLA-B8 antigen should only be considered a suggestive hypothesis. PMID:413751

  11. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism

    PubMed Central

    Lundgaard, Iben; Li, Baoman; Xie, Lulu; Kang, Hongyi; Sanggaard, Simon; Haswell, John Douglas R; Sun, Wei; Goldman, Siri; Blekot, Solomiya; Nielsen, Michael; Takano, Takahiro; Deane, Rashid; Nedergaard, Maiken

    2015-01-01

    Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using 2-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyze the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identifies the neuron as the principal locus of glucose uptake as visualized by functional brain imaging. PMID:25904018

  12. Regulation and butanol inhibition of d-xylose and d-glucose uptake in Clostridium acetobutylicum

    SciTech Connect

    Ounine, K.; Petitdemange, H.; Raval, G.; Gay, R.

    1985-04-01

    Clostridium acetobutylicum exhibited diauxic growth in the presence of mixtures of glucose and xylose. Both glucose- and xylose-grown cells had a glucose uptake activity. On the other hand, growth on xylose was associated with the induction of a xylose permease activity, which was repressed by glucose in xylose-induced cells. The rate of sugar uptake with increasing sugar concentrations showed saturation kinetics with an apparent K/sub m/ of 1.25 x 10/sup 5/ M for glucose and 5 x 10/sup 3/ M for xylose. Concomitant with the production of solvents, the activities of the glucose and xylose transport systems decreased. Among the main products of fermentation, butanol was shown to be a potent inhibitor of the growth of the organism and of the rate of sugar uptake as well as of sugar incorporation into cell materials. These inhibitory effects of butanol were more pronounced in xylose-grown cells than in glucose-grown cells. Butanol completely inhibited growth at a concentration of 14 g/liter for cultures growing on glucose and 8 g/liter for cultures growing on xylose. Concentrations of 7 and 10.5 g/liter of butanol caused a 50% inhibition of the xylose and glucose incorporations into cell materials. These inhibitory levels of butanol were found in typical glucose or xylose fermentations.

  13. Dexamethasone rapidly inhibits glucose uptake via non-genomic mechanisms in contracting myotubes.

    PubMed

    Gong, Hong; Liu, Lei; Ni, Chen-Xu; Zhang, Yi; Su, Wen-Jun; Lian, Yong-Jie; Peng, Wei; Zhang, Jun-Ping; Jiang, Chun-Lei

    2016-08-01

    Glucocorticoids (GCs) are a class of steroid hormones that regulate multiple aspects of glucose homeostasis. In skeletal muscle, it is well established that prolonged GC excess inhibits glucose uptake and utilization through glucocorticoid receptor (GR)-mediated transcriptional changes. However, it remains obscure that whether the rapid non-genomic effects of GC on glucose uptake are involved in acute exercise stress. Therefore, we used electric pulse stimulation (EPS)-evoked contracting myotubes to determine whether the non-genomic actions of GC were involved and its underlying mechanism(s). Pretreatment with dexamethasone (Dex, 10 μM) significantly prevented contraction-stimulated glucose uptake and glucose transporter 4 (Glut4) translocation within 20 min in C2C12 myotubes. Neither GC nuclear receptor antagonist (RU486) nor protein synthesis inhibitor (cycloheximide, Chx) affected the rapid inhibition effects of Dex. AMPK and CaMKII-dependent signaling pathways were associated with the non-genomic effects of Dex. These results provide evidence that GC rapidly suppresses glucose uptake in contracting myotubes via GR-independent non-genomic mechanisms. AMPK and CaMKII-mediated Glut4 translocation may play a critical role in GC-induced rapid inhibition of glucose uptake. PMID:27246478

  14. Driving and insulin-dependent diabetes.

    PubMed

    Frier, B M; Matthews, D M; Steel, J M; Duncan, L J

    1980-06-01

    A survey of 250 patients with insulin-dependent diabetes (IDD) holding a full motor vehicle driving licence revealed that 107 (42.8%) had not declared IDD on their application for a driving licence. 70 of these (28% of entire group) claimed that they were unaware of the statutory requirements. There was no difference in the declaration-rate between men and women. 159 patients (66%) declared IDD for their motor insurance. 86 patients (34.4%) had had severe or frequent hypoglycaemia in the preceding six months, during which they had been driving regularly. 34 patients (13.6%) admitted involvement in a driving accident since commencing treatment with insulin, and 13 of these patients were aware that hypoglycaemia had been an important causal factor. The prevalence of diabetic retinopathy and cataracts was considerable, but few patients (2.4%) had severe impairment of vision in both eyes. PMID:6104046

  15. Inhibitory Effect of Epinephrine on Insulin-stimulated Glucose Uptake by Rat Skeletal Muscle

    PubMed Central

    Chiasson, Jean-Louis; Shikama, Hisataka; Chu, David T. W.; Exton, John H.

    1981-01-01

    The effect of epinephrine on basal and insulin-stimulated glucose uptake in perfused hindlimbs of fed rats was studied. Insulin increased glucose uptake in a dose-dependent manner from a basal value of 1.5±0.3 up to a maximum value of 5.3±0.9 μmol/min per 100 g with 6 nM (1 m U/ml). Epinephrine at 10 nM and 0.1 μM also increased glucose uptake to 2.6±0.1 and 3.1±0.1 μmol/min per 100 g, respectively. These same concentrations of epinephrine, however, suppressed the insulin-stimulated glucose uptake to 3.2±0.3 μmol/min per 100 g. Both the stimulatory and inhibitory effects of epinephrine on glucose uptake were completely reversed by propranolol, but were not significantly altered by phentolamine. Uptake of 3-O-methylglucose and 2-deoxyglucose into thigh muscles of the perfused hindlimbs was stimulated fivefold by insulin, but was unaffected by epinephrine. Epinephrine also did not inhibit the stimulation of uptake by insulin. Epinephrine decreased the phosphorylation of 2-deoxyglucose, however, and caused the intracellular accumulation of free glucose. These last two effects were more prominent in the presence of insulin. Whereas epinephrine caused large rises in glucose-6-P and fructose-6-P, insulin did not alter the concentration of these metabolites either in the absence or presence of epinephrine. These data indicate that: (a) epinephrine has a stimulatory effect on glucose uptake by perfused rat hindlimbs that does not appear to be exerted on skeletal muscle; (b) epinephrine does not affect hexose transport in skeletal muscle; (c) epinephrine inhibits insulin-stimulated glucose uptake in skeletal muscle by inhibiting glucose phosphorylation. It is hypothesized that the inhibition of glucose phosphorylation is due to the stimulation of glycogenolysis, which leads to the accumulation of hexose phosphates, which inhibit hexokinase. PMID:6115864

  16. TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling

    PubMed Central

    Beaton, Nigel; Rudigier, Carla; Moest, Hansjörg; Müller, Sebastian; Mrosek, Nadja; Röder, Eva; Rudofsky, Gottfried; Rülicke, Thomas; Ukropec, Jozef; Ukropcova, Barbara; Augustin, Robert; Neubauer, Heike; Wolfrum, Christian

    2015-01-01

    Objective Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. Methods We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Results Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Conclusions Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans. PMID:26629404

  17. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus.

    PubMed

    Maxwell, S R; Thomason, H; Sandler, D; Leguen, C; Baxter, M A; Thorpe, G H; Jones, A F; Barnett, A H

    1997-06-01

    Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 +/- 11.3 vs. 427.5 +/- 19.2 mumol L-1; P < 0.001). This was attributable to lower urate (209.4 +/- 10.4 vs. 297.1 +/- 16.7 mumol L-1; P < 0.001) and vitamin C levels (63.6 +/- 6.0 vs. 87.5 +/- 4.9 mumol L-1; P < 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 +/- 25.4 vs. 473.9 +/- 30.2 mumol L-1; NS), reflecting lower urate (299.5 +/- 19.4 vs. 324.8 +/- 21.4 mumol L-1; NS) and vitamin C levels (38.6 +/- 5.7 vs. 58.5 +/- 5.3 mumol L-1; P < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.

  18. NFAT-133 increases glucose uptake in L6 myotubes by activating AMPK pathway.

    PubMed

    Thakkar, Chandni S; Kate, Abhijeet S; Desai, Dattatraya C; Ghosh, Asit Ranjan; Kulkarni-Almeida, Asha A

    2015-12-15

    NFAT-133 is an aromatic compound with cinammyl alcohol moiety, isolated from streptomycetes strain PM0324667. We have earlier reported that NFAT-133 increases insulin stimulated glucose uptake in L6 myotubes using a PPARγ independent mechanism and reduces plasma or blood glucose levels in diabetic mice. Here we investigated the effects of NFAT-133 on cellular signaling pathways leading to glucose uptake in L6 myotubes. Our studies demonstrate that NFAT-133 increases glucose uptake in a dose- and time-dependent manner independent of the effects of insulin. Treatment with Akti-1/2, wortmannin and increasing concentrations of insulin had no effect on NFAT-133 mediated glucose uptake. NFAT-133 induced glucose uptake is completely mitigated by Compound C, an AMPK inhibitor. Further, the kinases upstream of AMPK activation namely; LKB-1 and CAMKKβ are not involved in NFAT-133 mediated AMPK activation nor does the compound NFAT-133 have any effect on AMPK enzyme activity. Further analysis confirmed that NFAT-133 indirectly activates AMPK by reducing the mitochondrial membrane potential and increasing the ratio of AMP:ATP.

  19. Computer-aided rational design of the phosphotransferase system for enhanced glucose uptake in Escherichia coli.

    PubMed

    Nishio, Yousuke; Usuda, Yoshihiro; Matsui, Kazuhiko; Kurata, Hiroyuki

    2008-01-01

    The phosphotransferase system (PTS) is the sugar transportation machinery that is widely distributed in prokaryotes and is critical for enhanced production of useful metabolites. To increase the glucose uptake rate, we propose a rational strategy for designing the molecular architecture of the Escherichia coli glucose PTS by using a computer-aided design (CAD) system and verified the simulated results with biological experiments. CAD supports construction of a biochemical map, mathematical modeling, simulation, and system analysis. Assuming that the PTS aims at controlling the glucose uptake rate, the PTS was decomposed into hierarchical modules, functional and flux modules, and the effect of changes in gene expression on the glucose uptake rate was simulated to make a rational strategy of how the gene regulatory network is engineered. Such design and analysis predicted that the mlc knockout mutant with ptsI gene overexpression would greatly increase the specific glucose uptake rate. By using biological experiments, we validated the prediction and the presented strategy, thereby enhancing the specific glucose uptake rate.

  20. NFAT-133 increases glucose uptake in L6 myotubes by activating AMPK pathway.

    PubMed

    Thakkar, Chandni S; Kate, Abhijeet S; Desai, Dattatraya C; Ghosh, Asit Ranjan; Kulkarni-Almeida, Asha A

    2015-12-15

    NFAT-133 is an aromatic compound with cinammyl alcohol moiety, isolated from streptomycetes strain PM0324667. We have earlier reported that NFAT-133 increases insulin stimulated glucose uptake in L6 myotubes using a PPARγ independent mechanism and reduces plasma or blood glucose levels in diabetic mice. Here we investigated the effects of NFAT-133 on cellular signaling pathways leading to glucose uptake in L6 myotubes. Our studies demonstrate that NFAT-133 increases glucose uptake in a dose- and time-dependent manner independent of the effects of insulin. Treatment with Akti-1/2, wortmannin and increasing concentrations of insulin had no effect on NFAT-133 mediated glucose uptake. NFAT-133 induced glucose uptake is completely mitigated by Compound C, an AMPK inhibitor. Further, the kinases upstream of AMPK activation namely; LKB-1 and CAMKKβ are not involved in NFAT-133 mediated AMPK activation nor does the compound NFAT-133 have any effect on AMPK enzyme activity. Further analysis confirmed that NFAT-133 indirectly activates AMPK by reducing the mitochondrial membrane potential and increasing the ratio of AMP:ATP. PMID:26546724

  1. Beta-endorphin decreases fatigue and increases glucose uptake independently in normal and dystrophic mice.

    PubMed

    Khan, Salim; Evans, Anthony A L; Hughes, Sharon; Smith, Margaret E

    2005-04-01

    beta-Endorphin and a C-terminal analogue have been shown to decrease muscle fatigue and increase glucose uptake in muscles of normal mice. In order to provide evidence whether these peptides might be useful in muscle-wasting conditions and whether the two actions of the peptides are interdependent, the effect of beta-endorphin on muscle fatigue and glucose uptake was studied using isolated hemidiaphragm preparations of dystrophic mice as well as normal mice. Muscle contractions were elicited by high-frequency stimulation of the phrenic nerve. Glucose uptake was measured using (nonmetabolizable) 2-deoxy-D-[1-(3)H]glucose. beta-Endorphin and the C-terminal analogue reduced fatigue in normal muscles of males but not females. Insulin had no effect in either sex. The peptides increased 2-deoxyglucose uptake in contracting and noncontracting muscles of normal males and females. beta-Endorphin reduced fatigue and increased deoxyglucose uptake in dystrophic muscles. The effect on fatigue was not due to increased glucose uptake, as the energy substrate present was pyruvate. Nerve stimulation released beta-endorphin immunoreactivity from intramuscular nerves of dystrophic mice. It is hypothesized that beta-endorphin released from motor nerves as well as from the pituitary could be responsible for improving muscle function during exercise. beta-Endorphin or analogues could have therapeutic use in muscle-wasting disease. PMID:15704144

  2. Pathophysiological study of the non-insulin-dependent phase of type I diabetes mellitus.

    PubMed

    Torella, R; Salvatore, T; Cozzolino, D; Grandillo, F; Giugliano, D

    1988-01-01

    The usual practice of considering type I diabetes synonymous with insulin-dependent diabetes has been criticized. Since type I diabetes can have a non-insulin-dependent phase (pre-type I diabetes and/or honeymoon) the differentiation of two main types of diabetes according to insulin-dependency is not absolute. We studied the insulin, C-peptide and glucagon responses to various tests (OGTT, IVGTT, glibenclamide test, mixed meal tolerance test and ITT) performed during the non-insulin-dependent phase of 3 young patients (range 8-18 years) who developed ketosis 12-24 months after the discovery of fasting hyperglycemia, and in 6 patients (age 15-23 years) who presented a remission phase 4-6 months after the sudden clinical onset of type I diabetes. An insignificant insulin and C-peptide increase following i.v. glucose was observed in all patients, whereas the B-cell response to both oral glucose and other secretagogues was preserved, although at a subnormal level. In the three hyperglycemic and preketoacidotic patients the basal levels of glucagon were low and no significant increase after secretagogues was seen. Sensitivity to exogenous insulin in all patients was good. Thus, B-cell response in our patients was reminiscent of the differential responsiveness to various stimulants in the early stage of type II (non-insulin-dependent) diabetes. These results suggest that type I and type II diabetes can be characterized by the same functional B-cell defect during a period of their natural history.

  3. Acute regulation of glucose uptake in cardiac muscle of the American eel Anguilla rostrata.

    PubMed

    Rodnick; Bailey; West; Driedzic

    1997-01-01

    We investigated the effects of anoxia and contractile activity on glucose uptake and the intracellular location of hexokinase in cardiac muscle of the American eel Anguilla rostrata. Uptake of 2-deoxyglucose (2-DG) by ventricle strips at 15 °C was increased by 45 % by anoxia and by 85 % by contractile activity over basal conditions. The anoxia- and contraction-induced increase in basal 2-DG uptake was inhibited completely by 25 µmol l-1 cytochalasin B, suggesting that facilitated glucose transporters are involved. Maximal activity of hexokinase in whole homogenates (approximately 10 µmol min-1 g-1 tissue) was 200 times higher than the maximal rate of 2-DG uptake measured in vitro (46 nmol min-1 g-1 tissue). Only 20­25 % of hexokinase activity was localized to the mitochondrial fraction, and this was not altered by perfusion of the hearts with anoxic media. It is therefore unlikely that anoxia-induced stimulation of 2-DG uptake is mediated by intracellular translocation of hexokinase. As in the case of mammalian muscle, glucose 6-phosphate is a potent inhibitor of hexokinase in eel cardiac muscle (IC50=0.44 mmol l-1). In summary, anoxia and contractile activity significantly increase 2-DG uptake in cardiac muscle of American eels, and glucose transport may be rate-limiting for glucose utilization. Increased utilization of glucose during anoxia or contractile activity may involve the recruitment of facilitative glucose transport proteins to the cell surface of myocytes or an increase in the intrinsic activity of glucose transporters already residing at the cell surface.

  4. Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake

    PubMed Central

    Zeve, Daniel; Seo, Jin; Suh, Jae Myoung; Stenesen, Drew; Tang, Wei; Berglund, Eric D.; Wan, Yihong; Williams, Linda J.; Lim, Ajin; Martinez, Myrna J.; McKay, Renée M.; Millay, Douglas P.; Olson, Eric N.; Graff, Jonathan M.

    2012-01-01

    SUMMARY Adipose tissues provide circulating nutrients and hormones. We present in vivo mouse studies highlighting roles for Wnt signals in both aspects of metabolism. β-catenin activation in PPARγ–expressing fat progenitors (PBCA) decreased fat mass and induced fibrotic replacement of subcutaneous fat specifically. In spite of lipodystrophy, PBCA mice did not develop the expected diabetes and hepatosteatosis, but rather exhibited improved glucose metabolism and normal insulin sensitivity. Glucose uptake was increased in muscle independently of insulin, associated with cell surface translocation of glucose transporters and AMPK activation. Ex vivo assays showed these effects were likely secondary to blood-borne signals since PBCA sera or conditioned media from PBCA fat progenitors enhanced glucose uptake and activated AMPK in muscle cultures. Thus, adipose progenitor Wnt activation dissociates lipodystrophy from dysfunctional metabolism and highlights a fat-muscle endocrine axis, which may represent a potential therapy to lower blood glucose and improve metabolism. PMID:22482731

  5. Wnt signaling activation in adipose progenitors promotes insulin-independent muscle glucose uptake.

    PubMed

    Zeve, Daniel; Seo, Jin; Suh, Jae Myoung; Stenesen, Drew; Tang, Wei; Berglund, Eric D; Wan, Yihong; Williams, Linda J; Lim, Ajin; Martinez, Myrna J; McKay, Renée M; Millay, Douglas P; Olson, Eric N; Graff, Jonathan M

    2012-04-01

    Adipose tissues provide circulating nutrients and hormones. We present in vivo mouse studies highlighting roles for Wnt signals in both aspects of metabolism. β-catenin activation in PPARγ-expressing fat progenitors (PBCA) decreased fat mass and induced fibrotic replacement of subcutaneous fat specifically. In spite of lipodystrophy, PBCA mice did not develop the expected diabetes and hepatosteatosis, but rather exhibited improved glucose metabolism and normal insulin sensitivity. Glucose uptake was increased in muscle independently of insulin, associated with cell-surface translocation of glucose transporters and AMPK activation. Ex vivo assays showed these effects were likely secondary to blood-borne signals since PBCA sera or conditioned media from PBCA fat progenitors enhanced glucose uptake and activated AMPK in muscle cultures. Thus, adipose progenitor Wnt activation dissociates lipodystrophy from dysfunctional metabolism and highlights a fat-muscle endocrine axis, which may represent a potential therapy to lower blood glucose and improve metabolism.

  6. The interrelation between aPKC and glucose uptake in the skeletal muscle during contraction and insulin stimulation.

    PubMed

    Santos, J M; Benite-Ribeiro, S A; Queiroz, G; Duarte, J A

    2014-12-01

    Contraction and insulin increase glucose uptake in skeletal muscle. While the insulin pathway, better characterized, requires activation of phosphoinositide 3-kinase (PI3K) and atypical protein kinase (aPKC), muscle contraction seems to share insulin-activated components to increase glucose uptake. This study aimed to investigate the interrelation between the pathway involved in glucose uptake evoked by insulin and muscle contraction. Isolated muscle of rats was treated with solvent (control), insulin, wortmannin (PI3K inhibitor) and the combination of insulin plus wortmannin. After treatment, muscles were electrically stimulated (contracted) or remained at rest. Glucose transporter 4 (GLUT4) localization, glucose uptake and phospho-aPKC (aPKC activated form) were assessed. Muscle contraction and insulin increased glucose uptake in all conditions when compared with controls not stimulating an effect that was accompanied by an increase in GLUT4 and of phospho-aPKC at the muscle membrane. Contracted muscles treated with insulin did not show additive effects on glucose uptake or aPKC activity compared with the response when these stimuli were applied alone. Inhibition of PI3K blocked insulin effect on glucose uptake and aPKC but not in the contractile response. Thus, muscle contraction seems to stimulate aPKC and glucose uptake independently of PI3K. Therefore, aPKC may be a convergence point and a rate limit step in the pathway by which, insulin and contraction, increase glucose uptake in skeletal muscle.

  7. GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle

    PubMed Central

    Sjøberg, Kim A.; Holst, Jens J.; Rattigan, Stephen; Richter, Erik A.

    2013-01-01

    The insulinotropic gut hormone glucagon-like peptide-1 (GLP-1) has been proposed to have effects on vascular function and glucose disposal. However, whether GLP-1 is able to increase microvascular recruitment (MVR) in humans has not been investigated. GLP-1 was infused in the femoral artery in overnight-fasted, healthy young men. Microvascular recruitment was measured with real-time contrast-enhanced ultrasound and leg glucose uptake by the leg balance technique with and without inhibition of the insulinotropic response of GLP-1 by coinfusion of octreotide. As a positive control, MVR and leg glucose uptake were measured during a hyperinsulinemic-euglycemic clamp. Infusion of GLP-1 caused a rapid increase (P < 0.05) of 20 ± 12% (mean ± SE) in MVR in the vastus lateralis muscle of the infused leg after 5 min, and MVR further increased to 60 ± 8% above preinfusion levels by 60 min infusion. The effect was slightly slower but similar in magnitude in the noninfused contralateral leg, in which GLP-1 concentration was within the physiological range. Octreotide infusion did not prevent the GLP-1-induced increase in MVR. GLP-1 infusion did not increase leg glucose uptake with or without octreotide coinfusion. GLP-1 infusion in rats increased MVR by 28% (P < 0.05) but did not increase muscle glucose uptake. During the hyperinsulinemic clamp, MVR increased ∼40%, and leg glucose uptake increased 35-fold. It is concluded that GLP-1 in physiological concentrations causes a rapid insulin-independent increase in muscle MVR but does not affect muscle glucose uptake. PMID:24302010

  8. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans

    SciTech Connect

    Baron, A.D.; Brechtel, G.; Wallace, P.; Edelman, S.V.

    1988-12-01

    In vivo glucose uptake can occur via two mechanisms, namely, insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). Although the principal tissue sites for IMGU are skeletal muscle, the tissue sites for NIMGU at a given serum glucose concentration are not known. To examine this issue, rates of whole body glucose uptake (Rd) were measured at basal and during glucose clamp studies performed at euglycemia (approximately 90 mg/dl) and hyperglycemia (approximately 220 mg/dl) in six lean healthy men. Studies were performed during hyperinsulinemia (approximately 70 microU/ml) and during somatostatin-induced insulinopenia to measure IMGU and NIMGU, respectively. During each study, leg glucose balance (arteriovenous catheter technique) was also measured. With this approach, rates of whole body skeletal muscle IMGU and NIMGU can be estimated, and the difference between overall Rd and skeletal muscle glucose uptake represents non-skeletal muscle Rd. The results indicate that approximately 20% of basal Rd is into skeletal muscle. During insulinopenia approximately 86% of body NIMGU occurs in non-skeletal muscle tissues at euglycemia. When hyperglycemia was created, whole body NIMGU increased from 128 +/- 6 to 213 +/- 18 mg/min (P less than 0.01); NIMGU into non-skeletal muscle tissues was 134 +/- 11 and 111 +/- 6 mg/min at hyperglycemia and euglycemia, respectively, P = NS. Therefore, virtually all the hyperglycemia induced increment in NIMGU occurred in skeletal muscle. During hyperinsulinemia, IMGU in skeletal muscle represented 75 and 95% of body Rd, at euglycemia and hyperglycemia, respectively.

  9. Non-insulin-dependent (type II) diabetes mellitus.

    PubMed Central

    Rodger, W

    1991-01-01

    Non-insulin-dependent (type II) diabetes mellitus is an inherited metabolic disorder characterized by hyperglycemia with resistance to ketosis. The onset is usually after age 40 years. Patients are variably symptomatic and frequently obese, hyperlipidemic and hypertensive. Clinical, pathological and biochemical evidence suggests that the disease is caused by a combined defect of insulin secretion and insulin resistance. Goals in the treatment of hyperglycemia, dyslipidemia and hypertension should be appropriate to the patient's age, the status of diabetic complications and the safety of the regimen. Nonpharmacologic management includes meal planning to achieve a suitable weight, such that carbohydrates supply 50% to 60% of the daily energy intake, with limitation of saturated fats, cholesterol and salt when indicated, and physical activity appropriate to the patient's age and cardiovascular status. Follow-up should include regular visits with the physician, access to diabetes education, self-monitoring of the blood or urine glucose level and laboratory-based measurement of the plasma levels of glucose and glycated hemoglobin. If unacceptably high plasma glucose levels (e.g., 8 mmol/L or more before meals) persist the use of orally given hypoglycemic agents (a sulfonylurea agent or metformin or both) is indicated. Temporary insulin therapy may be needed during intercurrent illness, surgery or pregnancy. Long-term insulin therapy is recommended in patients with continuing symptoms or hyperglycemia despite treatment with diet modification and orally given hypoglycemic agents. The risk of pancreatitis may be reduced by treating severe hypertriglyceridemia (fasting serum level greater than 10 mmol/L) and atherosclerotic disease through dietary and, if necessary, pharmacologic management of dyslipidemia. Antihypertensive agents are available that have fewer adverse metabolic effects than thiazides and beta-adrenergic receptor blockers. New drugs are being developed that

  10. GLUT2-mediated glucose uptake and availability are required for embryonic brain development in zebrafish

    PubMed Central

    Marín-Juez, Rubén; Rovira, Mireia; Crespo, Diego; van der Vaart, Michiel; Spaink, Herman P; Planas, Josep V

    2015-01-01

    Glucose transporter 2 (GLUT2; gene name SLC2A2) has a key role in the regulation of glucose dynamics in organs central to metabolism. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, its role in the brain is not well understood. To decipher the role of GLUT2 in brain development, we knocked down slc2a2 (glut2), the functional ortholog of human GLUT2, in zebrafish. Abrogation of glut2 led to defective brain organogenesis, reduced glucose uptake and increased programmed cell death in the brain. Coinciding with the observed localization of glut2 expression in the zebrafish hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a but not those expressing neurod. Specificity of the morphant phenotype was demonstrated by the restoration of brain organogenesis, whole-embryo glucose uptake, brain apoptosis, and expression of proneural markers in rescue experiments. These results indicate that glut2 has an essential role during brain development by facilitating the uptake and availability of glucose and support the involvement of glut2 in brain glucose sensing. PMID:25294126

  11. Mild traumatic brain injury results in depressed cerebral glucose uptake: An (18)FDG PET study.

    PubMed

    Selwyn, Reed; Hockenbury, Nicole; Jaiswal, Shalini; Mathur, Sanjeev; Armstrong, Regina C; Byrnes, Kimberly R

    2013-12-01

    Moderate to severe traumatic brain injury (TBI) in humans and rats induces measurable metabolic changes, including a sustained depression in cerebral glucose uptake. However, the effect of a mild TBI on brain glucose uptake is unclear, particularly in rodent models. This study aimed to determine the glucose uptake pattern in the brain after a mild lateral fluid percussion (LFP) TBI. Briefly, adult male rats were subjected to a mild LFP and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)FDG), which was performed prior to injury and at 3 and 24 h and 5, 9, and 16 days post-injury. Locomotor function was assessed prior to injury and at 1, 3, 7, 14, and 21 days after injury using modified beam walk tasks to confirm injury severity. Histology was performed at either 10 or 21 days post-injury. Analysis of function revealed a transient impairment in locomotor ability, which corresponds to a mild TBI. Using reference region normalization, PET imaging revealed that mild LFP-induced TBI depresses glucose uptake in both the ipsilateral and contralateral hemispheres in comparison with sham-injured and naïve controls from 3 h to 5 days post-injury. Further, areas of depressed glucose uptake were associated with regions of glial activation and axonal damage, but no measurable change in neuronal loss or gross tissue damage was observed. In conclusion, we show that mild TBI, which is characterized by transient impairments in function, axonal damage, and glial activation, results in an observable depression in overall brain glucose uptake using (18)FDG-PET. PMID:23829400

  12. Mulberry leaf extract stimulates glucose uptake and GLUT4 translocation in rat adipocytes.

    PubMed

    Naowaboot, Jarinyaporn; Pannangpetch, Patchareewan; Kukongviriyapan, Veerapol; Prawan, Auemduan; Kukongviriyapan, Upa; Itharat, Arunporn

    2012-01-01

    Mulberry (Morus alba L.) leaf tea is promoted for its health benefits and the control of diabetes in Asian nations. The blood glucose lowering activity of mulberry leaf extract (MA) has been proven; however, the molecular basis underlying this effect remains unclear. The aim of the present work is to elucidate its mechanism of the antihyperglycemic action, by examining the effect of MA on glucose uptake and the translocation of glucose transporter 4 protein (GLUT4) to the plasma membrane of adipocytes isolated from diabetic rats. The incubation of adipocytes with 5-45 μg/ml MA resulted in 31-54% increase of glucose uptake in a dose-dependent manner. This glucose uptake enhancing effect was inhibited by the phosphoinositol 3-kinase (PI3-K) inhibitor, wortmannin (100 nM). The GLUT4 protein on the plasma membrane fraction of adipocytes was markedly increased after treatment with 15 μg/ml MA extract. Interestingly, gallic acid, one of the phenolic compounds found in MA extract, increased glucose uptake and enhanced the translocation of GLUT4 at concentrations comparable to the amount of gallic acid in the effective concentration ranges of MA. Thus, it is likely that gallic acid contributes, at least in part, to its antihyperglycemic activity. The present results suggest that the antihyperglycemic action of MA is mediated by increasing glucose uptake via the activation of PI3-K signaling pathway and translocation of GLUT4 to the plasma membrane. These findings are the first molecular evidence supporting the mulberry tea as herbal medicine for diabetic patients. PMID:22298456

  13. Circulating lipids and glycaemic control in insulin dependent diabetic children.

    PubMed Central

    Azad, K; Parkin, J M; Court, S; Laker, M F; Alberti, K G

    1994-01-01

    The prevalence of dyslipidaemia in children with insulin dependent diabetes mellitus (IDDM) and its relation to glycaemic control was studied in a group of 51 diabetic children and a control population of 132 schoolchildren. The prevalence of dyslipidaemia in the fasting state was increased in the diabetic group (39%) compared with control subjects (17%). Serum cholesterol concentration alone was raised in 25% of diabetic subjects while serum cholesterol and triglycerides were raised in 14%, compared with 16% and 0.7% respectively in control subjects. Serum total cholesterol (5.1 v 4.5 mmol/l), low density lipoprotein cholesterol (3.2 v 2.6 mmol/l), non-esterified fatty acids (0.91 v 0.50 mmol/l), and triglycerides (0.94 v 0.76 mmol/l) were higher in diabetic children. Serum total cholesterol, triglycerides, and apolipoprotein (apo)B concentrations increased with worsening control, while serum high density lipoprotein cholesterol and apoA-I concentrations were unaltered. There were also positive correlations between glycated haemoglobin and total cholesterol, triglycerides, and apoB in diabetic children. Thus, abnormalities in circulating lipids are common in young subjects with IDDM but largely disappear if blood glucose concentrations are reasonably controlled. PMID:7944528

  14. AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells

    PubMed Central

    Kim, Nami; Lee, Jung Ok; Lee, Hye Jeong; Lee, Yong Woo; Kim, Hyung Ip; Kim, Su Jin; Park, Sun Hwa; Lee, Chul Su; Ryoo, Sun Woo; Hwang, Geum-Sook; Kim, Hyeon Soo

    2016-01-01

    Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-α (PKCα). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicate that isoeugenol exerts beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in skeletal muscle. PMID:26585419

  15. AMPK, a metabolic sensor, is involved in isoeugenol-induced glucose uptake in muscle cells.

    PubMed

    Kim, Nami; Lee, Jung Ok; Lee, Hye Jeong; Lee, Yong Woo; Kim, Hyung Ip; Kim, Su Jin; Park, Sun Hwa; Lee, Chul Su; Ryoo, Sun Woo; Hwang, Geum-Sook; Kim, Hyeon Soo

    2016-02-01

    Isoeugenol exerts various beneficial effects on human health. However, the mechanisms underlying these effects are poorly understood. In this study, we observed that isoeugenol activated AMP-activated protein kinase (AMPK) and increased glucose uptake in rat L6 myotubes. Isoeugenol-induced increase in intracellular calcium concentration and glucose uptake was inhibited by STO-609, an inhibitor of calcium/calmodulin-dependent protein kinase kinase (CaMKK). Isoeugenol also increased the phosphorylation of protein kinase C-α (PKCα). Chelation of calcium with BAPTA-AM blocked isoeugenol-induced AMPK phosphorylation and glucose uptake. Isoeugenol stimulated p38MAPK phosphorylation that was inhibited after pretreatment with compound C, an AMPK inhibitor. Isoeugenol also increased glucose transporter type 4 (GLUT4) expression and its translocation to the plasma membrane. GLUT4 translocation was not observed after the inhibition of AMPK and CaMKK. In addition, isoeugenol activated the Akt substrate 160 (AS160) pathway, which is downstream of the p38MAPK pathway. Knockdown of the gene encoding AS160 inhibited isoeugenol-induced glucose uptake. Together, these results indicate that isoeugenol exerts beneficial health effects by activating the AMPK/p38MAPK/AS160 pathways in skeletal muscle.

  16. Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus.

    PubMed

    Ivy, J L

    1997-11-01

    Recent epidemiological studies indicate that individuals who maintain a physically active lifestyle are much less likely to develop impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). Moreover, it was found that the protective effect of physical activity was strongest for individuals at highest risk of developing NIDDM. Reducing the risk of insulin resistance and NIDDM by regularly performed exercise is also supported by several aging studies. It has been found that older individuals who vigorously train on a regular basis exhibit a greater glucose tolerance and a lower insulin response to a glucose challenge than sedentary individuals of similar age and weight. While the evidence is substantial that aerobic exercise training can reduce the risk of impaired glucose tolerance and NIDDM, the evidence that exercise training is beneficial in the treatment of NIDDM is not particularly strong. Many of the early studies investigating the effects of exercise training on NIDDM could not demonstrate improvements in fasting plasma glucose and insulin levels, or glucose tolerance. The adequacy of the training programmes in many of these studies, however, is questionable. More recent studies using prolonged, vigorous exercise-training protocols have produced more favourable results. There are several important adaptations to exercise training that may be beneficial in the prevention and treatment of insulin resistance, impaired glucose tolerance and NIDDM. An increase in abdominal fat accumulation and loss of muscle mass are highly associated with the development of insulin resistance. Exercise training results in preferential loss of fat from the central regions of the body and should therefore contribute significantly in preventing or alleviating insulin resistance due to its development. Likewise, exercise training can prevent muscle atrophy and stimulate muscle development. Several months of weight training has been found to significantly lower

  17. HLA antigens in insulin dependent and non-insulin dependent Spanish diabetic patients.

    PubMed

    Serrano-Ríos, M; Regueiro, J R; Severino, R; López-Larrea, C; Arnaiz-Villena, A

    1983-01-01

    HLA-A, -B, -C, -DR and Bw4, Bw6 antigens and Bf and GLO alleles have been studied in a sample of Spanish insulin dependent (IDD) and non-insulin dependent (NIDD) diabetic patients. In IDD's there was no significant increase of B8 and B15; an increase of B18 secondary to that of DR3 has been found. DR4 was also increased in our sample. The GLO-S/DR2 haplotype was found to be decreased in IDD. It was observed that (Aw30)-B18-Cw5-Bw6-DR3-BfF1 is the commonest ID diabetic haplotype in our population. A relationship between DR4 and early IDD onset was also found. No association was found between HLA, or Bf, and age of onset, macroangiopathy, microangiopathy, retinopathy, nephropathy and peripheral or autonomic neuropathy. In NIDD's, DR3 was increased and DR3-non BfF1 and DR3-non B18 RRs were higher than DR3 RR.Aw30 and Cw5 tended to be decreased, although not significantly. These findings further support the hypothesis that several closely linked diabetic susceptibility factors may exist within an HLA haplotype (i.e.: (Aw30)-B18-Cw5-Bw6-DR3-BfF1 in our population) and that all of them may be necessary for developing an IDD form; lack of one or several factors might lead to the acquisition of the NIDD form. PMID:6352349

  18. Selenium-enriched exopolysaccharides improve skeletal muscle glucose uptake of diabetic KKAy mice via AMPK pathway.

    PubMed

    Zhou, Xihong; Chen, Jingqing; Wang, Fengqin; Yang, Hangxian; Yang, Ren; Wang, Xinxia; Wang, Yizhen

    2014-06-01

    Selenium-enriched exopolysaccharides (EPS) produced by Enterobacter cloacae Z0206 have been proven to possess effect on reducing blood glucose level in diabetic mice. To investigate the specific mechanism, we studied the effects of oral supply with EPS on skeletal muscle glucose transportation and consumption in high-fat-diet-induced diabetic KKAy mice. We found that EPS supplementation increased expressions of glucose transporter 4 (Glut4), hexokinase 2 (hk2), phosphorylation of AMP-activated kinase subunit α2 (pAMPKα2), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and increased expression of characteristic protein of oxidative fibers such as troponin I and cytochrome c (Cytc). Furthermore, we found that EPS increased glucose uptake and expressions of pAMPKα2 and PGC-1α in palmitic acid (PA)-induced C2C12 cells. However, while EPS inhibited AMPKα2 with interference RNA (iRNA), effects of EPS on the improvement of glucose uptake diminished. These results indicated that EPS may improve skeletal muscle glucose uptake of diabetic KKAy mice through AMPKα2-PGC-1α pathway. PMID:24729044

  19. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

    PubMed Central

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling. PMID:27537838

  20. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    PubMed

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling. PMID:27537838

  1. Akt inhibitors reduce glucose uptake independently of their effects on Akt.

    PubMed

    Tan, Shi-Xiong; Ng, Yvonne; James, David E

    2010-11-15

    The protein kinase Akt is involved in various cellular processes, including cell proliferation, growth and metabolism. Hyperactivation of Akt is commonly observed in human tumours and so this pathway has been the focus of targeted drug discovery. However, Akt also plays an essential role in other physiological processes, such as the insulin-regulated transport of glucose into muscle and fat cells. This process, which is essential for whole-body glucose homoeostasis in mammals, is thought to be mediated via Akt-dependent movement of GLUT4 glucose transporters to the plasma membrane. In the present study, we have investigated the metabolic side effects of non-ATP-competitive allosteric Akt inhibitors. In 3T3-L1 adipocytes, these inhibitors caused a decrease in the Akt signalling pathway concomitant with reduced glucose uptake. Surprisingly, a similar reduction in GLUT4 translocation to the plasma membrane was not observed. Further investigation revealed that the inhibitory effects of these compounds on glucose uptake in 3T3-L1 adipocytes were independent of the Akt signalling pathway. The inhibitors also inhibited glucose transport into other cell types, including human erythrocytes and T-47D breast cancer cells, suggesting that these effects are not specific to GLUT4. We conclude that these drugs may, at least in part, inhibit tumorigenesis through inhibition of tumour cell glucose transport.

  2. Muscle glucose uptake in the rat after suspension with single hindlimb weight bearing

    NASA Technical Reports Server (NTRS)

    Stump, Craig S.; Woodman, Christopher R.; Fregosi, Ralph F.; Tipton, Charles M.

    1993-01-01

    An examination is conducted of the effect of nonweight-bearing conditions, and the systemic influences of simulated microgravity on rat hindlimb muscles. The results obtained suggest that the increases in hindlimb muscle glucose uptake and extracellular space associated with simulated microgravity persist with hindlimb weightbearing, despite the prevention of muscle atrophy. The mechanism (or mechanisms) responsible for these effects are currently unknown.

  3. Exercise and Type 2 Diabetes: Molecular Mechanisms Regulating Glucose Uptake in Skeletal Muscle

    ERIC Educational Resources Information Center

    Stanford, Kristin I.; Goodyear, Laurie J.

    2014-01-01

    Exercise is a well-established tool to prevent and combat type 2 diabetes. Exercise improves whole body metabolic health in people with type 2 diabetes, and adaptations to skeletal muscle are essential for this improvement. An acute bout of exercise increases skeletal muscle glucose uptake, while chronic exercise training improves mitochondrial…

  4. Effect of guava (Psidium guajava L.) leaf extract on glucose uptake in rat hepatocytes.

    PubMed

    Cheng, Fang-Chi; Shen, Szu-Chuan; Wu, James Swi-Bea

    2009-06-01

    People in oriental countries, including Japan and Taiwan, boil guava leaves (Psidium guajava L.) in water and drink the extract as a folk medicine for diabetes. The present study investigated the enhancement of aqueous guava leaf extract on glucose uptake in rat clone 9 hepatocytes and searched for the active compound. The extract was eluted with MeOH-H(2)O solutions through Diaion, Sephadex, and MCI-gel columns to separate into fractions with different polarities. The uptake test of 2-[1-(14)C] deoxy-D-glucose in rat clone 9 hepatocytes was performed to evaluate the hypoglycemic effect of these fractions. The active compound was identified by nuclear magnetic resonance analysis and high-performance liquid chromatography (HPLC). The results revealed that phenolics are the principal component of the extract, that high polarity fractions of the guava leaf extract are enhancers to glucose uptake in rat clone 9 hepatocytes, and that quercetin is the major active compound. We suggest that quercetin in the aqueous extract of guava leaves promotes glucose uptake in liver cells, and contributes to the alleviation of hypoglycemia in diabetes as a consequence.

  5. Uptake of D-xylose and D-glucose by Spirochaeta aurantia.

    PubMed Central

    Roberts, S; Paden, C A; Greenberg, E P

    1984-01-01

    Uptake of D-[14C]glucose and D-[14C]xylose by Spirochaeta aurantia was demonstrated to be osmotic shock sensitive and to require a high-energy phosphorylated compound rather than a proton motive force. These features are similar to those of binding protein-mediated transport systems in other gram-negative bacteria. PMID:6735985

  6. Catecholamine stimulation, substrate competition, and myocardial glucose uptake in conscious dogs assessed with positron emission tomography.

    PubMed

    Merhige, M E; Ekas, R; Mossberg, K; Taegtmeyer, H; Gould, K L

    1987-11-01

    Uptake of radiolabelled deoxyglucose out of proportion to reduced coronary flow demonstrated by positron emission tomography has been used to identify reversibly ischemic, viable myocardium. For this concept to be applied reliably in the clinical setting, factors that may depress glucose availability independent of tissue viability, such as adrenergic stimulation and substrate competition, must be examined. Accordingly, we studied the effect of catecholamine stimulation by dopamine on myocardial glucose uptake in vivo using chronically instrumented, intact dogs and positron emission tomography. We measured myocardial activity of [2-18F]-2-deoxyglucose (FDG) and 82Rb in glucose-loaded animals randomly studied during dopamine infusion, during insulin infusion, and then during their combined infusion. Myocardial FDG uptake was significantly decreased when animals were treated with dopamine, compared with treatment in the same animals with insulin. When insulin was added to the dopamine infusion, myocardial FDG uptake was restored. In contrast, myocardial activity of 82Rb, which is taken up in proportion to coronary flow, was similar under all three experimental conditions. Plasma glucose, free fatty acid, and lactate concentrations were determined before and during each infusion. The depression of myocardial FDG activity seen during dopamine infusion and its reversal with addition of insulin can be explained on the basis of effects of these hormones on substrate availability and competition.

  7. Evaluation of Glucose Uptake in Normal and Cancer Cell Lines by Positron Emission Tomography.

    PubMed

    Maddalena, Francesca; Lettini, Giacomo; Gallicchio, Rosj; Sisinni, Lorenza; Simeon, Vittorio; Nardelli, Anna; Venetucci, Angela Assunta; Storto, Giovanni; Landriscina, Matteo

    2015-01-01

    To date, there is no definitive demonstration of the utility of positron emission tomography (PET) in studying glucose metabolism in cultured cell lines. Thus, this study was designed to compare PET to more standardized methods for the quantitative assessment of glucose uptake in nontransformed and transformed living cells and to validate PET for metabolic studies in vitro. Human colon and breast carcinoma cell lines and mouse embryo fibroblasts were evaluated for [(18)F]fluorodeoxyglucose ([(18)F]FDG) uptake by PET and autoradiography and 2-deoxyglucose (2-DG) incorporation by colorimetric assay and analyzed for the radiotoxic effects of [(18)F]FDG and the expression levels of glucose transporters. Indeed, [(18)F]FDG incorporation on PET was comparable to [(18)F]FDG uptake by autoradiography and 2-DG incorporation by colorimetric assay, although radiotracer-based methods exhibited more pronounced differences between individual cell lines. As expected, these data correlated with glucose transporters 1 to 4 and hexokinase II expression in tumor cell lines and mouse fibroblasts. Notably, [(18)F]FDG incorporation resulted in low apoptotic rates, with fibroblasts being slightly more sensitive to radiotracer-induced cell death. The quantitative analysis of [(18)F]FDG uptake in living cells by PET represents a valuable and reproducible method to study tumor cell metabolism in vitro, being representative of the differences in the molecular profile of normal and tumor cell lines.

  8. Leucaena leucocephala fruit aqueous extract stimulates adipogenesis, lipolysis, and glucose uptake in primary rat adipocytes.

    PubMed

    Kuppusamy, Umah Rani; Arumugam, Bavani; Azaman, Nooriza; Jen Wai, Chai

    2014-01-01

    Leucaena leucocephala had been traditionally used to treat diabetes. The present study was designed to evaluate in vitro "insulin-like" activities of Leucaena leucocephala (Lam.) deWit. aqueous fruit extract on lipid and glucose metabolisms. The ability of the extract to stimulate adipogenesis, inhibit lipolysis, and activate radio-labeled glucose uptake was assessed using primary rat adipocytes. Quantitative Real-Time RT-PCR was performed to investigate effects of the extract on expression levels of genes (protein kinases B, AKT; glucose transporter 4, GLUT4; hormone sensitive lipase, HSL; phosphatidylinositol-3-kinases, PI3KA; sterol regulatory element binding factor 1, Srebp1) involved in insulin-induced signaling pathways. L. leucocephala aqueous fruit extract stimulated moderate adipogenesis and glucose uptake into adipocytes when compared to insulin. Generally, the extract exerted a considerable level of lipolytic effect at lower concentration but decreased gradually at higher concentration. The findings concurred with RT-PCR analysis. The expressions of GLUT4 and HSL genes were upregulated by twofold and onefold, respectively, whereas AKT, PI3KA, and Srebp1 genes were downregulated. The L. leucocephala aqueous fruit extract may be potentially used as an adjuvant in the treatment of Type 2 diabetes mellitus and weight management due to its enhanced glucose uptake and balanced adipogenesis and lipolysis properties. PMID:25180205

  9. Leucaena leucocephala Fruit Aqueous Extract Stimulates Adipogenesis, Lipolysis, and Glucose Uptake in Primary Rat Adipocytes

    PubMed Central

    Kuppusamy, Umah Rani; Azaman, Nooriza; Jen Wai, Chai

    2014-01-01

    Leucaena leucocephala had been traditionally used to treat diabetes. The present study was designed to evaluate in vitro “insulin-like” activities of Leucaena leucocephala (Lam.) deWit. aqueous fruit extract on lipid and glucose metabolisms. The ability of the extract to stimulate adipogenesis, inhibit lipolysis, and activate radio-labeled glucose uptake was assessed using primary rat adipocytes. Quantitative Real-Time RT-PCR was performed to investigate effects of the extract on expression levels of genes (protein kinases B, AKT; glucose transporter 4, GLUT4; hormone sensitive lipase, HSL; phosphatidylinositol-3-kinases, PI3KA; sterol regulatory element binding factor 1, Srebp1) involved in insulin-induced signaling pathways. L. leucocephala aqueous fruit extract stimulated moderate adipogenesis and glucose uptake into adipocytes when compared to insulin. Generally, the extract exerted a considerable level of lipolytic effect at lower concentration but decreased gradually at higher concentration. The findings concurred with RT-PCR analysis. The expressions of GLUT4 and HSL genes were upregulated by twofold and onefold, respectively, whereas AKT, PI3KA, and Srebp1 genes were downregulated. The L. leucocephala aqueous fruit extract may be potentially used as an adjuvant in the treatment of Type 2 diabetes mellitus and weight management due to its enhanced glucose uptake and balanced adipogenesis and lipolysis properties. PMID:25180205

  10. Interleukin-1 beta stimulates glucose uptake of human peritoneal mesothelial cells in vitro.

    PubMed

    Kruse, M; Mahiout, A; Kliem, V; Kurz, P; Koch, K M; Brunkhorst, R

    1996-01-01

    To investigate whether the glucose uptake (GU) of human peritoneal mesothelial cells (HPMC) is mediated by glucose transporters and whether this uptake is influenced by interleukin 1-beta (IL-1 beta), we measured 2-deoxy-(3H)-GU of HPMC in vitro, after exposing the cells for different times (two and 12 hours) to increasing concentrations (0.1, 1.0, and 2.0 ng/mL) of IL-1 beta. To exclude a noncarrier-mediated transport, GU was also tested in the presence of cytochalasin B. All experiments were performed in triplicate in the cells of two donors. Cytochalasin B inhibits GU of HPMC almost completely. GU of HPMC is not stimulated by insulin. GU is stimulated by IL-1 beta in a dose-dependent manner. These data indicate a GU of HPMC, which is mediated by a glucose transporter and stimulated by IL-1 beta. The increased uptake of glucose from the dialysate in patients with peritonitis may be mediated by a (cytokine-induced) increased activity of HPMC glucose transporters.

  11. In vivo radiometric analysis of glucose uptake and distribution in mouse bone

    PubMed Central

    Zoch, Meredith L; Abou, Diane S; Clemens, Thomas L; Thorek, Daniel L J; Riddle, Ryan C

    2016-01-01

    Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting 18F-fluorodeoxyglucose ([18F]-FDG) and non-invasive, high-resolution positron emission tomography/computed tomography (PET/CT) imaging and ex vivo autoradiography. Assessment of [18F]-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog. Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that [18F]-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of [18F]-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism. PMID:27088042

  12. In vivo radiometric analysis of glucose uptake and distribution in mouse bone.

    PubMed

    Zoch, Meredith L; Abou, Diane S; Clemens, Thomas L; Thorek, Daniel L J; Riddle, Ryan C

    2016-01-01

    Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting (18)F-fluorodeoxyglucose ([(18)F]-FDG) and non-invasive, high-resolution positron emission tomography/computed tomography (PET/CT) imaging and ex vivo autoradiography. Assessment of [(18)F]-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog. Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that [(18)F]-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of [(18)F]-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism. PMID:27088042

  13. Impacts of parturition and body condition score on glucose uptake capacity of bovine monocyte subsets.

    PubMed

    Eger, Melanie; Hussen, Jamal; Drong, Caroline; Meyer, Ulrich; von Soosten, Dirk; Frahm, Jana; Daenicke, Sven; Breves, Gerhard; Schuberth, Hans-Joachim

    2015-07-15

    The peripartal period of dairy cows is associated with a higher incidence of infectious diseases like mastitis or metritis, particularly in high-yielding animals. The onset of lactation induces a negative energy balance and a shift of glucose distribution toward the udder. Glucose is used as primary fuel by monocytes which give rise to macrophages, key cells in the defense against pathogens. The aim of this study was to analyze whether animals with high or low body condition score (BCS) differ in composition and glucose uptake capacities of bovine monocyte subsets. Blood samples were taken from 27 dairy cows starting 42 days before parturition until day 56 after parturition. The cows were allocated to two groups according to their BCS. A feeding regime was applied, in which the BCS high group received higher amounts of concentrate before parturition and concentrate feeding was more restricted in the BCS high group after parturition compared with the BCS low group, to promote postpartal lipolysis and enhance negative energy balance in the BCS high group. Blood cell counts of classical (cM), intermediate (intM) and nonclassical monocytes (ncM) were increased at day 7 after calving. In the BCS low group intM numbers were significantly higher compared to the BCS high group at day 7 after parturition. Within the BCS low group cows suffering from mastitis or metritis showed significantly higher numbers of cM, intM and ncM at day 7 after parturition. Classical monocytes and intM showed similar glucose uptake capacities while values for ncM were significantly lower. Compared with antepartal capacities and irrespective of BCS and postpartal mastitis or metritis, glucose uptake of all monocyte subsets decreased after parturition. In conclusion, whereas glucose uptake capacity of bovine monocyte subsets is altered by parturition, it is not linked to the energy supply of the animals or to postpartal infectious diseases.

  14. Non-Invasive, Simultaneous Quantification of Vascular Oxygenation and Glucose Uptake in Tissue

    PubMed Central

    Rajaram, Narasimhan; Reesor, Andrew F.; Mulvey, Christine S.; Frees, Amy E.; Ramanujam, Nirmala

    2015-01-01

    We report the development of non-invasive, fiber-based diffuse optical spectroscopy for simultaneously quantifying vascular oxygenation (SO2) and glucose uptake in solid tumors in vivo. Glucose uptake was measured using a fluorescent glucose analog, 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose (2-NBDG). Quantification of label-free SO2 and 2-NBDG-fluorescence-based glucose uptake 60 minutes after administration of the tracer (2-NBDG60) was performed using computational models of light-tissue interaction. This study was carried out on normal tissue and 4T1 and 4T07 murine mammary tumor xenografts in vivo. Injection of 2-NBDG did not cause a significant change in optical measurements of SO2, demonstrating its suitability as a functional reporter of tumor glucose uptake. Correction of measured 2-NBDG-fluorescence for the effects of absorption and scattering significantly improved contrast between tumor and normal tissue. The 4T1 and 4T07 tumors showed significantly decreased SO2, and 4T1 tumors demonstrated increased 2-NBDG60 compared with normal tissue (60 minutes after the administration of 2-NBDG when perfusion-mediated effects have cleared). 2-NBDG-fluorescence was found to be highly sensitive to food deprivation-induced reduction in blood glucose levels, demonstrating that this endpoint is indeed sensitive to glycolytic demand. 2-NBDG60 was also found to be linearly related to dose, underscoring the importance of calibrating for dose when comparing across animals or experiments. 4T1 tumors demonstrated an inverse relationship between 2-NBDG60 and SO2 that was consistent with the Pasteur effect, particularly when exposed to hypoxic gas breathing. Our results illustrate the potential of optical spectroscopy to provide valuable information about the metabolic status of tumors, with important implications for cancer prognosis. PMID:25635865

  15. Acute Alcohol Intoxication Decreases Glucose Metabolism but Increases Acetate Uptake in the Human Brain

    PubMed Central

    Volkow, Nora D.; Kim, Sung Won; Wang, Gene-Jack; Alexoff, David; Logan, Jean; Muench, Lisa; Shea, Colleen; Telang, Frank; Fowler, Joanna S.; Wong, Christopher; Benveniste, Helene; Tomasi, Dardo

    2012-01-01

    Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in thalamus. In contrast, alcohol intoxication caused a significant increase in [1-11C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in cerebellum and the smallest in thalamus. In heavy alcohol drinkers [1-11C]acetate brain uptake during alcohol challenge trended to be higher than in occasional drinkers (p <0.06) and the increases in [1-11C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-11C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (ie ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID:22947541

  16. Acute alcohol intoxication decreases glucose metabolism but increases acetate uptake in the human brain.

    PubMed

    Volkow, Nora D; Kim, Sung Won; Wang, Gene-Jack; Alexoff, David; Logan, Jean; Muench, Lisa; Shea, Colleen; Telang, Frank; Fowler, Joanna S; Wong, Christopher; Benveniste, Helene; Tomasi, Dardo

    2013-01-01

    Alcohol intoxication results in marked reductions in brain glucose metabolism, which we hypothesized reflect not just its GABAergic enhancing effects but also the metabolism of acetate as an alternative brain energy source. To test this hypothesis we separately assessed the effects of alcohol intoxication on brain glucose and acetate metabolism using Positron Emission Tomography (PET). We found that alcohol intoxication significantly decreased whole brain glucose metabolism (measured with FDG) with the largest decrements in cerebellum and occipital cortex and the smallest in the thalamus. In contrast, alcohol intoxication caused a significant increase in [1-(11)C]acetate brain uptake (measured as standard uptake value, SUV), with the largest increases occurring in the cerebellum and the smallest in the thalamus. In heavy alcohol drinkers [1-(11)C]acetate brain uptake during alcohol challenge tended to be higher than in occasional drinkers (p<0.06) and the increases in [1-(11)C]acetate uptake in cerebellum with alcohol were positively associated with the reported amount of alcohol consumed (r=0.66, p<0.01). Our findings corroborate a reduction of brain glucose metabolism during intoxication and document an increase in brain acetate uptake. The opposite changes observed between regional brain metabolic decrements and regional increases in [1-(11)C]acetate uptake support the hypothesis that during alcohol intoxication the brain may rely on acetate as an alternative brain energy source and provides preliminary evidence that heavy alcohol exposures may facilitate the use of acetate as an energy substrate. These findings raise the question of the potential therapeutic benefits that increasing plasma acetate concentration (i.e. ketogenic diets) may have in alcoholics undergoing alcohol detoxification. PMID:22947541

  17. [Physiopathology of non-insulin-dependent diabetes: current data and therapeutic consequences].

    PubMed

    Broussolle, C; Orgiazzi, J; Noël, G

    1990-01-01

    Non insulin-dependent diabetes mellitus results from the combination in varying proportions of low plasma insulin levels (insulinopenia), peripheral resistance to insulin and increased hepatic glucose production. Abnormalities of insulin secretion can be demonstrated without and after stimulation. Insulin resistance mainly occurs in skeletal muscle and is primarily due to a "postreceptor" defect. A pancreatic peptide, amylin, may participate in insulin resistance. Hepatic glucose production correlates with high fasting plasma glucose concentrations. Whatever its initial mechanism, hyperglycaemia maintains low insulin secretion and insulin resistance by its toxicity. In the light of these data, the effects of weight loss in obese non insulin-dependent diabetics have become clearer. The action of biguanides on insulin sensitivity is confirmed. Sulphonylureas have a pancreatic and an extrapancreatic action. The normoglycaemia obtained by intermittent insulin therapy can break the vicious circle of glucose toxicity. The use of prolonged insulin therapy is discussed. Finally, new compounds with an original mode of action offer hopes for the future. PMID:2204978

  18. Ursolic Acid Increases Glucose Uptake through the PI3K Signaling Pathway in Adipocytes

    PubMed Central

    He, Yonghan; Li, Wen; Li, Ying; Zhang, Shuocheng; Wang, Yanwen; Sun, Changhao

    2014-01-01

    Background Ursolic acid (UA), a triterpenoid compound, is reported to have a glucose-lowering effect. However, the mechanisms are not fully understood. Adipose tissue is one of peripheral tissues that collectively control the circulating glucose levels. Objective The objective of the present study was to determine the effect and further the mechanism of action of UA in adipocytes. Methods and Results The 3T3-L1 preadipocytes were induced to differentiate and treated with different concentrations of UA. NBD-fluorescent glucose was used as the tracer to measure glucose uptake and Western blotting used to determine the expression and activity of proteins involved in glucose transport. It was found that 2.5, 5 and 10 µM of UA promoted glucose uptake in a dose-dependent manner (17%, 29% and 35%, respectively). 10 µM UA-induced glucose uptake with insulin stimulation was completely blocked by the phosphatidylinositol (PI) 3-kinase (PI3K) inhibitor wortmannin (1 µM), but not by SB203580 (10 µM), the inhibitor of mitogen-activated protein kinase (MAPK), or compound C (2.5 µM), the inhibitor of AMP-activated kinase (AMPK) inhibitor. Furthmore, the downstream protein activities of the PI3K pathway, phosphoinositide-dependent kinase (PDK) and phosphoinositide-dependent serine/threoninekinase (AKT) were increased by 10 µM of UA in the presence of insulin. Interestingly, the activity of AS160 and protein kinase C (PKC) and the expression of glucose transporter 4 (GLUT4) were stimulated by 10 µM of UA under either the basal or insulin-stimulated status. Moreover, the translocation of GLUT4 from cytoplasm to cell membrane was increased by UA but decreased when the PI3K inhibitor was applied. Conclusions Our results suggest that UA stimulates glucose uptake in 3T3-L1 adipocytes through the PI3K pathway, providing important information regarding the mechanism of action of UA for its anti-diabetic effect. PMID:25329874

  19. A proteolytic pathway that controls glucose uptake in fat and muscle

    PubMed Central

    Belman, Jonathan P.; Habtemichael, Estifanos N.; Bogan, Jonathan S.

    2013-01-01

    Insulin regulates glucose uptake by controlling the subcellular location of GLUT4 glucose transporters. GLUT4 is sequestered within fat and muscle cells during low-insulin states, and is translocated to the cell surface upon insulin stimulation. The TUG protein is a functional tether that sequesters GLUT4 at the Golgi matrix. To stimulate glucose uptake, insulin triggers TUG endoproteolytic cleavage. Cleavage accounts for a large proportion of the acute effect of insulin to mobilize GLUT4 to the cell surface. During ongoing insulin exposure, endocytosed GLUT4 recycles to the plasma membrane directly from endosomes, and bypasses a TUG-regulated trafficking step. Insulin acts through the TC10α GTPase and its effector protein, PIST, to stimulate TUG cleavage. This action is coordinated with insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases, and with other signals to direct overall GLUT4 targeting. Data support the idea that the N-terminal TUG cleavage product, TUGUL, functions as a novel ubiquitin-like protein modifier to facilitate GLUT4 movement to the cell surface. The C-terminal TUG cleavage product is extracted from the Golgi matrix, which vacates an “anchoring” site to permit subsequent cycles of GLUT4 retention and release. Together, GLUT4 vesicle translocation and TUG cleavage may coordinate glucose uptake with physiologic effects of other proteins present in the GLUT4-containing vesicles, and with potential additional effects of the TUG C-terminal product. Understanding this TUG pathway for GLUT4 retention and release will shed light on the regulation of glucose uptake and the pathogenesis of type 2 diabetes. PMID:24114239

  20. A proteolytic pathway that controls glucose uptake in fat and muscle.

    PubMed

    Belman, Jonathan P; Habtemichael, Estifanos N; Bogan, Jonathan S

    2014-03-01

    Insulin regulates glucose uptake by controlling the subcellular location of GLUT4 glucose transporters. GLUT4 is sequestered within fat and muscle cells during low-insulin states, and is translocated to the cell surface upon insulin stimulation. The TUG protein is a functional tether that sequesters GLUT4 at the Golgi matrix. To stimulate glucose uptake, insulin triggers TUG endoproteolytic cleavage. Cleavage accounts for a large proportion of the acute effect of insulin to mobilize GLUT4 to the cell surface. During ongoing insulin exposure, endocytosed GLUT4 recycles to the plasma membrane directly from endosomes, and bypasses a TUG-regulated trafficking step. Insulin acts through the TC10α GTPase and its effector protein, PIST, to stimulate TUG cleavage. This action is coordinated with insulin signals through AS160/Tbc1D4 and Tbc1D1 to modulate Rab GTPases, and with other signals to direct overall GLUT4 targeting. Data support the idea that the N-terminal TUG cleavage product, TUGUL, functions as a novel ubiquitin-like protein modifier to facilitate GLUT4 movement to the cell surface. The C-terminal TUG cleavage product is extracted from the Golgi matrix, which vacates an "anchoring" site to permit subsequent cycles of GLUT4 retention and release. Together, GLUT4 vesicle translocation and TUG cleavage may coordinate glucose uptake with physiologic effects of other proteins present in the GLUT4-containing vesicles, and with potential additional effects of the TUG C-terminal product. Understanding this TUG pathway for GLUT4 retention and release will shed light on the regulation of glucose uptake and the pathogenesis of type 2 diabetes.

  1. Angiotensin 1-7 improves insulin sensitivity by increasing skeletal muscle glucose uptake in vivo.

    PubMed

    Echeverría-Rodríguez, Omar; Del Valle-Mondragón, Leonardo; Hong, Enrique

    2014-01-01

    The renin-angiotensin system (RAS) regulates skeletal muscle insulin sensitivity through different mechanisms. The overactivation of the ACE (angiotensin-converting enzyme)/Ang (angiotensin) II/AT1R (Ang II type 1 receptor) axis has been associated with the development of insulin resistance, whereas the stimulation of the ACE2/Ang 1-7/MasR (Mas receptor) axis improves insulin sensitivity. The in vivo mechanisms by which this axis enhances skeletal muscle insulin sensitivity are scarcely known. In this work, we investigated whether rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis and determined the effect of Ang 1-7 on rat skeletal muscle glucose uptake in vivo. Western blot analysis revealed the expression of ACE2 and MasR, while Ang 1-7 levels were detected in rat soleus muscle by capillary zone electrophoresis. The euglycemic clamp exhibited that Ang 1-7 by itself did not promote glucose transport, but it increased insulin-stimulated glucose disposal in the rat. In a similar manner, captopril (an ACE inhibitor) enhanced insulin-induced glucose uptake and this effect was blocked by the MasR antagonist A-779. Our results show for the first time that rat soleus muscle expresses the ACE2/Ang 1-7/MasR axis of the RAS, and Ang 1-7 improves insulin sensitivity by enhancing insulin-stimulated glucose uptake in rat skeletal muscle in vivo. Thus, endogenous (systemic and/or local) Ang 1-7 could regulate insulin-mediated glucose transport in vivo.

  2. Sodium-Glucose Transporter-2 (SGLT2; SLC5A2) Enhances Cellular Uptake of Aminoglycosides

    PubMed Central

    Jiang, Meiyan; Wang, Qi; Karasawa, Takatoshi; Koo, Ja-Won; Li, Hongzhe; Steyger, Peter S.

    2014-01-01

    Aminoglycoside antibiotics, like gentamicin, continue to be clinically essential worldwide to treat life-threatening bacterial infections. Yet, the ototoxic and nephrotoxic side-effects of these drugs remain serious complications. A major site of gentamicin uptake and toxicity resides within kidney proximal tubules that also heavily express electrogenic sodium-glucose transporter-2 (SGLT2; SLC5A2) in vivo. We hypothesized that SGLT2 traffics gentamicin, and promotes cellular toxicity. We confirmed in vitro expression of SGLT2 in proximal tubule-derived KPT2 cells, and absence in distal tubule-derived KDT3 cells. D-glucose competitively decreased the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescent analog of glucose, and fluorescently-tagged gentamicin (GTTR) by KPT2 cells. Phlorizin, an SGLT2 antagonist, strongly inhibited uptake of 2-NBDG and GTTR by KPT2 cells in a dose- and time-dependent manner. GTTR uptake was elevated in KDT3 cells transfected with SGLT2 (compared to controls); and this enhanced uptake was attenuated by phlorizin. Knock-down of SGLT2 expression by siRNA reduced gentamicin-induced cytotoxicity. In vivo, SGLT2 was robustly expressed in kidney proximal tubule cells of heterozygous, but not null, mice. Phlorizin decreased GTTR uptake by kidney proximal tubule cells in Sglt2+/− mice, but not in Sglt2−/− mice. However, serum GTTR levels were elevated in Sglt2−/− mice compared to Sglt2+/− mice, and in phlorizin-treated Sglt2+/− mice compared to vehicle-treated Sglt2+/− mice. Loss of SGLT2 function by antagonism or by gene deletion did not affect gentamicin cochlear loading or auditory function. Phlorizin did not protect wild-type mice from kanamycin-induced ototoxicity. We conclude that SGLT2 can traffic gentamicin and contribute to gentamicin-induced cytotoxicity. PMID:25268124

  3. Mapping brain glucose uptake with chemical exchange-sensitive spin-lock magnetic resonance imaging.

    PubMed

    Jin, Tao; Mehrens, Hunter; Hendrich, Kristy S; Kim, Seong-Gi

    2014-08-01

    Uptake of administered D-glucose (Glc) or 2-deoxy-D-glucose (2DG) has been indirectly mapped through the chemical exchange (CE) between glucose hydroxyl and water protons using CE-dependent saturation transfer (glucoCEST) magnetic resonance imaging (MRI). We propose an alternative technique-on-resonance CE-sensitive spin-lock (CESL) MRI-to enhance responses to glucose changes. Phantom data and simulations suggest higher sensitivity for this 'glucoCESL' technique (versus glucoCEST) in the intermediate CE regime relevant to glucose. Simulations of CESL signals also show insensitivity to B0-fluctuations. Several findings are apparent from in vivo glucoCESL studies of rat brain at 9.4 Tesla with intravenous injections. First, dose-dependent responses are nearly linearly for 0.25-, 0.5-, and 1-g/kg Glc administration (obtained with 12-second temporal resolution), with changes robustly detected for all doses. Second, responses at a matched dose of 1 g/kg are much larger and persist for a longer duration for 2DG versus Glc administration, and are minimal for mannitol as an osmolality control. And third, with similar increases in steady-state blood glucose levels, glucoCESL responses are ∼2.2 times higher for 2DG versus Glc, consistent with their different metabolic properties. Overall, we show that glucoCESL MRI could be a highly sensitive and quantifiable tool for glucose transport and metabolism studies.

  4. Insulin stimulates glucose uptake via a phosphatidylinositide 3-kinase-linked signaling pathway in bovine mammary epithelial cells.

    PubMed

    Zhao, K; Liu, H-Y; Zhou, M-M; Zhao, F-Q; Liu, J-X

    2014-01-01

    The aim of this study was to investigate the effects of insulin on glucose uptake in lactating bovine mammary epithelial cells (BMEC). Primary BMEC were cultured in Dulbecco's modified Eagle's medium/nutrient mixture F-12 and treated with different levels of insulin (0, 5, 50, and 500 ng/mL) for 48 h after a 24-h starvation without fetal calf serum. Compared with the control cells (0 ng of insulin/mL), cell proliferation was enhanced by insulin treatment at all tested levels. Insulin significantly increased glucose uptake at a concentration of 500 ng/mL. In addition, the protein synthesis inhibitor cycloheximide (0.5mg/mL) counteracted the insulin-elevated glucose uptake, thereby suggesting that newly synthesized transporter protein might take part in the insulin-induced glucose uptake. Furthermore, pretreatment of the cells with SB203580, an inhibitor of p38 mitogen-activated protein kinase, did not influence the insulin-induced glucose uptake, but LY294002, a specific inhibitor of phosphatidylinositide 3-kinase, significantly reduced the insulin-stimulated glucose uptake. These results indicated that insulin-induced glucose uptake in BMEC may involve the phosphatidylinositide 3-kinase- but not mitogen-activated protein kinase-mediated signaling pathways.

  5. Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes.

    PubMed

    Mitsuhashi, Kazuteru; Senmaru, Takafumi; Fukuda, Takuya; Yamazaki, Masahiro; Shinomiya, Katsuhiko; Ueno, Morio; Kinoshita, Shigeru; Kitawaki, Jo; Katsuyama, Masato; Tsujikawa, Muneo; Obayashi, Hiroshi; Nakamura, Naoto; Fukui, Michiaki

    2016-01-01

    Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2-[(3)H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100 nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes by inducing the LKB1/AMPK signaling pathway.

  6. Glucose uptake-stimulatory activity of Tinospora cordifolia stem extracts in Ehrlich ascites tumor cell model system.

    PubMed

    Joladarashi, Darukeshwara; Chilkunda, Nandini D; Salimath, Paramahans Veerayya

    2014-01-01

    Diabetes mellitus is a multifunctional disorder with several causes and multiple consequences. Nutraceuticals play a vital role in ameliorating diabetic condition. The stems of the plant, Tinospora cordifolia (T. cordifolia) are often used in Ayurvedic medicine for the management of diabetes. Earlier studies have shown that T. cordifolia to be a potent antidiabetic plant material by virtue of being rich in nutraceuticals. In the present study we were interested to know if, T. cordifolia stem extracts are able to promote glucose uptake through glucose transporters, 1 (GLUT1) and 3 (GLUT3), which are responsible for basal glucose uptake. Hence, Ehrlich ascites tumor (EAT) cells were chosen as a model which harbours both GLUT1 and GLUT3 and glucose uptake was measured using a fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG). Serially, solvent extracted T. cordifolia stems, especially water, ethanol and methanol extracts showed glucose uptake activity. Uptake was stimulated in a dose dependent manner at dosages of 1-100 μg. Glucose-stimulating activity does not seem to be solely due to polyphenol content since methanol extract, with high amount of polyphenol content (9.5 ± 0.1 g kg(-1)), did not stimulate higher glucose uptake activity when compared to water extract. PMID:24426067

  7. mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue.

    PubMed

    Albert, Verena; Svensson, Kristoffer; Shimobayashi, Mitsugu; Colombi, Marco; Muñoz, Sergio; Jimenez, Veronica; Handschin, Christoph; Bosch, Fatima; Hall, Michael N

    2016-03-01

    Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin-stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon β-adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold-induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold-induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation. PMID:26772600

  8. Stimulation of glucose uptake by insulin-like growth factor II in human muscle is not mediated by the insulin-like growth factor II/mannose 6-phosphate receptor.

    PubMed Central

    Burguera, B; Elton, C W; Caro, J F; Tapscott, E B; Pories, W J; Dimarchi, R; Sakano, K; Dohm, G L

    1994-01-01

    Although the growth-promoting effects of insulin-like growth factor II (IGF-II) have been intensively studied, the acute actions of this hormone on glucose metabolism have been less well evaluated, especially in skeletal muscle of humans. We and other groups have shown that IGFs reduce glycaemic levels in humans and stimulate glucose uptake in rat muscle. The purpose of the present study was to evaluate the effect of IGF-II on glucose transport in muscle of normal and obese patients with and without non-insulin-dependent diabetes mellitus (NIDDM), as well as to identify the receptor responsible for this action. 2-Deoxyglucose transport was determined in vitro using a muscle-fibre strip preparation. IGF-II were investigated in biopsy material of rectus abdominus muscle taken from lean and obese patients and obese patients with NIDDM at the time of surgery. In the lean group, IGF-II (100 nM) stimulated glucose transport 2.1-fold, which was slightly less than stimulation by insulin (2.8-fold) at the same concentration. Binding of IGF-II was approx. 25% of that of insulin at 1 nM concentrations of both hormones. Obesity with or without NIDDM significantly reduced IGF-II-stimulated glucose uptake compared with the lean group. In order to explore which receptor mediated the IGF-II effect, we compared glucose uptake induced by IGF-II and two IGF-II analogues: [Leu27]IGF-II, with high affinity for the IGF-II/Man 6-P receptor but markedly reduced affinity for the IGF-I and insulin receptors, and [Arg54,Arg55]IGF-II was similar to that of IGF-II, whereas [Leu27]IGF-II had a very diminished effect. Results show that IGF-II is capable of stimulating muscle glucose uptake in lean but not in obese subjects and this effect seems not to be mediated via an IGF-II/Man 6-P receptor. Images Figure 2 PMID:8010960

  9. CD226 reduces endothelial cell glucose uptake under hyperglycemic conditions with inflammation in type 2 diabetes mellitus

    PubMed Central

    Dong, Zilong; Zhang, Jinxue; Sun, Yizheng; Jin, Boquan; Gao, Feng; Guo, Shuzhong; Zhuang, Ran

    2016-01-01

    CD226 is a co-stimulatory adhesion molecule found on immune and endothelial cells. Here, we evaluated a possible role for CD226 in inhibiting glucose uptake in isolated human umbilical vein endothelial cells (HUVECs) and in wild-type (WT) and CD226 knockout (KO) mice with high-fat diet (HFD)-induced type 2 diabetes (T2DM). CD226 expression increased under hyperglycemic conditions in the presence of TNF-α. Furthermore, CD226 knockdown improved glucose uptake in endothelial cells, and CD226 KO mice exhibited increased glucose tolerance. Levels of soluble CD226 in plasma were higher in T2DM patients following an oral glucose tolerance test (OGTT) than under fasting conditions. Our results indicate that low-grade inflammation coupled with elevated blood glucose increases CD226 expression, resulting in decreased endothelial cell glucose uptake in T2DM. PMID:26910838

  10. Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice

    PubMed Central

    Beglopoulos, V.; Tulloch, J.; Roe, A. D.; Daumas, S.; Ferrington, L.; Watson, R.; Fan, Z.; Hyman, B. T.; Kelly, P. A. T.; Bard, F.; Morris, R. G. M.

    2016-01-01

    Earlier diagnosis and treatment of Alzheimer's disease would greatly benefit from the identification of biomarkers at the prodromal stage. Using a prominent animal model of aspects of the disease, we here show using clinically relevant methodologies that very young, pre-pathological PDAPP mice, which overexpress mutant human amyloid precursor protein in the brain, exhibit two cryptic deficits that are normally undetected using standard methods of assessment. Despite learning a spatial memory task normally and displaying normal brain glucose uptake, they display faster forgetting after a long delay following performance to a criterion, together with a strong impairment of brain glucose uptake at the time of attempted memory retrieval. Preliminary observations suggest that these deficits, likely caused by an impairment in systems consolidation, could be rescued by immunotherapy with an anti-β-amyloid antibody. Our data suggest a biomarker strategy for the early detection of β-amyloid-related abnormalities. PMID:27249364

  11. A complex of Rab13 with MICAL-L2 and α-actinin-4 is essential for insulin-dependent GLUT4 exocytosis

    PubMed Central

    Sun, Yi; Jaldin-Fincati, Javier; Liu, Zhi; Bilan, Philip J.; Klip, Amira

    2016-01-01

    Insulin promotes glucose uptake into skeletal muscle through recruitment of glucose transporter 4 (GLUT4) to the plasma membrane. Rab GTPases are molecular switches mobilizing intracellular vesicles, and Rab13 is necessary for insulin-regulated GLUT4–vesicle exocytic translocation in muscle cells. We show that Rab13 engages the scaffold protein MICAL-L2 in this process. RNA interference–mediated knockdown of MICAL-L2 or truncated MICAL-L2 (MICAL-L2-CT) impaired insulin-stimulated GLUT4 translocation. Insulin increased Rab13 binding to MICAL-L2, assessed by pull down and colocalization under confocal fluorescence and structured illumination microscopies. Association was also visualized at the cell periphery using TIRF microscopy. Insulin further increased binding of MICAL-L2 to α-actinin-4 (ACTN4), a protein involved in GLUT4 translocation. Rab13, MICAL-L2, and ACTN4 formed an insulin-dependent complex assessed by pull down and confocal fluorescence imaging. Of note, GLUT4 associated with the complex in response to insulin, requiring the ACTN4-binding domain in MICAL-L2. This was demonstrated by pull down with distinct fragments of MICAL-L2 and confocal and structured illumination microscopies. Finally, expression of MICAL-L2-CT abrogated the insulin-dependent colocalization of Rab13 with ACTN4 or Rab13 with GLUT4. Our findings suggest that MICAL-L2 is an effector of insulin-activated Rab13, which links to GLUT4 through ACTN4, localizing GLUT4 vesicles at the muscle cell periphery to enable their fusion with the membrane. PMID:26538022

  12. Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

    SciTech Connect

    Tomioka, Shigemasa; Kaneko, Miyuki; Satomura, Kazuhito; Mikyu, Tomiko; Nakajo, Nobuyoshi

    2009-10-09

    We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2-{sup 3}H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 {mu}M) significantly increased V{sub max} but not K{sub m} of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

  13. Browning of white adipose tissue uncouples glucose uptake from insulin signaling.

    PubMed

    Mössenböck, Karin; Vegiopoulos, Alexandros; Rose, Adam J; Sijmonsma, Tjeerd P; Herzig, Stephan; Schafmeier, Tobias

    2014-01-01

    Presence of thermogenically active adipose tissue in adult humans has been inversely associated with obesity and type 2 diabetes. While it had been shown that insulin is crucial for the development of classical brown fat, its role in development and function of inducible brown-in-white (brite) adipose tissue is less clear. Here we show that insulin deficiency impaired differentiation of brite adipocytes. However, adrenergic stimulation almost fully induced the thermogenic program under these settings. Although brite differentiation of adipocytes as well as browning of white adipose tissue entailed substantially elevated glucose uptake by adipose tissue, the capacity of insulin to stimulate glucose uptake surprisingly was not higher in the brite state. Notably, in line with the insulin-independent stimulation of glucose uptake, our data revealed that brite recruitment results in induction of solute carrier family 2 (GLUT-1) expression in adipocytes and inguinal WAT. These results for the first time demonstrate that insulin signaling is neither essential for brite recruitment, nor is it improved in cells or tissues upon browning.

  14. 18F-FDG-PET imaging of rat spinal cord demonstrates altered glucose uptake acutely after contusion injury

    PubMed Central

    von Leden, Ramona E.; Selwyn, Reed G.; Jaiswal, Shalini; Wilson, Colin M.; Khayrullina, Guzal; Byrnes, Kimberly R.

    2016-01-01

    Spinal cord injury (SCI) results in an acute reduction in neuronal and glial cell viability, disruption in axonal tract integrity, and prolonged increases in glial activity and inflammation, all of which can influence regional metabolism and glucose utilization. To date, the understanding of glucose uptake and utilization in the injured spinal cord is limited. Positron emission tomography (PET)-based measurements of glucose uptake may therefore serve as a novel bio-marker for SCI. This study aimed to determine the acute and sub-acute glucose uptake pattern after SCI to determine its potential as a novel non-invasive tool for injury assessment and to begin to understand the glucose uptake pattern following acute SCI. Briefly, adult male Sprague-Dawley rats were subjected to moderate contusion SCI, confirmed by locomotor function and histology. PET imaging with [18F]Fluorodeoxyglucose (FDG) was performed prior to injury and at 6 and 24 hours and 15 days post-injury (dpi). FDG-PET imaging revealed significantly depressed glucose uptake at 6 hours post-injury at the lesion epicenter that returned to sham/naïve levels at 24 hours and 15 dpi after moderate injury. FDG uptake at 15 dpi was likely influenced by a combination of elevated glial presence and reduced neuronal viability. These results show that moderate SCI results in acute depression in glucose uptake followed by an increase in glucose uptake that may be related to neuroinflammation. This acute and sub-acute uptake, which is dependent on cellular responses, may represent a therapeutic target. PMID:27084688

  15. Diagnostic perspective of saliva in insulin dependent diabetes mellitus children: An in vivo study

    PubMed Central

    Lakshmi, P. V. S. Deepa; Sridevi, E.; Sai Sankar, A. J.; Manoj Kumar, M. G.; Sridhar, M.; Sujatha, B.

    2015-01-01

    Background and Objectives: The absence, destruction, or loss of β-cells of pancreas results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). Presently, diagnosis and periodic monitoring of diabetes is achieved by evaluating blood glucose levels as it is relatively invasive and dreaded by children. In the light of this, present study was planned to compare salivary glucose values with blood glucose values and the biochemical characteristics of saliva in IDDM children were evaluated and obtained results were compared with the salivary parameters of normal children. Materials and Methods: Thirty IDDM children and 30 healthy children were selected for the study. Fasting blood sample and unstimulated salivary sample were collected from all the subjects and were subjected for analysis. Results: A weak positive correlation was noticed between fasting blood glucose and salivary glucose values in IDDM children. But a mean average of salivary glucose was high in IDDM children when compared with healthy children. The biochemical parameters like acid phosphatase, total protein count, and α-amylase were increased, whereas salivary urea did not show significant variation between the groups. Conclusion: With presently used diagnostic armamentarium, estimation of salivary glucose cannot replace the standard method of estimation of glucose in diabetic mellitus children. The established relationship was very weak with many variations. PMID:26681845

  16. Glucose uptake mediated by glucose transporter 1 is essential for early tooth morphogenesis and size determination of murine molars.

    PubMed

    Ida-Yonemochi, Hiroko; Nakatomi, Mitsushiro; Harada, Hidemitsu; Takata, Hiroki; Baba, Otto; Ohshima, Hayato

    2012-03-01

    Glucose is an essential source of energy for body metabolism and is transported into cells by glucose transporters (GLUTs). Well-characterized class I GLUT is subdivided into GLUTs1-4, which are selectively expressed depending on tissue glucose requirements. However, there is no available data on the role of GLUTs during tooth development. This study aims to clarify the functional significance of class I GLUT during murine tooth development using immunohistochemistry and an in vitro organ culture experiment with an inhibitor of GLUTs1/2, phloretin, and Glut1 and Glut2 short interfering RNA (siRNA). An intense GLUT1-immunoreaction was localized in the enamel organ of bud-stage molar tooth germs, where the active cell proliferation occurred. By the bell stage, the expression of GLUT1 in the dental epithelium was dramatically decreased in intensity, and subsequently began to appear in the stratum intermedium at the late bell stage. On the other hand, GLUT2-immunoreactivity was weakly observed in the whole tooth germs throughout all stages. The inhibition of GLUTs1/2 by phloretin in the bud-stage tooth germs induced the disturbance of primary enamel knot formation, resulting in the developmental arrest of the explants and the squamous metaplasia of dental epithelial cells. Furthermore, the inhibition of GLUTs1/2 in cap-to-bell-stage tooth germs reduced tooth size in a dose dependent manner. These findings suggest that the expression of GLUT1 and GLUT2 in the dental epithelial and mesenchymal cells seems to be precisely and spatiotemporally controlled, and the glucose uptake mediated by GLUT1 plays a crucial role in the early tooth morphogenesis and tooth size determination. PMID:22226978

  17. Coping Styles in Youths with Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Hanson, Cindy L.; And Others

    1989-01-01

    Evaluated relationships between two coping styles and two health outcomes in 135 youth with insulin-dependent diabetes mellitus (IDDM). Found that poor adherence to treatment, older adolescent age, and long duration of IDDM correlated with ventilation and avoidance coping. High ventilation and avoidance coping was predicted by high stress, low…

  18. Effect of Three Statins on Glucose Uptake of Cardiomyocytes and its Mechanism

    PubMed Central

    Jiang, Zhenhuan; Yu, Bo; Li, Yang

    2016-01-01

    Background The aim of this study was to investigate the effects of different statins on glucose uptake and to confirm its mechanism in primary cultured rat cardiomyocytes after administration of atorvastatin, pravastatin, and rosuvastatin. Material/Methods Primary cultured rat cardiomyocytes were randomly assigned to 5 groups: normal control group (OB), insulin group (S1), statin 1-μM (S2), 5-μM (S3), and 10-μM (S4) groups for 3 different statins. The 2-[3H]-DG uptake of each group was determined and the mRNA and protein expression levels of glucose transporter type 4 (GLUT4), insulin receptor substrate (IRs), and RhoA were assessed. Results After treatment with different concentrations of statins and insulin, the 2-[3H]-DG uptake showed a significant negative correlation with the concentration of atorvastatin (P<0.05), and no significant correlation with pravastatin and rosuvastatin. The mRNA and protein expression levels of GLUT4 and IRs-1 in primary cultured cardiomyocytes were both significantly reduced by atorvastatin treatment (P<0.05). Pravastatin and rosuvastatin showed no significant effects on GLUT4 and IRs-1 expression. The mRNA and protein expression levels of RhoA both showed no significant difference when treated with the 3 statins. Conclusions These results confirm that atorvastatin can inhibit insulin-induced glucose uptake in primary cultured rat cardiomyocytes by regulating the PI3K/Akt insulin signal transduction pathway. PMID:27510725

  19. Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes

    PubMed Central

    2004-01-01

    The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10–100 μM. These three flavonoids show a competitive pattern of inhibition, with Ki=16, 33.5 and 90 μM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells. PMID:15469417

  20. Effect of Three Statins on Glucose Uptake of Cardiomyocytes and its Mechanism.

    PubMed

    Jiang, Zhenhuan; Yu, Bo; Li, Yang

    2016-01-01

    BACKGROUND The aim of this study was to investigate the effects of different statins on glucose uptake and to confirm its mechanism in primary cultured rat cardiomyocytes after administration of atorvastatin, pravastatin, and rosuvastatin. MATERIAL AND METHODS Primary cultured rat cardiomyocytes were randomly assigned to 5 groups: normal control group (OB), insulin group (S1), statin 1-μM (S2), 5-μM (S3), and 10-μM (S4) groups for 3 different statins. The 2-[3H]-DG uptake of each group was determined and the mRNA and protein expression levels of glucose transporter type 4 (GLUT4), insulin receptor substrate (IRs), and RhoA were assessed. RESULTS After treatment with different concentrations of statins and insulin, the 2-[3H]-DG uptake showed a significant negative correlation with the concentration of atorvastatin (P<0.05), and no significant correlation with pravastatin and rosuvastatin. The mRNA and protein expression levels of GLUT4 and IRs-1 in primary cultured cardiomyocytes were both significantly reduced by atorvastatin treatment (P<0.05). Pravastatin and rosuvastatin showed no significant effects on GLUT4 and IRs-1 expression. The mRNA and protein expression levels of RhoA both showed no significant difference when treated with the 3 statins. CONCLUSIONS These results confirm that atorvastatin can inhibit insulin-induced glucose uptake in primary cultured rat cardiomyocytes by regulating the PI3K/Akt insulin signal transduction pathway. PMID:27510725

  1. Calcium-calmodulin-dependent kinase II (CaMKII) mediates insulin-stimulated proliferation and glucose uptake.

    PubMed

    Illario, Maddalena; Monaco, Sara; Cavallo, Anna Lina; Esposito, Iolanda; Formisano, Pietro; D'Andrea, Luca; Cipolletta, Ersilia; Trimarco, Bruno; Fenzi, Gianfranco; Rossi, Guido; Vitale, Mario

    2009-05-01

    Cellular growth and glucose uptake are regulated by multiple signals generated by the insulin receptor. The mechanisms of individual modulation of these signals remain somewhat elusive. We investigated the role of CaMKII in insulin signalling in a rat skeletal muscle cell line, demonstrating that CaMKII modulates the insulin action on DNA synthesis and the negative feedback that down regulates glucose uptake. Insulin stimulation generated partly independent signals leading to the rapid activation of Akt, Erk-1/2 and CaMKII. Akt activation was followed by Glut-4 translocation to the plasma membrane and increase of glucose uptake. Then, IRS-1 was phosphorylated at S612, the IRS-1/p85PI3K complex was disrupted, Akt was no more phosphorylated and both Glut-4 translocation and glucose uptake were reduced. Inhibition of CaMKII abrogated the insulin-induced Erk-1/2 activation, DNA synthesis and phosphorylation of IRS-1 at S612. Inhibition of CaMKII also abrogated the down-regulation of insulin-stimulated Akt phosphorylation, Glut-4 membrane translocation and glucose uptake. These results demonstrate that: 1 - CaMKII modulates the insulin-induced Erk-1/2 activation and cell proliferation; 2 - after the initial stimulation of the IRS-1/Akt pathway, CaMKII mediates the down-regulation of stimulated glucose uptake. This represents a novel mechanism in the selective control of insulin signals, and a possible site for pharmacological intervention.

  2. Humoral antibacterial immunity in first degree relatives of insulin-dependent diabetics.

    PubMed

    Schernthaner, G; Ludwig, H; Mayr, W R; Eibl, M

    1978-09-01

    Humoral immunity to bacterial antigens was investigated in 68 tissue typed and glucose tolerance tested first degree blood relatives of insulin dependent diabetics (IDD). The data were compared with those obtained in 60 IDDs and in 55 healthy controls. The prevalence of bacterial antibodies to E. coli, staphylococci, pertussis and diphtheria toxins were just slightly, but not significantly reduced in the blood relations compared with controls. Incidence of antibacterial antibodies was almost identical in blood relations with impaired and in those with normal glucose tolerance. By contrast, antibody formation to E. coli and staphylococci (p less than 0,0005, p less than 0,0005) respectively was significantly impaired in IDD. No correlation between genes of the major histocompatibility complex and humoral antibacterial immunity could be observed in IDD and blood relations. In conclusion, antibacterial antibody formation was found to be severely impaired in IDD patients but to be almost normal in blood relations of insulin dependent diabetics. These findings suggest that the humoral antibacterial immunodeficiency observed in IDD is a disease associated process probably independent of major histocompatibility complex linked genes. PMID:710677

  3. Coupling of glutamate and glucose uptake in cultured Bergmann glial cells.

    PubMed

    Mendez-Flores, Orquidia G; Hernández-Kelly, Luisa C; Suárez-Pozos, Edna; Najimi, Mustapha; Ortega, Arturo

    2016-09-01

    Glutamate, the main excitatory neurotransmitter in the vertebrate brain, exerts its actions through specific membrane receptors present in neurons and glial cells. Over-stimulation of glutamate receptors results in neuronal death, phenomena known as excitotoxicity. A family of sodium-dependent, glutamate uptake transporters mainly expressed in glial cells, removes the amino acid from the synaptic cleft preventing neuronal death. The sustained sodium influx associated to glutamate removal in glial cells, activates the sodium/potassium ATPase restoring the ionic balance, additionally, glutamate entrance activates glutamine synthetase, both events are energy demanding, therefore glia cells increase their ATP expenditure favouring glucose uptake, and triggering several signal transduction pathways linked to proper neuronal glutamate availability, via the glutamate/glutamine shuttle. To further characterize these complex transporters interactions, we used the well-established model system of cultured chick cerebellum Bergmann glia cells. A time and dose-dependent increase in the activity, plasma membrane localization and protein levels of glucose transporters was detected upon d-aspartate exposure. Interestingly, this increase is the result of a protein kinase C-dependent signaling cascade. Furthermore, a glutamate-dependent glucose and glutamate transporters co-immunoprecipitation was detected. These results favour the notion that glial cells are involved in glutamatergic neuronal physiology. PMID:27184733

  4. Magnetic Resonance Imaging of Glucose Uptake and Metabolism in Patients with Head and Neck Cancer.

    PubMed

    Wang, Jihong; Weygand, Joseph; Hwang, Ken-Pin; Mohamed, Abdallah S R; Ding, Yao; Fuller, Clifton D; Lai, Stephen Y; Frank, Steven J; Zhou, Jinyuan

    2016-01-01

    Imaging metabolic dysfunction, a hallmark of solid tumors, usually requires radioactive tracers. Chemical exchange saturation transfer (CEST) imaging can potentially detect and visualize glucose uptake and metabolism, without the need for radioisotopes. Here, we tested the feasibility of using glucose CEST (glucoCEST) to image unlabeled glucose uptake in head and neck cancer by using a clinical 3T magnetic resonance imaging (MRI) scanner. The average CEST contrast between tumors and normal tissue in 17 patients was 7.58% (P = 0.006) in the 3-4 ppm offset frequency range and 5.06% (P = 0.02) in 1-5 ppm range. In a subgroup of eight patients, glucoCEST signal enhancement was higher in tumors than in normal muscle (4.98% vs. 1.28%, P < 0.021). We conclude that glucoCEST images of head and neck cancer can be obtained with a clinical 3T MRI scanner. PMID:27461165

  5. Magnetic Resonance Imaging of Glucose Uptake and Metabolism in Patients with Head and Neck Cancer

    PubMed Central

    Wang, Jihong; Weygand, Joseph; Hwang, Ken-Pin; Mohamed, Abdallah S. R.; Ding, Yao; Fuller, Clifton D.; Lai, Stephen Y.; Frank, Steven J.; Zhou, Jinyuan

    2016-01-01

    Imaging metabolic dysfunction, a hallmark of solid tumors, usually requires radioactive tracers. Chemical exchange saturation transfer (CEST) imaging can potentially detect and visualize glucose uptake and metabolism, without the need for radioisotopes. Here, we tested the feasibility of using glucose CEST (glucoCEST) to image unlabeled glucose uptake in head and neck cancer by using a clinical 3T magnetic resonance imaging (MRI) scanner. The average CEST contrast between tumors and normal tissue in 17 patients was 7.58% (P = 0.006) in the 3–4 ppm offset frequency range and 5.06% (P = 0.02) in 1–5 ppm range. In a subgroup of eight patients, glucoCEST signal enhancement was higher in tumors than in normal muscle (4.98% vs. 1.28%, P < 0.021). We conclude that glucoCEST images of head and neck cancer can be obtained with a clinical 3T MRI scanner. PMID:27461165

  6. Preconditioning L6 Muscle Cells with Naringin Ameliorates Oxidative Stress and Increases Glucose Uptake

    PubMed Central

    Dhanya, R.; Arun, K. B.; Nisha, V. M.; Syama, H. P.; Nisha, P.; Santhosh Kumar, T. R.; Jayamurthy, P.

    2015-01-01

    Enhanced oxidative stress contributes to pathological changes in diabetes and its complications. Thus, strategies to reduce oxidative stress may alleviate these pathogenic processes. Herein, we have investigated Naringin mediated regulation of glutathione (GSH) & intracellular free radical levels and modulation of glucose uptake under oxidative stress in L6 cell lines. The results from the study demonstrated a marked decrease in glutathione with a subsequent increase in free radical levels, which was reversed by the pretreatment of Naringin. We also observed that the increased malondialdehyde level, the marker of lipid peroxidation on induction of oxidative stress was retrieved on Naringin pretreatment. Addition of Naringin (100 μM) showed approximately 40% reduction in protein glycation in vitro. Furthermore, we observed a twofold increase in uptake of fluorescent labeled glucose namely 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2 - NBDG) on Naringin treatment in differentiated L6 myoblast. The increased uptake of 2-NBDG by L6 myotubes may be attributed due to the enhanced translocation of GLUT4. Our results demonstrate that Naringin activate GSH synthesis through a novel antioxidant defense mechanism against excessive Reactive Oxygen Species (ROS) production, contributing to the prevention of oxidative damage in addition to its effect on glycemic control. PMID:26147673

  7. BRAF inhibition decreases cellular glucose uptake in melanoma in association with reduction in cell volume

    PubMed Central

    Theodosakis, Nicholas; Held, Matthew A.; Marzuka-Alcala, Alexander; Meeth, Katrina M.; Micevic, Goran; Long, Georgina V.; Scolyer, Richard A.; Stern, David F.; Bosenberg, Marcus W.

    2015-01-01

    BRAF kinase inhibitors have dramatically impacted treatment of BRAFV600E/K-driven metastatic melanoma. Early responses assessed using [18F]fluorodeoxyglucose uptake-positron emission tomography (FDG-PET) have shown dramatic reduction of radiotracer signal within two weeks of treatment. Despite high response rates, relapse occurs in nearly all cases, frequently at sites of treated metastatic disease. It remains unclear whether initial loss of 18FDG uptake is due to tumor cell death or other reasons. Here we provide evidence of melanoma cell volume reduction in a patient cohort treated with BRAF inhibitors. We present data demonstrating that BRAF inhibition reduces melanoma glucose uptake per cell, but that this change is no longer significant following normalization for cell volume changes. We also demonstrate that volume normalization greatly reduces differences in transmembrane glucose transport and hexokinase-mediated phosphorylation. Mechanistic studies suggest that this loss of cell volume is due in large part to decreases in new protein translation as a consequence of vemurafenib treatment. Ultimately, our findings suggest that cell volume regulation constitutes an important physiologic parameter that may significantly contribute to radiographic changes observed in clinic. PMID:25948295

  8. Generalized sensory stimulation of conscious rats increases labeling of oxidative pathways of glucose metabolism when the brain glucose-oxygen uptake ratio rises.

    PubMed

    Dienel, Gerald A; Wang, Robert Y; Cruz, Nancy F

    2002-12-01

    Interpretation of functional metabolic brain images requires understanding of metabolic shifts in working brain. Because the disproportionately higher uptake of glucose compared with oxygen ("aerobic glycolysis") during sensory stimulation is not fully explained by changes in levels of lactate or glycogen, metabolic labeling by [6-14C]glucose was used to evaluate utilization of glucose during brief brain activation. Increased labeling of tricarboxylic acid cycle-derived amino acids, mainly glutamate but also gamma-aminobutyric acid, reflects a rise in oxidative metabolism during aerobic glycolysis. The size of the glutamate, lactate, alanine, and aspartate pools changed during stimulation. Brain lactate was derived from blood-borne glucose and its specific activity was twice that of alanine, revealing pyruvate compartmentation. Glycogen labeling doubled during recovery compared with rest and activation; only 4% to 8% of the total 14C was recovered in lactate plus glycogen. Restoration of glycogen levels was slow, and diversion of glucose from oxidative pathways to restore its level could cause a prolonged reduction of the global O2/glucose uptake ratio. The rise in the brain glucose-oxygen uptake ratio during activation does not simply reflect an upward shift of glycolysis under aerobic conditions; instead, it involves altered fluxes into various (oxidative and biosynthetic) pathways with different time courses.

  9. Glycaemic effects of bread and marmalade in insulin-dependent diabetes.

    PubMed

    Lean, M E; Tennison, B R; Williams, D R

    1985-03-01

    The glycaemic responses of 12 C-peptide negative insulin-dependent diabetics were studied following four breakfasts with different carbohydrate sources. Total energy content of the meals was the usual for each subject, carbohydrate supplying 55% and fat 32%. The meals comprised: wholemeal bread with margarine; white bread with margarine; marmalade made with sucrose, and cheddar cheese; and marmalade (22% of total energy) on wholemeal bread with margarine. The study demonstrated powerfully that there were no statistically significant or clinically relevant differences between the meals in post-prandial glucose peak elevation, or in incremental area under the blood glucose curve to 120 mins. On these grounds, sucrose, in amounts considered acceptable to the general population, need not be prohibited from diabetic diets.

  10. Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal.

    PubMed

    Domingo-Espín, Joan; Lindahl, Maria; Nilsson-Wolanin, Oktawia; Cushman, Samuel W; Stenkula, Karin G; Lagerstedt, Jens O

    2016-07-01

    Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I-stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes. PMID:27207515

  11. Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal.

    PubMed

    Domingo-Espín, Joan; Lindahl, Maria; Nilsson-Wolanin, Oktawia; Cushman, Samuel W; Stenkula, Karin G; Lagerstedt, Jens O

    2016-07-01

    Apolipoprotein A-I (apoA-I) of HDL is central to the transport of cholesterol in circulation. ApoA-I also provides glucose control with described in vitro effects of apoA-I on β-cell insulin secretion and muscle glucose uptake. In addition, apoA-I injections in insulin-resistant diet-induced obese (DIO) mice lead to increased glucose-stimulated insulin secretion (GSIS) and peripheral tissue glucose uptake. However, the relative contribution of apoA-I as an enhancer of GSIS in vivo and as a direct stimulator of insulin-independent glucose uptake is not known. Here, DIO mice with instant and transient blockade of insulin secretion were used in glucose tolerance tests and in positron emission tomography analyses. Data demonstrate that apoA-I to an equal extent enhances GSIS and acts as peripheral tissue activator of insulin-independent glucose uptake and verify skeletal muscle as an apoA-I target tissue. Intriguingly, our analyses also identify the heart as an important target tissue for the apoA-I-stimulated glucose uptake, with potential implications in diabetic cardiomyopathy. Explorations of apoA-I as a novel antidiabetic drug should extend to treatments of diabetic cardiomyopathy and other cardiovascular diseases in patients with diabetes.

  12. Reduced glucose uptake and Aβ in brain regions with hyperintensities in connected white matter

    PubMed Central

    Rusinek, H.; Tsui, W.; Mosconi, L.; Li, Y.; Osorio, R.S.; Williams, S.; Randall, C.; Spector, N.; McHugh, P.; Murray, J.; Pirraglia, E.; Vallabhajosula, S.; Raj, A.; de Leon, M.J.

    2014-01-01

    Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDGPET) in connected GM. WML masks from 72 cognitively normal (age 61.7±9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r=0.20, p<0.05 corrected) and lower PiB uptake (r=0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (β=0.045) and FDG-PET (β=0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition. PMID:24999038

  13. Reduced glucose uptake and Aβ in brain regions with hyperintensities in connected white matter.

    PubMed

    Glodzik, L; Kuceyeski, A; Rusinek, H; Tsui, W; Mosconi, L; Li, Y; Osorio, R S; Williams, S; Randall, C; Spector, N; McHugh, P; Murray, J; Pirraglia, E; Vallabhajosula, S; Raj, A; de Leon, M J

    2014-10-15

    Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDG-PET) in connected GM. WML masks from 72 cognitively normal (age 61.7 ± 9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r = 0.20, p<0.05 corrected) and lower PiB uptake (r = 0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (β = 0.045) and FDG-PET (β = 0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition.

  14. Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes.

    PubMed

    Li, Yiming; Tran, Van H; Duke, Colin C; Roufogalis, Basil D

    2012-09-01

    In this study we investigate the active constituents of the rhizome of Zingiber officinale, Roscoe (ginger) and determine their activity on glucose uptake in cultured L6 myotubes and the molecular mechanism underlying this action. Freeze-dried ginger powder was extracted with ethyl acetate (1 kg/3 L) to give the total ginger extract, which was then separated into seven fractions, consisting of nonpolar to moderately polar compounds, using a short-column vacuum chromatographic method. The most active fraction (F7) was further purified for identification of its active components. The effect of the extract, fractions, and purified compounds on glucose uptake was evaluated using radioactive labelled 2-[1,2-³H]-deoxy-D-glucose in L6 myotubes. The pungent phenolic gingerol constituents were identified as the major active compounds in the ginger extract enhancing glucose uptake. (S)-[6]-Gingerol was the most abundant component among the gingerols, however, (S)-[8]-gingerol was the most potent on glucose uptake. The activity of (S)-[8]-gingerol was found to be associated primarily with an increase in surface distribution of GLUT4 protein on the L6 myotube plasma membrane, as detected by expression of hemagglutinin epitope-tagged GLUT4 in L6 muscle cells. The enhancement of glucose uptake in L6 rat skeletal muscle cells by the gingerol pungent principles of the ginger extract supports the potential of ginger and its pungent components for the prevention and management of hyperglycemia and type 2 diabetes. PMID:22828920

  15. Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

    PubMed Central

    Kristensen, Jonas Møller; Treebak, Jonas T.; Schjerling, Peter; Goodyear, Laurie

    2014-01-01

    Metformin-induced activation of the 5′-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P < 0.01) but not of AMPK KD mice. Insulin signaling at the level of Akt protein expression or Thr308 and Ser473 phosphorylation was not changed by metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr308/Ser473 and TBC1D4 Thr642/Ser711 phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment. PMID:24644243

  16. Vibrational imaging of glucose uptake activity in live cells and tissues by stimulated Raman scattering microscopy (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hu, Fanghao; Chen, Zhixing; Zhang, Luyuan; Shen, Yihui; Wei, Lu; Min, Wei

    2016-03-01

    Glucose is consumed as an energy source by virtually all living organisms, from bacteria to humans. Its uptake activity closely reflects the cellular metabolic status in various pathophysiological transformations, such as diabetes and cancer. Extensive efforts such as positron emission tomography, magnetic resonance imaging and fluorescence microscopy have been made to specifically image glucose uptake activity but all with technical limitations. Here, we report a new platform to visualize glucose uptake activity in live cells and tissues with subcellular resolution and minimal perturbation. A novel glucose analogue with a small alkyne tag (carbon-carbon triple bond) is developed to mimic natural glucose for cellular uptake, which can be imaged with high sensitivity and specificity by targeting the strong and characteristic alkyne vibration on stimulated Raman scattering (SRS) microscope to generate a quantitative three dimensional concentration map. Cancer cells with differing metabolic characteristics can be distinguished. Heterogeneous uptake patterns are observed in tumor xenograft tissues, neuronal culture and mouse brain tissues with clear cell-cell variations. Therefore, by offering the distinct advantage of optical resolution but without the undesirable influence of bulky fluorophores, our method of coupling SRS with alkyne labeled glucose will be an attractive tool to study energy demands of living systems at the single cell level.

  17. Functional expression of the glucose transporter of Zymomonas mobilis leads to restoration of glucose and fructose uptake in Escherichia coli mutants and provides evidence for its facilitator action.

    PubMed Central

    Weisser, P; Krämer, R; Sahm, H; Sprenger, G A

    1995-01-01

    The Zymomonas mobilis genes encoding the glucose facilitator (glf), glucokinase (glk), or fructokinase (frk) were cloned and expressed in a lacIq-Ptac system using Escherichia coli K-12 mutants deficient in uptake and phosphorylation of glucose and fructose. Growth on glucose or fructose was restored when the respective genes (glf-glk or glf-frk) were expressed. In E. coli glf+ strains, both glucose and fructose were taken up via facilitated diffusion (Km, 4.1 mM for glucose and 39 mM for fructose; Vmax at 15 degrees C, 75 and 93 nmol min-1 mg-1 [dry weight] for glucose and fructose, respectively). For both substrates, counterflow maxima were observed. PMID:7768841

  18. Compensatory responses of the insulin signaling pathway restore muscle glucose uptake following long-term denervation

    PubMed Central

    Callahan, Zachary J; Oxendine, Michael; Wheatley, Joshua L; Menke, Chelsea; Cassell, Emily A; Bartos, Amanda; Geiger, Paige C; Schaeffer, Paul J

    2015-01-01

    We investigated the role of muscle activity in maintaining normal glucose homeostasis via transection of the sciatic nerve, an extreme model of disuse atrophy. Mice were killed 3, 10, 28, or 56 days after transection or sham surgery. There was no difference in muscle weight between sham and transected limbs at 3 days post surgery, but it was significantly lower following transection at the other three time points. Transected muscle weight stabilized by 28 days post surgery with no further loss. Myocellular cross-sectional area was significantly smaller at 10, 28, and 56 days post transection surgery. Additionally, muscle fibrosis area was significantly greater at 56 days post transection. In transected muscle there was reduced expression of genes encoding transcriptional regulators of metabolism (PPARα, PGC-1α, PGC-1β, PPARδ), a glycolytic enzyme (PFK), a fatty acid transporter (M-CPT 1), and an enzyme of mitochondrial oxidation (CS) with transection. In denervated muscle, glucose uptake was significantly lower at 3 days but was greater at 56 days under basal and insulin-stimulated conditions. Although GLUT 4 mRNA was significantly lower at all time points in transected muscle, Western blot analysis showed greater expression of GLUT4 at 28 and 56 days post surgery. GLUT1 mRNA was unchanged; however, GLUT1 protein expression was also greater in transected muscles. Surgery led to significantly higher protein expression for Akt2 as well as higher phosphorylation of Akt. While denervation may initially lead to reduced glucose sensitivity, compensatory responses of insulin signaling appeared to restore and improve glucose uptake in long-term-transected muscle. PMID:25896980

  19. Highly variable gastric emptying in patients with insulin dependent diabetes mellitus.

    PubMed Central

    Nowak, T V; Johnson, C P; Kalbfleisch, J H; Roza, A M; Wood, C M; Weisbruch, J P; Soergel, K H

    1995-01-01

    Some diabetic patients--particularly those with nausea and vomiting--frequently have evidence of delayed gastric emptying while other diabetic patients may in fact exhibit accelerated gastric emptying. Whether the presence or absence of symptoms of upper gastrointestinal dysfunction correlated with objective measures of gastric emptying in insulin dependent diabetic subjects was investigated. Twenty one insulin dependent diabetic patients underwent a solid phase gastric emptying scintiscan using in vivo labelled chicken liver. Thirteen patients had symptoms suggestive of gastrointestinal dysfunction (nausea, vomiting, early satiety, or constipation), while eight patients had no gastrointestinal symptoms. Eleven patients had orthostatic hypotension. All patients had been diabetic since childhood or adolescence. As a group, the diabetic patients showed a half time (T50) of gastric emptying (mean (SD) 150.0 min (163.7) that was not significantly different from that of 12 healthy control subjects (148.1 min (62.4)). Those diabetic patients without gastrointestinal symptoms and without orthostatic hypotension, however, showed a gastric emptying half time (70.1 min (41.6)) that was significantly faster than that of the control subjects. Conversely, those diabetic patients with nausea, vomiting, and early satiety (or early satiety alone) showed T50 values that were significantly greater than those of the diabetic patients without these symptoms. No correlation was found between the T50 value and the duration of diabetes, the fasting blood glucose at the time of study, or the respiratory variation in heart rate (E:I ratio). These observations indicate that highly variable rates of gastric emptying occur in insulin dependent diabetic patients, and that accelerated gastric emptying may occur in diabetic patients who have no symptoms of gastrointestinal dysfunction. PMID:7672674

  20. Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism

    SciTech Connect

    Moreira, Liliana; Araújo, Isabel; Costa, Tito; Correia-Branco, Ana; Faria, Ana; Martel, Fátima; Keating, Elisa

    2013-07-15

    In this study we characterized {sup 3}H-2-deoxy-D-glucose ({sup 3}H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon {sup 3}H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells {sup 3}H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (V{sub max}) and affinity (K{sub m}), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin-stimulated. This suggests that {sup 3}H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited {sup 3}H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4 h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. -- Highlights: • Glucose uptake by MCF7 and MDA-MB-231 cells is mainly mediated by GLUT1. • QUE and EGCG inhibit cellular glucose uptake thus abolishing the Warburg effect. • This process induces cytotoxicity and proliferation arrest in MCF7 cells. • The flavonoids’ effects are independent of estrogen receptor signalling.

  1. Characterization of Secondary Metabolites from Purple Ipomoea batatas Leaves and Their Effects on Glucose Uptake.

    PubMed

    Lee, Chia-Lin; Lee, Shou-Lun; Chen, Chao-Jung; Chen, Hsin-Chun; Kao, Ming-Ching; Liu, Chuan-Hao; Chen, Jau-Yang; Lai, Yen-Ting; Wu, Yang-Chang

    2016-01-01

    Ipomoea batatas has long been used in folk medicine for the treatment of hyperglycemia or as a food additive for the prevention of type 2 diabetes. However, neither the plant extract nor its active components have been evaluated systematically. In this work four crude extracts, including n-hexane- (IBH), 95% MeOH- (IBM), n-BuOH- (IBB), and H₂O-soluble (IBW) fractions, were prepared by fractionation of a methanolic extract of purple I. batatas leaves. Twenty-four pure compounds 1-24 were then isolated by various chromatographic techniques and their structures identified from NMR and MS data. Glucose uptake assays in differentiated 3T3-L1 adipocytes and rat primary hepatocytes, as well as western blot analysis, were carried out to evaluate the antidiabetic activity of this species. The IBH crude fraction, with methyl decanoate (22) as a major and active compound, showed the greatest effect on glucose uptake, most likely via activation of Glut4 and regulation of the PI3K/AKT pathway. Quercetin 3-O-β-d-sophoroside (1), quercetin (3), benzyl β-d-glucoside (10), 4-hydroxy-3-methoxybenzaldehyde (12), and methyl decanoate (22) could be important components contributing to the antidiabetic effects. We conclude that purple I. batatas leaves have potential as an antidiabetic plant source and the active constituents 1, 3, 10, 12, and 22 are promising lead candidates for future investigation. PMID:27338312

  2. Dual role for myosin II in GLUT4-mediated glucose uptake in 3T3-L1 adipocytes

    SciTech Connect

    Fulcher, F. Kent; Smith, Bethany T.; Russ, Misty; Patel, Yashomati M.

    2008-10-15

    Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles to the plasma membrane. Our previous studies demonstrated that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. The experiments described in this report are the first to show a dual role for the myosin IIA isoform specifically in regulating insulin-stimulated glucose uptake in adipocytes. We demonstrate that inhibition of MLCK but not RhoK results in impaired insulin-stimulated glucose uptake. Furthermore, our studies show that insulin specifically stimulates the phosphorylation of the RLC associated with the myosin IIA isoform via MLCK. In time course experiments, we determined that GLUT4 translocates to the plasma membrane prior to myosin IIA recruitment. We further show that recruitment of myosin IIA to the plasma membrane requires that myosin IIA be activated via phosphorylation of the RLC by MLCK. Our findings also reveal that myosin II is required for proper GLUT4-vesicle fusion at the plasma membrane. We show that once at the plasma membrane, myosin II is involved in regulating the intrinsic activity of GLUT4 after insulin stimulation. Collectively, our results are the first to reveal that myosin IIA plays a critical role in mediating insulin-stimulated glucose uptake in 3T3-LI adipocytes, via both GLUT4 vesicle fusion at the plasma membrane and GLUT4 activity.

  3. Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus.

    PubMed

    Ghorbani, Ahmad; Shafiee-Nick, Reza

    2015-02-15

    Diabetes is associated with several complications such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. Currently, insulin is the main used medication for management of insulin-dependent diabetes mellitus (type-1 diabetes). In this metabolic syndrome, in addition to decrease of endogenous insulin, the plasma level of connecting peptide (C-peptide) is also reduced due to beta cell destruction. Studies in the past decade have shown that C-peptide is much more than a byproduct of insulin biosynthesis and possess different biological activities. Therefore, it may be possible that C-peptide deficiency be involved, at least in part, in the development of different complications of diabetes. It has been shown that a small level of remaining C-peptide is associated with significant metabolic benefit. The purpose of this review is to describe beneficial effects of C-peptide replacement on pathological features associated with insulin-dependent diabetes. Also, experimental and clinical findings on the effects of C-peptide on whole-body glucose utilization, adipose tissue metabolism and tissues blood flow are summarized and discussed. The hypoglycemic, antilipolytic and vasodilator effects of C-peptide suggest that it may contribute to fine-tuning of the tissues metabolism under different physiologic or pathologic conditions. Therefore, C-peptide replacement together with the classic insulin therapy may prevent, retard, or ameliorate diabetic complications in patients with type-1 diabetes. PMID:25685285

  4. Chlorpropamide-alcohol flushing: a definition of its relation to non-insulin-dependent diabetes.

    PubMed

    Pyke, D A; Leslie, R D

    1978-12-01

    The single-challenge test for chlorpropamide-alcohol flushing (CPAF) was used to study two groups of patients with non-insulin-dependent diabetes and a family history of the disease who were distinguished only by their age at diagnosis (under and over 30). Their relatives were also studied. The proportions of patients showing CPAF in both groups were similar, and the family histories suggested dominant inheritance. When offspring of diabetics in whom the disease was diagnosed early were studied CPAF seemed to precede the appearance of diabetes. We conclude that the patients in both groups had the same, distinct syndrome, which is characterised by diabetes diagnosed at any age that is inherited as an autosomal dominant trait and associated with CPAF. This syndrome, which constitutes about one-fifth of all cases of non-insulin-dependent diabetes, may be detected with a single-challenge CPAF test before the onset of glucose intolerance. CPAF therefore acts as a genetic marker for the syndrome. PMID:728708

  5. Cardiovascular complications of non-insulin-dependent diabetes: the JCR:LA-cp rat.

    PubMed

    Clark, T A; Pierce, G N

    2000-01-01

    Diabetes is a serious medical and financial burden on western societies. It is the seventh leading cause of death in the United States and Canada. The disease is due to a primary defect in glucose tolerance and carbohydrate metabolism resulting from either a deficiency of insulin (Insulin-dependent (type I) diabetes mellitus - IDDM) or a state of insulin resistance (Non-insulin-dependent (type II) diabetes mellitus - NIDDM). NIDDM comprises greater than 80% of total diabetic cases. Associated with the primary metabolic defects are equally deleterious secondary complications affecting the renal, ocular, nervous and cardiovascular systems. The cardiovascular complications account for a major proportion of diabetic mortality. As such, it is of paramount importance to develop or find an animal model expressing complications homologous to the human condition. Many models of NIDDM are available to the diabetic researcher but choosing an accurate one can be difficult. The following compares the advantages and limitations of one such model, the JCR:LA-cp rat to other NIDDM models commonly used today.

  6. Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells.

    PubMed

    Chin, Emily N; Martin, Joshua A; Kim, Soyoung; Fakhraldeen, Saja A; Alexander, Caroline M

    2016-03-01

    Lrp5 is typically described as a Wnt signaling receptor, albeit a less effective Wnt signaling receptor than the better-studied sister isoform, Lrp6. Here we show that Lrp5 is only a minor player in the response to Wnt3a-type ligands in mammary epithelial cells; instead, Lrp5 is required for glucose uptake, and glucose uptake regulates the growth rate of mammary epithelial cells in culture. Thus, a loss of Lrp5 leads to profound growth suppression, whether growth is induced by serum or by specific growth factors, and this inhibition is not due to a loss of Wnt signaling. Depletion of Lrp5 decreases glucose uptake, lactate secretion, and oxygen consumption rates; inhibition of glucose consumption phenocopies the loss of Lrp5 function. Both Lrp5 knockdown and low external glucose induce mitochondrial stress, as revealed by the accumulation of reactive oxygen species (ROS) and the activation of the ROS-sensitive checkpoint, p38α. In contrast, loss of function of Lrp6 reduces Wnt responsiveness but has little impact on growth. This highlights the distinct functions of these two Lrp receptors and an important Wnt ligand-independent role of Lrp5 in glucose uptake in mammary epithelial cells. PMID:26711269

  7. Lrp5 Has a Wnt-Independent Role in Glucose Uptake and Growth for Mammary Epithelial Cells

    PubMed Central

    Chin, Emily N.; Martin, Joshua A.; Kim, Soyoung; Fakhraldeen, Saja A.

    2015-01-01

    Lrp5 is typically described as a Wnt signaling receptor, albeit a less effective Wnt signaling receptor than the better-studied sister isoform, Lrp6. Here we show that Lrp5 is only a minor player in the response to Wnt3a-type ligands in mammary epithelial cells; instead, Lrp5 is required for glucose uptake, and glucose uptake regulates the growth rate of mammary epithelial cells in culture. Thus, a loss of Lrp5 leads to profound growth suppression, whether growth is induced by serum or by specific growth factors, and this inhibition is not due to a loss of Wnt signaling. Depletion of Lrp5 decreases glucose uptake, lactate secretion, and oxygen consumption rates; inhibition of glucose consumption phenocopies the loss of Lrp5 function. Both Lrp5 knockdown and low external glucose induce mitochondrial stress, as revealed by the accumulation of reactive oxygen species (ROS) and the activation of the ROS-sensitive checkpoint, p38α. In contrast, loss of function of Lrp6 reduces Wnt responsiveness but has little impact on growth. This highlights the distinct functions of these two Lrp receptors and an important Wnt ligand-independent role of Lrp5 in glucose uptake in mammary epithelial cells. PMID:26711269

  8. Coordinated Regulation of Vasopressin Inactivation and Glucose Uptake by Action of TUG Protein in Muscle*

    PubMed Central

    Habtemichael, Estifanos N.; Alcázar-Román, Abel; Rubin, Bradley R.; Grossi, Laura R.; Belman, Jonathan P.; Julca, Omar; Löffler, Michael G.; Li, Hongjie; Chi, Nai-Wen; Samuel, Varman T.; Bogan, Jonathan S.

    2015-01-01

    In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, TUG, to promote GLUT4 translocation and glucose uptake. Here we show that TUG proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive TUG proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to TUG, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in TUG-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which TUG controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake. PMID:25944897

  9. Production of extracellular protease and glucose uptake in Bacillus clausii in steady-state and transient continuous cultures.

    PubMed

    Christiansen, Torben; Nielsen, Jens

    2002-08-28

    The production of the extracellular alkaline protease Savinase (EC 3.4.21.62) and glucose uptake in a non-sporulating strain of Bacillus clausii were investigated by analysing steady-state and transients during continuous cultivations. The specific production rate was found to have an optimum at a dilution rate between 0.14 and 0.17 h(-1), whereas the yield of Savinase on glucose was found to increase with decreasing specific growth rate. A linear relationship between the ribosomal RNA content and the specific production rate was found, indicating that the translational capacity may be limiting for product formation. The dynamics of the production of Savinase were studied during step changes in the dilution rate. During a step down in the dilution rate the specific production rate decreased immediately until it reached a new steady value. During a step-up an initial cease in the production rate was observed, but when glucose stopped to accumulate the production rate was regained. The glucose uptake was further investigated when chemostat cultures growing at different dilution rates were exposed to glucose pulses. The maximal glucose uptake capacity was found to be dependent on the initial specific growth rate. Furthermore, the adaptation to high glucose concentrations was faster at high dilution rates than at low dilution rates. PMID:12084482

  10. [The normalisation of blood sugar using a non-miniaturised artifical pancreas. Application for 24 hours in 7 insulin-dependent diabetics (author's transl)].

    PubMed

    Slama, G; Klein, J C; Tardieu, M C; Tchobroutsky, G

    1977-06-25

    Seven insulin-dependent diabetic were treated for 24 to 36 hours by intravenous injections of insulin adapted to variations in blood glucose using a fairly voluminous automatic regulation device. This artificial pancreas consists of a modified Technicon blood sugar apparatus which provides continuous estimation of blood glucose using non-haemolysed whole blood by a glucose oxidase method with an inertia time of 6 minutes, a table calculator and a newly developed interpretation and command electronic unit (GlucostatR). Normalisation of blood glucose was obtained for at least 24 hours, during and between meals, during a period following an oral glucose load and throughout the night.

  11. Dibenzoylmethane Exerts Metabolic Activity through Regulation of AMP-Activated Protein Kinase (AMPK)-Mediated Glucose Uptake and Adipogenesis Pathways

    PubMed Central

    Kim, Nami; Kim, Hong Min; Lee, Eun Soo; Lee, Jung Ok; Lee, Hye Jeong; Lee, Soo Kyung; Moon, Ji Wook; Kim, Ji Hae; Kim, Joong Kwan; Kim, Su Jin; Park, Sun Hwa; Chung, Choon Hee; Kim, Hyeon Soo

    2015-01-01

    Dibenzoylmethane (DBM) has been shown to exert a variety of beneficial effects on human health. However, the mechanism of action is poorly understood. In this study, DBM increased phosphorylation of AMP-activated protein kinase (AMPK) and stimulated glucose uptake in a skeletal muscle cell line. Both knockdown of AMPK with siRNA and inhibition with AMPK inhibitor blocked DBM-induced glucose uptake. DBM increased the concentration of intracellular calcium and glucose uptake due to DBM was abolished by STO-609 (a calcium/calmodulin-dependent protein kinase inhibitor). DBM stimulated phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which was blocked by pretreatment with compound C, an AMPK inhibitor. The expression of glucose transporter type 4 (GLUT4) was increased by DBM. The translocation of GLUT4 to the plasma membrane was also increased by DBM in AMPK dependently. In addition, DBM suppressed weight gain and prevented fat accumulation in the liver and abdomen in mice fed a high-fat diet. In pre-adipocyte cells, DBM decreased the activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis. Expression of the adipogenic gene, fatty acid synthase (FAS), was suppressed by DBM in an AMPK-dependent manner. These results showed that the beneficial metabolic effects of DBM might be due to regulation of glucose uptake via AMPK in skeletal muscle and inhibition of adipogenesis in pre-adipocytes. PMID:25756788

  12. Uptake and metabolism of D-glucose in isolated acinar and ductal cells from rat submandibular glands.

    PubMed

    Cetik, Sibel; Rzajeva, Aigun; Hupkens, Emeline; Malaisse, Willy J; Sener, Abdullah

    2014-07-01

    The present study deals with the possible effects of selected environmental agents upon the uptake and metabolism of d-glucose in isolated acinar and ductal cells from the rat submandibular salivary gland. In acinar cells, the uptake of d-[U-(14) C]glucose and its non-metabolised analogue 3-O-[(14) C-methyl]-d-glucose was not affected significantly by phloridzin (0.1 mM) or substitution of extracellular NaCl (115 mM) by an equimolar amount of CsCl, whilst cytochalasin B (20 μM) decreased significantly such an uptake. In ductal cells, both phloridzin and cytochalasin B decreased the uptake of d-glucose and 3-O-methyl-d-glucose. Although the intracellular space was comparable in acinar and ductal cells, the catabolism of d-glucose (2.8 or 8.3 mM) was two to four times higher in ductal cells than in acinar cells. Phloridzin (0.1 mM), ouabain (1.0 mM) and cytochalasin B (20 μM) all impaired d-glucose catabolism in ductal cells. Such was also the case in ductal cells incubated in the absence of extracellular Ca(2+) or in media in which NaCl was substituted by CsCl. It is proposed that the ductal cells in the rat submandibular gland are equipped with several systems mediating the insulin-sensitive, cytochalasin B-sensitive and phloridzin-sensitive transport of d-glucose across the plasma membrane.

  13. α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake.

    PubMed

    Shi, Ting; Papay, Robert S; Perez, Dianne M

    2016-01-01

    While α(1)-adrenergic receptors (ARs) have been previously shown to limit ischemic cardiac damage, the mechanisms remain unclear. Most previous studies utilized low oxygen conditions in addition to ischemic buffers with glucose deficiencies, but we discovered profound differences if the two conditions are separated. We assessed both mouse neonatal and adult myocytes and HL-1 cells in a series of assays assessing ischemic damage under hypoxic or low glucose conditions. We found that α(1)-AR stimulation protected against increased lactate dehydrogenase release or Annexin V(+) apoptosis under conditions that were due to low glucose concentration not to hypoxia. The α(1)-AR antagonist prazosin or nonselective protein kinase C (PKC) inhibitors blocked the protective effect. α(1)-AR stimulation increased (3)H-deoxyglucose uptake that was blocked with either an inhibitor to glucose transporter 1 or 4 (GLUT1 or GLUT4) or small interfering RNA (siRNA) against PKCδ. GLUT1/4 inhibition also blocked α(1)-AR-mediated protection from apoptosis. The PKC inhibitor rottlerin or siRNA against PKCδ blocked α(1)-AR stimulated GLUT1 or GLUT4 plasma membrane translocation. α(1)-AR stimulation increased plasma membrane concentration of either GLUT1 or GLUT4 in a time-dependent fashion. Transgenic mice overexpressing the α(1A)-AR but not α(1B)-AR mice displayed increased glucose uptake and increased GLUT1 and GLUT4 plasma membrane translocation in the adult heart while α(1A)-AR but not α(1B)-AR knockout mice displayed lowered glucose uptake and GLUT translocation. Our results suggest that α(1)-AR activation is anti-apoptotic and protective during cardiac ischemia due to glucose deprivation and not hypoxia by enhancing glucose uptake into the heart via PKCδ-mediated GLUT translocation that may be specific to the α(1A)-AR subtype.

  14. Effect of Withania somnifera on insulin sensitivity in non-insulin-dependent diabetes mellitus rats.

    PubMed

    Anwer, Tarique; Sharma, Manju; Pillai, Krishna Kolappa; Iqbal, Muzaffar

    2008-06-01

    We investigated the effect of an aqueous extract of Withania somnifera (WS) on insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (100 mg/kg) to 2 days old rat pups. WS (200 and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e. 75 days after streptozotocin injection). A group of citrate control rats (group I) were also maintained that has received citrate buffer on the second day of their birth. A significant increase in blood glucose, glycosylated haemoglobin (HbA(1)c) and serum insulin levels were observed in NIDDM control rats. Treatment with WS reduced the elevated levels of blood glucose, HbA(1)c and insulin in the NIDDM rats. An oral glucose tolerance test was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with WS. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. WS treatment significantly improved insulin sensitivity index (K(ITT)) that was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas WS treatment significantly prevented the rise in HOMA-R in NIDDM-treated rats. Our data suggest that aqueous extract of WS normalizes hyperglycemia in NIDDM rats by improving insulin sensitivity.

  15. The esters of carboxylic nutrients as insulinotropic tools in non-insulin-dependent diabetes mellitus.

    PubMed

    Malaisse, W J

    1995-10-01

    1. In non-insulin-dependent diabetes mellitus, the pancreatic B-cell displays a preferential impairment of its secretory response to D-glucose. 2. A number of agents could be used to restore secretory activity in the diseased B-cell. 3. In this respect, esters of carboxylic nutrients, such as succinic or glutamic acid, present the advantages of stimulating both proinsulin biosynthesis and insulin release, remaining efficient in models of B-cell glucotoxicity, augmenting the secretory response to hypoglycemic pharmacological agents, protecting the B-cell against cytotoxic aggressions, and exerting a long-term beneficial effect upon the secretory potential of the endocrine pancreas. 4. Potential limitations of this new therapeutical approach, such as the generation of methanol from the esters, their postulated inefficacy after enteral administration, or the occurrence of extrapancreatic metabolic effects may be circumvented. 5. The esters of carboxylic nutrients could even be used in other cells endangered by ATP depletion. PMID:7590101

  16. [Limitations of insulin-dependent drugs in the treatment of type 2 diabetes mellitus].

    PubMed

    Valerón, Pino Fuente; de Pablos-Velasco, Pedro L

    2013-09-01

    In this study, we review the efficacy and safety limitations of insulin-dependent oral antidiabetic agents. In terms of efficiency, the main drawback of metformin, sulfonylureas, gliptins and -to a lesser extent-glitazones is durability. No drug per se is able to maintain stable blood glucose control for years. Metformin, sulfonylureas and gliptins have demonstrated safety. Experience with the first two drug groups is more extensive. The main adverse effect of metformin is gastrointestinal discomfort. Major concerns related to the use of sulfonylureas are hypoglycemia and weight gain. The use of pioglitazone has been associated with an increased risk of bladder cancer, edema, heart failure, weight gain, and distal bone fractures in postmenopausal women. The most common adverse reactions associated with glucagon-like peptide-1 agonists are gastrointestinal discomfort that sometimes leads to treatment discontinuation.

  17. Deoxyandrographolide promotes glucose uptake through glucose transporter-4 translocation to plasma membrane in L6 myotubes and exerts antihyperglycemic effect in vivo.

    PubMed

    Arha, Deepti; Pandeti, Sukanya; Mishra, Akansha; Srivastava, Swayam Prakash; Srivastava, Arvind Kumar; Narender, Tadigoppula; Tamrakar, Akhilesh Kumar

    2015-12-01

    Skeletal muscle is the principal site for postprandial glucose utilization and augmenting the rate of glucose utilization in this tissue may help to control hyperglycemia associated with diabetes mellitus. Here, we explored the effect of Deoxyandrographolide (DeoAn) isolated from the Andrographis paniculata Nees on glucose utilization in skeletal muscle and investigated its antihyperglycemic effect in vivo in streptozotocin-induced diabetic rats and genetically diabetic db/db mice. In L6 myotubes, DeoAn dose-dependently stimulated glucose uptake by enhancing the translocation of glucose transporter 4 (GLUT4) to cell surface, without affecting the total cellular GLUT4 and GLUT1 content. These effects of DeoAn were additive to insulin. Further analysis revealed that DeoAn activated PI-3-K- and AMPK-dependent signaling pathways, account for the augmented glucose transport in L6 myotubes. Furthermore, DeoAn lowered postprandial blood glucose levels in streptozotocin-induced diabetic rats and also suppressed the rises in the fasting blood glucose, serum insulin, triglycerides and LDL-Cholesterol levels of db/db mice. These findings suggest the therapeutic efficacy of the DeoAn for type 2 diabetes mellitus and can be potential phytochemical for its management.

  18. Tedium among patients with insulin-dependent diabetes mellitus.

    PubMed

    Lundman, B; Asplund, K; Norberg, A

    1988-01-01

    Tedium assessment and factor analysis of psychosocial variables were performed in 158 insulin-dependent diabetic patients. High tedium scores correlated significantly (P less than 0.05) with high education, lack of self-monitoring, many reported problems concerning insulin injections, diet, strict planning of the activities of everyday life and anxiety concerning complications. There was also a significant relationship between low tedium scores and reported positive effects of the diabetes. There was a higher proportion (ns) of high tedium scores among patients in poor or good metabolic control than in those with intermediate metabolic control. PMID:3372882

  19. Honokiol and magnolol stimulate glucose uptake by activating PI3K-dependent Akt in L6 myotubes.

    PubMed

    Choi, Sun-Sil; Cha, Byung-Yoon; Lee, Young-Sil; Yonezawa, Takayuki; Teruya, Toshiaki; Nagai, Kazuo; Woo, Je-Tae

    2012-01-01

    Honokiol and magnolol, ingredients of Magnolia officinalis, which is used in traditional Chinese and Japanese medicines, have been reported to have antioxidant, anticancer, and antiangiogenic effects. Effects of these compounds on glucose metabolism in adipocytes have also been reported. However, their effects on skeletal muscle glucose uptake and the underlying molecular mechanisms are still unknown. Here, we investigated the direct effects and signaling pathways activated by honokiol and magnolol in skeletal muscle cells using L6 myotubes. We found that honokiol and magnolol dose-dependently acutely stimulated glucose uptake without synergistic effects of combined administration in L6 myotubes. Treatment with honokiol and magnolol also stimulated glucose transporter-4 translocation to the cell surface. Honokiol- and magnolol-stimulated glucose uptake was blocked by the phosphatidylinositol-3 kinase inhibitor, wortmannin. Both honokiol and magnolol stimulated Akt phosphorylation, a key element in the insulin signaling pathway, which was completely inhibited by wortmannin. These results suggest that honokiol and magnolol might have beneficial effects on glucose metabolism by activating the insulin signaling pathway. PMID:22674833

  20. Hypoxia-induced increases in glucose uptake do not cause oxidative injury or advanced glycation end-product (AGE) formation in vascular endothelial cells.

    PubMed

    Viator, Ryan J; Khader, Heba; Hingorani, Neha; Long, Sara; Solodushko, Victor; Fouty, Brian

    2015-07-01

    An increase in glucose uptake by endothelial cells exposed to hyperglycemia is the presumed initiating event that causes systemic vascular disease in individuals with diabetes. Diabetics do not develop clinically significant pulmonary vascular disease, however, despite the pulmonary circulation's exposure to the same level of glucose. We hypothesized that pulmonary artery endothelial cells are protected from the detrimental effects of hyperglycemia because they take up less glucose than endothelial cells in the systemic circulation, either because of intrinsic differences between the two cell types or because the lower oxygen tension in the pulmonary arterial blood depresses glucose uptake. To test this hypothesis, we exposed normoglycemic and hyperglycemic bovine pulmonary artery (PAECs) and aortic endothelial cells (AECs) from the same animal to progressively lower oxygen tensions and determined glucose uptake. In contrast with our initial hypothesis, we detected no significant difference in glucose uptake between the two cell types. Furthermore, glucose uptake in both PAECs and AECs increased, not decreased, as the oxygen tension dropped; this oxygen-dependent increase in glucose uptake in endothelial cells predominated over the hyperglycemia-mediated decrease in glucose uptake that has been reported by others. Despite the increase in glucose uptake at lower oxygen tensions, we detected no corresponding increase in protein carbonylation or advanced glycation endproducts. These results demonstrate that small physiologically relevant changes in oxygen tension can have an important impact on glucose uptake in endothelial cells. These results also demonstrate that an increase in glucose uptake, by itself, is not sufficient to generate ROS-mediated protein carbonylation or increase intracellular advanced glycation endproducts in vascular endothelial cells. PMID:26177960

  1. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.

    PubMed

    Lovell, M A; Xie, C; Markesbery, W R

    2000-10-15

    Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD.

  2. Differential impact of non-insulin-dependent diabetes mellitus and insulin-dependent diabetes mellitus on breast reconstruction outcomes.

    PubMed

    Qin, Charles; Vaca, Elbert; Lovecchio, Francis; Ver Halen, Jon P; Hansen, Nora M; Kim, John Y S

    2014-07-01

    While the comparative safety of breast reconstruction in diabetic patients has been previously studied, we examine the differential effects of insulin and non-insulin-dependence on surgical/medical outcomes. Patients undergoing implant/expander or autologous breast reconstruction were extracted from the National Surgical Quality Improvement Program 2005-2012 database. Preoperative and postoperative variables were analyzed using chi-square and Student's t test as appropriate. Multivariate regression modeling was used to evaluate whether non-insulin-dependent diabetes mellitus (NIDDM) or insulin-dependent diabetes mellitus (IDDM) is independently associated with adverse 30-day events following breast reconstruction. Of 29,736 patients meeting inclusion criteria, 23,042 (77.5 %) underwent implant/expander reconstructions, of which 815 had NIDDM and 283 had IDDM. Of the 6,694 (22.5 %) patients who underwent autologous reconstructions, 286 had NIDDM and 94 had IDDM. Rates of overall and surgical complications significantly differed among non-diabetic, NIDDM and IDDM patients in both the implant/expander and autologous cohorts on univariate analysis. After multivariate analysis, NIDDM was significantly associated with surgical complications (OR 1.511); IDDM was significantly associated with medical (OR 1.815) and overall complications (OR 1.852); and any type of diabetes was significantly associated with surgical (OR 1.58) and overall (OR 1.361) complications after autologous reconstruction. Diabetes of any type was not associated with any type of complication after implant/expander reconstruction. In this large, multi-institutional study, diabetes mellitus was significantly associated with adverse outcomes after autologous, but not implant-based breast reconstruction. The multivariate analysis in this study adds granularity to the differential effects of NIDDM and IDDM on complication risk.

  3. Administration of aspartame in non-insulin-dependent diabetics.

    PubMed

    Stern, S B; Bleicher, S J; Flores, A; Gombos, G; Recitas, D; Shu, J

    1976-11-01

    A study was designed to determine the effect of the consumption of the nutritive sweetener aspartame on non-insulin-dependent diabetics. Forty-three adult diabetics between the ages of 21 and 70 completed a 90-day study; all were diabetics whose conditions were managed by diet and/or hypoglycemic agents. Participants in the blind study were instructed to continue their usual diet and to take two capsules of an assigned preparation three times daily with meals, either the aspartame or the placebo. The 1.8 g of aspartame administered is approximately three times the expected daily consumption of aspartame if used as a sweetener to replace sugar. Throughout the study subjects were examined for (1) symptoms of intolerance, (2) fasting plasma phenylalanine levels exceeding 4 mg/100 ml, and (3) deterioration of diabetic control. At the conclusion of the study subjects exhibited no symptoms that could be traced to the administration of aspartame or the placebo, and diabetic control was unaffected by the chronic administration of these substances. Aspartame seems to be well tolerated by non-insulin-dependent diabetics.

  4. Rhus coriaria ameliorates insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) rats.

    PubMed

    Anwer, Tarique; Sharma, Manju; Khan, Gyas; Iqbal, Muzaffar; Ali, Mohammad Sajid; Alam, Mohammad Sarfaraz; Safhi, Mohammed Mohsen; Gupta, Nakul

    2013-01-01

    We have investigated the effect of methanolic extract of Rhus coriaria (RC) on hyperinsulinemia, glucose intolerance and insulin sensitivity in non-insulin-dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by single intraperitoneal injection of streptozotocin (STZ, 100 mg/kg) to 2 days old rat pups. RC (200 mg/kg and 400 mg/kg) was administered orally once a day for 5 weeks after the animals were confirmed diabetic (i.e, 90 days after STZ injection). A group of citrate control rats were also maintained which has received citrate buffer on the 2nd day of their birth. There was a significant increase in blood glucose, glycosylated hemoglobin (HbA1c) and serum insulin levels were observed in NIDDM control rats. Treatment with RC reduced the elevated levels of blood glucose, HbA1c and insulin in the NIDDM rats. An oral glucose tolerance test (OGTT) was also performed in the same groups, in which we found a significant improvement in glucose tolerance in the rats treated with RC. The insulin sensitivity was assessed for both peripheral insulin resistance and hepatic insulin resistance. RC treatment significantly improved insulin sensitivity index (K(ITT)) which was significantly decreased in NIDDM control rats. There was significant rise in homeostasis model assessment of insulin resistance (HOMA-R) in NIDDM control rats whereas RC treatment significantly prevented the rise in HOMA-R in NIDDM treated rats. Our data suggest that methanolic extract of RC significantly delayed the onset of hyperinsulinemia and glucose intolerance and improved insulin sensitivity in NIDDM rats.

  5. Pongamol from Pongamia pinnata stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells.

    PubMed

    Tamrakar, Akhilesh K; Jaiswal, Natasha; Yadav, Prem P; Maurya, Rakesh; Srivastava, Arvind K

    2011-06-01

    Skeletal muscle is the major site of postprandial glucose disposal and augmenting glucose uptake into this tissue may attenuate insulin resistance that precedes type 2 diabetes mellitus. Here, we investigated the effect of pongamol, an identified lead molecule from the fruits of Pongamia pinnata, on glucose uptake and GLUT4 translocation in skeletal muscle cells. In L6-GLUT4myc myotubes treatment with pongamol significantly promoted both glucose transport and GLUT4 translocation to the cell surface in a concentration-dependent manner, without changing the total amount of GLUT4 protein and GLUT4 mRNA, effects that were also additive with insulin. Cycloheximide treatment inhibited the effect of pongamol on GLUT4 translocation suggesting the requirement of new protein synthesis. The pongamol-induced increase in GLUT4 translocation was completely abolished by wortmannin, and pongamol significantly potentiated insulin-mediated phosphorylation of AKT (Ser-473). We conclude that pongamol-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane, driven by a PI-3-K/AKT dependent mechanism. PMID:21497640

  6. Kinetic analysis of the uptake of glucose and corn oil used as carbon sources in batch cultures of Gibberella fujikuroi.

    PubMed

    Rios-Iribe, Erika Y; Hernández-Calderón, Oscar M; Escamilla-Silva, Eleazar M

    2016-11-01

    This study determined the specific uptake rate of glucose and corn oil substrates used as carbon sources in batch cultures of Gibberella fujikuroi. We tested three biological models of growth rate: Monod, logistic and lag-exponential. With respect to the substrate consumption rate, we tested two models: constant cell yield (CCY) and law of mass action (LMA). The experimental data obtained from the culture with glucose as substrate correlated satisfactorily with the logistic/LMA model, indicating that the cell yield was variable. In the case of corn oil as carbon source, considering total residual lipids as substrate in the culture broth, the model with the best correlation was the lag-exp/CCY model. The quantification by GC of the three main fatty acids (linoleic, oleic and palmitic) in the culture medium showed a cumulative behavior, with a maximum concentration of each acid at 36 h. We established a more explicit mechanism of the consumption of corn oil, consisting of two stages: generation of fatty acids by hydrolysis and consumption by cellular uptake. The kinetic of hydrolysable lipids was of first order. We found that the hydrolysis rate of corn oil is not a limiting factor for the uptake of fatty acids by the microorganism. We also established, based on the analysis of the identical mathematical structure of consumption kinetics, that the uptake of fatty acids is faster than the uptake of glucose.

  7. Kinetic analysis of the uptake of glucose and corn oil used as carbon sources in batch cultures of Gibberella fujikuroi.

    PubMed

    Rios-Iribe, Erika Y; Hernández-Calderón, Oscar M; Escamilla-Silva, Eleazar M

    2016-11-01

    This study determined the specific uptake rate of glucose and corn oil substrates used as carbon sources in batch cultures of Gibberella fujikuroi. We tested three biological models of growth rate: Monod, logistic and lag-exponential. With respect to the substrate consumption rate, we tested two models: constant cell yield (CCY) and law of mass action (LMA). The experimental data obtained from the culture with glucose as substrate correlated satisfactorily with the logistic/LMA model, indicating that the cell yield was variable. In the case of corn oil as carbon source, considering total residual lipids as substrate in the culture broth, the model with the best correlation was the lag-exp/CCY model. The quantification by GC of the three main fatty acids (linoleic, oleic and palmitic) in the culture medium showed a cumulative behavior, with a maximum concentration of each acid at 36 h. We established a more explicit mechanism of the consumption of corn oil, consisting of two stages: generation of fatty acids by hydrolysis and consumption by cellular uptake. The kinetic of hydrolysable lipids was of first order. We found that the hydrolysis rate of corn oil is not a limiting factor for the uptake of fatty acids by the microorganism. We also established, based on the analysis of the identical mathematical structure of consumption kinetics, that the uptake of fatty acids is faster than the uptake of glucose. PMID:27646209

  8. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    SciTech Connect

    Bolinder, J.; Ostman, J.; Arner, P.

    1982-10-01

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono-/sup 125/I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis.

  9. Green tea (-)-epigallocatechin gallate suppresses IGF-I and IGF-II stimulation of 3T3-L1 adipocyte glucose uptake via the glucose transporter 4, but not glucose transporter 1 pathway.

    PubMed

    Ku, Hui-Chen; Tsuei, Yi-Wei; Kao, Chung-Cheng; Weng, Jueng-Tsueng; Shih, Li-Jane; Chang, Hsin-Huei; Liu, Chi-Wei; Tsai, Shu-Wei; Kuo, Yow-Chii; Kao, Yung-Hsi

    2014-04-01

    This study investigated the pathways involved in EGCG modulation of insulin-like growth factor (IGF)-stimulated glucose uptake in 3T3-L1 adipocytes. EGCG inhibited IGF-I and IGF-II stimulation of adipocyte glucose uptake with dose and time dependencies. EGCG at 20μM for 2h decreased IGF-I- and IGF-II-stimulated glucose uptake by 59% and 64%, respectively. Pretreatment of adipocytes with antibody against the EGCG receptor (also known as the 67-kDa laminin receptor; 67LR), prevented the effects of EGCG on IGF-increased glucose uptake, but pretreatment with normal rabbit immunoglobulin did not. This suggests that the 67LR mediates the anti-IGF effect of EGCG on adipocyte glucose uptake. Further analysis indicated EGCG, IGF-I, and IGF-II did not alter total levels of GLUT1 or GLUT4 protein. However, EGCG prevented the IGF-increased GLUT4 levels in the plasma membrane and blocked the IGF-decreased GLUT4 levels in low-density microsomes. Neither EGCG nor its combination with IGF altered GLUT1 protein levels in the plasma membrane and low-density microsomes. EGCG also suppressed the IGF-stimulated phosphorylation of IGF signaling molecules, PKCζ/λ, but not AKT and ERK1/2, proteins. This study suggests that EGCG suppresses IGF stimulation of 3T3-L1 adipocyte glucose uptake through inhibition of the GLUT4 translocation, but not through alterations of the GLUT1 pathway.

  10. The chemokine CCL5 regulates glucose uptake and AMP kinase signaling in activated T cells to facilitate chemotaxis.

    PubMed

    Chan, Olivia; Burke, J Daniel; Gao, Darrin F; Fish, Eleanor N

    2012-08-24

    Recruitment of effector T cells to sites of infection or inflammation is essential for an effective adaptive immune response. The chemokine CCL5 (RANTES) activates its cognate receptor, CCR5, to initiate cellular functions, including chemotaxis. In earlier studies, we reported that CCL5-induced CCR5 signaling activates the mTOR/4E-BP1 pathway to directly modulate mRNA translation. Specifically, CCL5-mediated mTOR activation contributes to T cell chemotaxis by initiating the synthesis of chemotaxis-related proteins. Up-regulation of chemotaxis-related proteins may prime T cells for efficient migration. It is now clear that mTOR is also a central regulator of nutrient sensing and glycolysis. Herein we describe a role for CCL5-mediated glucose uptake and ATP accumulation to meet the energy demands of chemotaxis in activated T cells. We provide evidence that CCL5 is able to induce glucose uptake in an mTOR-dependent manner. CCL5 treatment of ex vivo activated human CD3(+) T cells also induced the activation of the nutrient-sensing kinase AMPK and downstream substrates ACC-1, PFKFB-2, and GSK-3β. Using 2-deoxy-d-glucose, an inhibitor of glucose uptake, and compound C, an inhibitor of AMPK, experimental data are presented that demonstrate that CCL5-mediated T cell chemotaxis is dependent on glucose, as these inhibitors inhibit CCL5-mediated chemotaxis in a dose-dependent manner. Altogether, these findings suggest that both glycolysis and AMPK signaling are required for efficient T cell migration in response to CCL5. These studies extend the role of CCL5 mediated CCR5 signaling beyond lymphocyte chemotaxis and demonstrate a role for chemokines in promoting glucose uptake and ATP production to match energy demands of migration.

  11. Insulin-mediated hepatic glucose uptake is impaired in type 2 diabetes: evidence for a relationship with glycemic control.

    PubMed

    Iozzo, Patricia; Hallsten, Kirsti; Oikonen, Vesa; Virtanen, Kirsi A; Kemppainen, Jukka; Solin, Olof; Ferrannini, Ele; Knuuti, Juhani; Nuutila, Pirjo

    2003-05-01

    Impaired hepatic glucose uptake (HGU) has been implicated in the development of hyperglycemia in type 2 diabetes; the relative impact of plasma glucose and insulin levels on this process remains controversial. We compared the effects of euglycemic hyperinsulinemia on HGU, skeletal muscle glucose uptake, and hepatic influx rate-constant (H-Ki) in 38 diet-treated diabetic patients and 22 nondiabetic controls, using positron emission tomography with (18)F-fluorodeoxyglucose and the insulin clamp technique. Control subjects were divided into two subgroups: one including older, heavier, insulin-resistant controls (whole-body glucose uptake, M = 21.4 +/- 5.4 micromol x min(-1) x kg(-1)) to match characteristics of diabetic patients (M = 20.4 +/- 9.9); the other including younger, leaner, insulin-sensitive controls (M = 48.2 +/- 9.9, P < 0.01). Skeletal muscle glucose uptake showed a similar group distribution as the M value. Insulin clearance rates were lower, whereas glycosylated hemoglobin and clamp plasma insulin levels were higher in diabetic patients than in controls. HGU and H-Ki were similar in the two nondiabetic subgroups and lower in diabetic patients than in controls (1.9 +/- 0.5 vs. 2.3 +/- 0.7 micromol x min(-1) x 100 ml(-1), and 0.37 +/- 0.09 vs. 0.44 +/- 0.14 ml x min(-1) x 100 ml(-1), P < or = 0.01). In the whole dataset, H-Ki was inversely related to fasting plasma glucose (correlation coefficient = -0.40, P = 0.0018). In diabetic subjects, H-Ki was reciprocally related to glycosylated hemoglobin (correlation coefficient = -0.36, P = 0.029). We conclude that insulin-mediated HGU is impaired, in type 2 diabetes, in some proportion to the degree of glycemic control.

  12. Chemical approach to positional isomers of glucose-platinum conjugates reveals specific cancer targeting through glucose-transporter mediated uptake in vitro and in vivo

    PubMed Central

    Patra, Malay; Awuah, Samuel G.; Lippard, Stephen J.

    2016-01-01

    Glycoconjugation is a promising strategy for specific targeting of cancer. In this study, we investigated the effect of D-glucose substitution position on the biological activity of glucose-platinum conjugates (Glc-Pts). We synthesized and characterized all possible positional isomers (C1α, C1β, C2, C3, C4 and C6) of a Glc-Pt. The synthetic routes presented here could in principle be extended to prepare glucose-conjugates with different active ingredients than platinum. The biological activities of the compounds were evaluated both in vitro and in vivo. We discovered that variation in position of substitution of D-glucose not only alters the cellular uptake and cytotoxicity profile but also the GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose transporter 1. The C1α- and C2-substituted Glc-Pts (1α and 2) accumulate in cancer cells most efficiently compared to the others, whereas the C3-Glc-Pt (3) is taken up least efficiently. Compounds 1α and 2 are more potent compared to 3 in DU145 cells. The α- and β-anomer of the C1-Glc-Pt also differ significantly in their cellular uptake and activity profiles. No significant differences in uptake of the Glc-Pts were observed in noncancerous RWPE2 cells. The GLUT1 specificity of the Glc-Pts was evaluated by determining the cellular uptake in the absence and presence of the GLUT1 inhibitor cytochalasin B, and by comparing their anticancer activity in DU145 cells and a GLUT1 knockdown cell line. The results reveal that C2-substituted Glc-Pt 2 has the highest GLUT1 specific internalization, which also reflects the best cancer targeting ability. In a syngeneic breast cancer mouse model overexpressing GLUT1, compound 2 showed antitumor efficacy and selective uptake in tumors with no observable toxicity. This study thus reveals the synthesis of all positional isomers of D-glucose substitution for platinum warhead with detailed glycotargeting characterization in cancer. PMID:27570149

  13. Hepatocellular adenoma showing high uptake of (18)F-fluorodeoxyglucose (FDG) via an increased expression of glucose transporter 2 (GLUT-2).

    PubMed

    Nakashima, Takaaki; Takayama, Yukihisa; Nishie, Akihiro; Asayama, Yoshiki; Baba, Shingo; Yamashita, Youichi; Shirabe, Ken; Kubo, Yuichiro; Hida, Tomoyuki; Honda, Hiroshi

    2014-01-01

    Hepatocellular adenoma (HCA) is a benign liver neoplasm composed of hepatocytes. We experienced HCA demonstrating a high uptake of (18)F-fluorodeoxyglucose (FDG) on positron emission tomography-computed tomography, mimicking a malignant tumor. The mechanism underlying the uptake of FDG has not been identified. Here, we discuss that an enhancement of glucose metabolism via an increased expression of glucose transporter 2 may have a role in the high uptake of FDG shown by HCAs.

  14. Child abuse suspicion masquerading new onset insulin dependent diabetes mellitus.

    PubMed

    Shles, Ayelet; Fainmesser, Pinchas; Eliakim, Alon; Nemet, Dan

    2011-01-01

    The identification and diagnosis of child abuse is a challenging task to the pediatrician. The increased awareness among both the public and medical personnel, while improving attentiveness to this important subject, can sometimes result in misdiagnosing medical conditions, thus causing distress and delay in required treatment. Numerous reports have described conditions mimicking non-accidental injuries; most of these include dermatological findings related to skin diseases, medical conditions causing pathological fractures, and rare diseases with unusual physical findings. We present a case of a 9.5-year-old child in which the workup for a suspected abusive event led to a delay in the diagnosis of insulin dependent diabetes mellitus later presented as diabetic ketoacidosis. PMID:22145485

  15. Genetics of type 1 insulin-dependent diabetes mellitus.

    PubMed

    Froguel, P

    1997-01-01

    Many human insulin-dependent (type 1) diabetes mellitus (IDDM) genes have recently been mapped. The HLA region on chromosome 6 and the insulin gene promoter on chromosome 11p have been extensively investigated. Genome scanning of many families with several affected individuals has successfully mapped other predisposing loci situated on different chomosomal regions. In addition, the positional cloning of IDDM susceptibility genes is in progress. Advances in high throughput genotyping and large-scale sequencing, and the availability of high-density maps of human genes will help to identify IDDM genes. Understanding the genetic basis of IDDM will aid in the design of new strategies to prevent or cure the disease. PMID:9350449

  16. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs.

    PubMed

    Coate, Katie C; Kraft, Guillaume; Irimia, Jose M; Smith, Marta S; Farmer, Ben; Neal, Doss W; Roach, Peter J; Shiota, Masakazu; Cherrington, Alan D

    2013-02-01

    The cellular events mediating the pleiotropic actions of portal vein glucose (PoG) delivery on hepatic glucose disposition have not been clearly defined. Likewise, the molecular defects associated with postprandial hyperglycemia and impaired hepatic glucose uptake (HGU) following consumption of a high-fat, high-fructose diet (HFFD) are unknown. Our goal was to identify hepatocellular changes elicited by hyperinsulinemia, hyperglycemia, and PoG signaling in normal chow-fed (CTR) and HFFD-fed dogs. In CTR dogs, we demonstrated that PoG infusion in the presence of hyperinsulinemia and hyperglycemia triggered an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which occurred in association with further augmentation in HGU and glycogen synthesis (GSYN) in vivo. In contrast, 4 weeks of HFFD feeding markedly reduced GK protein content and impaired the activation of GS in association with diminished HGU and GSYN in vivo. Furthermore, the enzymatic changes associated with PoG sensing in chow-fed animals were abolished in HFFD-fed animals, consistent with loss of the stimulatory effects of PoG delivery. These data reveal new insight into the molecular physiology of the portal glucose signaling mechanism under normal conditions and to the pathophysiology of aberrant postprandial hepatic glucose disposition evident under a diet-induced glucose-intolerant condition.

  17. The Aspergillus nidulans ATM Kinase Regulates Mitochondrial Function, Glucose Uptake and the Carbon Starvation Response

    PubMed Central

    Krohn, Nadia Graciele; Brown, Neil Andrew; Colabardini, Ana Cristina; Reis, Thaila; Savoldi, Marcela; Dinamarco, Taísa Magnani; Goldman, Maria Helena S.; Goldman, Gustavo Henrique

    2013-01-01

    Mitochondria supply cellular energy and also perform a role in the adaptation to metabolic stress. In mammals, the ataxia-telangiectasia mutated (ATM) kinase acts as a redox sensor controlling mitochondrial function. Subsequently, transcriptomic and genetic studies were utilized to elucidate the role played by a fungal ATM homolog during carbon starvation. In Aspergillus nidulans, AtmA was shown to control mitochondrial function and glucose uptake. Carbon starvation responses that are regulated by target of rapamycin (TOR) were shown to be AtmA-dependent, including autophagy and hydrolytic enzyme secretion. AtmA also regulated a p53-like transcription factor, XprG, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Thus, AtmA possibly represents a direct or indirect link between mitochondrial stress, metabolism, and growth through the influence of TOR and XprG function. The coordination of cell growth and division with nutrient availability is crucial for all microorganisms to successfully proliferate in a heterogeneous environment. Mitochondria supply cellular energy but also perform a role in the adaptation to metabolic stress and the cross-talk between prosurvival and prodeath pathways. The present study of Aspergillus nidulans demonstrated that AtmA also controlled mitochondrial mass, function, and oxidative phosphorylation, which directly or indirectly influenced glucose uptake. Carbon starvation responses, including autophagy, shifting metabolism to the glyoxylate cycle, and the secretion of carbon scavenging enzymes were AtmA-dependent. Transcriptomic profiling of the carbon starvation response demonstrated how TOR signaling and the retrograde response, which signals mitochondrial dysfunction, were directly or indirectly influenced by AtmA. The AtmA kinase was also shown to influence a p53-like transcription factor, inhibiting starvation-induced XprG-dependent protease secretion and cell death. Therefore, in response to metabolic

  18. Influence of age of aggregates and prokaryotic abundance on glucose and leucine uptake by heterotrophic marine prokaryotes.

    PubMed

    Azúa, Iñigo; Unanue, Marian; Ayo, Begoña; Artolozaga, Itxaso; Iriberri, Juan

    2007-03-01

    The kinetics of glucose and leucine uptake in attached and free-living prokaryotes in two types of microcosms with different nutrient qualities were compared. Microcosm type M1, derived from unaltered seawater, and microcosm type M2, from phytoplankton cultures, clearly expressed different kinetic parameters (Vmax/cell and K' m). In aggregates with low cell densities (M1 microcosm), the attached prokaryotes benefited from attachment as reflected in the higher potential uptake rates, while in aggregates with high cell densities (M2 microcosm) differences in the potential uptake rates of attached and free-living prokaryotes were not evident. The aging process and the chemical changes in aggregates of M2 microcosms were followed for 15-20 days. The results showed that as the aggregates aged and prokaryotic abundance increased, attached prokaryotes decreased their potential uptake rate and their K' m for substrate. This suggests an adaptive response by attached prokaryotes when aggregates undergo quantitative and qualitative impoverishment.

  19. Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle

    PubMed Central

    Castorena, Carlos M.; Arias, Edward B.; Sharma, Naveen; Bogan, Jonathan S.

    2014-01-01

    To fully understand skeletal muscle at the cellular level, it is essential to evaluate single muscle fibers. Accordingly, the major goals of this study were to determine if there are fiber type-related differences in single fibers from rat skeletal muscle for: 1) contraction-stimulated glucose uptake and/or 2) the abundance of GLUT4 and other metabolically relevant proteins. Paired epitrochlearis muscles isolated from Wistar rats were either electrically stimulated to contract (E-Stim) or remained resting (No E-Stim). Single fibers isolated from muscles incubated with 2-deoxy-d-[3H]glucose (2-DG) were used to determine fiber type [myosin heavy chain (MHC) isoform protein expression], 2-DG uptake, and abundance of metabolically relevant proteins, including the GLUT4 glucose transporter. E-Stim, relative to No E-Stim, fibers had greater (P < 0.05) 2-DG uptake for each of the isolated fiber types (MHC-IIa, MHC-IIax, MHC-IIx, MHC-IIxb, and MHC-IIb). However, 2-DG uptake for E-Stim fibers was not significantly different among these five fiber types. GLUT4, tethering protein containing a UBX domain for GLUT4 (TUG), cytochrome c oxidase IV (COX IV), and filamin C protein levels were significantly greater (P < 0.05) in MHC-IIa vs. MHC-IIx, MHC-IIxb, or MHC-IIb fibers. TUG and COX IV in either MHC-IIax or MHC-IIx fibers exceeded values for MHC-IIxb or MHC-IIb fibers. GLUT4 levels for MHC-IIax fibers exceeded MHC-IIxb fibers. GLUT4, COX IV, filamin C, and TUG abundance in single fibers was significantly (P < 0.05) correlated with each other. Differences in GLUT4 abundance among the fiber types were not accompanied by significant differences in contraction-stimulated glucose uptake. PMID:25491725

  20. Evolved hexose transporter enhances xylose uptake and glucose/xylose co-utilization in Saccharomyces cerevisiae

    DOE PAGESBeta

    Reider Apel, Amanda; Ouellet, Mario; Szmidt-Middleton, Heather; Keasling, Jay D.; Mukhopadhyay, Aindrila

    2016-01-19

    Enhancing xylose utilization has been a major focus in Saccharomyces cerevisiae strain-engineering efforts. The incentive for these studies arises from the need to use all sugars in the typical carbon mixtures that comprise standard renewable plant-biomass-based carbon sources. While major advances have been made in developing utilization pathways, the efficient import of five carbon sugars into the cell remains an important bottleneck in this endeavor. Here we use an engineered S. cerevisiae BY4742 strain, containing an established heterologous xylose utilization pathway, and imposed a laboratory evolution regime with xylose as the sole carbon source. We obtained several evolved strains withmore » improved growth phenotypes and evaluated the best candidate using genome resequencing. We observed remarkably few single nucleotide polymorphisms in the evolved strain, among which we confirmed a single amino acid change in the hexose transporter HXT7 coding sequence to be responsible for the evolved phenotype. Lastly, the mutant HXT7(F79S) shows improved xylose uptake rates (Vmax = 186.4 ± 20.1 nmol•min-1•mg-1) that allows the S. cerevisiae strain to show significant growth with xylose as the sole carbon source, as well as partial co-utilization of glucose and xylose in a mixed sugar cultivation.« less

  1. Cellular location of insulin-triggered signals and implications for glucose uptake.

    PubMed

    Patel, Nish; Huang, Carol; Klip, Amira

    2006-01-01

    Insulin stimulation of glucose uptake into muscle and fat cells requires movement of GLUT4-containing vesicles from intracellular compartments to the plasma membrane. Accordingly, insulin-derived signals must arrive at and be recognized by the appropriate intracellular GLUT4 pools. We describe the insulin signals participating in GLUT4 translocation, and review evidence that they are recruited to intracellular membranes in conjunction with cytoskeletal elements. Such segregation may facilitate the encounter between signals and target vesicles. In most animal and cellular models of insulin resistance, insulin-stimulated GLUT4 translocation to the plasma membrane is reduced. Insulin resistance caused by oxidative stress does not affect early insulin signals, rather their intracellular localization is altered. In this and several other insulin-resistant states, insulin-induced actin remodelling is concomitantly diminished. We summarize evidence suggesting that spatial localization of signals is critical for efficient insulin action, and that the cytoskeleton may act as a scaffold to promote efficient translocation of GLUT4 to the cell surface.

  2. Evolved hexose transporter enhances xylose uptake and glucose/xylose co-utilization in Saccharomyces cerevisiae

    PubMed Central

    Reider Apel, Amanda; Ouellet, Mario; Szmidt-Middleton, Heather; Keasling, Jay D.; Mukhopadhyay, Aindrila

    2016-01-01

    Enhancing xylose utilization has been a major focus in Saccharomyces cerevisiae strain-engineering efforts. The incentive for these studies arises from the need to use all sugars in the typical carbon mixtures that comprise standard renewable plant-biomass-based carbon sources. While major advances have been made in developing utilization pathways, the efficient import of five carbon sugars into the cell remains an important bottleneck in this endeavor. Here we use an engineered S. cerevisiae BY4742 strain, containing an established heterologous xylose utilization pathway, and imposed a laboratory evolution regime with xylose as the sole carbon source. We obtained several evolved strains with improved growth phenotypes and evaluated the best candidate using genome resequencing. We observed remarkably few single nucleotide polymorphisms in the evolved strain, among which we confirmed a single amino acid change in the hexose transporter HXT7 coding sequence to be responsible for the evolved phenotype. The mutant HXT7(F79S) shows improved xylose uptake rates (Vmax = 186.4 ± 20.1 nmol•min−1•mg−1) that allows the S. cerevisiae strain to show significant growth with xylose as the sole carbon source, as well as partial co-utilization of glucose and xylose in a mixed sugar cultivation. PMID:26781725

  3. Effects of sciatic nerve transection on glucose uptake in the presence and absence of lactate in the frog dorsal root ganglia and spinal cord.

    PubMed

    Rigon, F; Horst, A; Kucharski, L C; Silva, R S M; Faccioni-Heuser, M C; Partata, W A

    2014-08-01

    Frogs have been used as an alternative model to study pain mechanisms because the simplicity of their nervous tissue and the phylogenetic aspect of this question. One of these models is the sciatic nerve transection (SNT), which mimics the clinical symptoms of "phantom limb", a condition that arises in humans after amputation or transverse spinal lesions. In mammals, the SNT increases glucose metabolism in the central nervous system, and the lactate generated appears to serve as an energy source for nerve cells. An answerable question is whether there is elevated glucose uptake in the dorsal root ganglia (DRG) after peripheral axotomy. As glucose is the major energy substrate for frog nervous tissue, and these animals accumulate lactic acid under some conditions, bullfrogs Lithobates catesbeianus were used to demonstrate the effect of SNT on DRG and spinal cord 1-[14C] 2-deoxy-D-glucose (14C-2-DG) uptake in the presence and absence of lactate. We also investigated the effect of this condition on the formation of 14CO2 from 14C-glucose and 14C-L-lactate, and plasmatic glucose and lactate levels. The 3-O-[14C] methyl-D-glucose (14C-3-OMG) uptake was used to demonstrate the steady-state tissue/medium glucose distribution ratio under these conditions. Three days after SNT, 14C-2-DG uptake increased, but 14C-3-OMG uptake remained steady. The increase in 14C-2-DG uptake was lower when lactate was added to the incubation medium. No change was found in glucose and lactate oxidation after SNT, but lactate and glucose levels in the blood were reduced. Thus, our results showed that SNT increased the glucose metabolism in the frog DRG and spinal cord. The effect of lactate on this uptake suggests that glucose is used in glycolytic pathways after SNT. PMID:25627385

  4. Bile enhances glucose uptake, reduces permeability, and modulates effects of lectins, trypsin inhibitors and saponins on intestinal tissue.

    PubMed

    Bakke, Anne Marie; Chikwati, Elvis M; Venold, Fredrik F; Sahlmann, Christian; Holm, Halvor; Penn, Michael H; Oropeza-Moe, Marianne; Krogdahl, Åshild

    2014-02-01

    Antinutritional factors (ANFs) can disrupt digestive and other intestinal functions. ANFs in soybean meal (SBM) are implicated in proliferative and inflammatory responses in the intestine of various (functionally) monogastric animals, including Atlantic salmon (Salmo salar L.). The goal of the current study was to investigate the effect of ex vivo exposure of mid and distal intestinal tissue of salmon to soybean saponins (SAP), lectin (LEC) and Kunitz' trypsin inhibitor (KTI), singly and in combination, on epithelial function, as assessed by measuring in vitro glucose uptake pathways along a glucose concentration gradient. As solubilization of SAP in the calcium-containing Ringer's solution was problematic but resolved with the addition of a physiological concentration of bile collected from the gall bladder of salmon, an evaluation of bile effects became an added element. Results indicated that bile increased baseline glucose absorption and possibly transport, and also had a protective effect on the epithelial barrier, at least partially due to taurocholate. Compared to controls, tissues exposed to LEC+bile, KTI+bile and LEC+KTI+bile exhibited increased glucose uptake at the higher glucose concentrations, apparently due to markedly increased tissue permeability. Addition of SAP, however, attenuated the response, possibly by binding bile components. SAP+bile, also in combination with LEC and/or KTI, as well as LEC, KTI and LEC+KTI without bile often reduced transcellular glucose uptake pathways, while maintaining low tissue permeability. SAP+LEC+KTI+bile, LEC and KTI caused the most marked reductions. The distal intestine was more affected, reflecting the restriction of in vivo SBM-induced inflammatory changes to this region. PMID:24291392

  5. Stem Cells in the Treatment of Insulin-Dependent Diabetes Mellitus

    PubMed Central

    Borisov, M. A.; Petrakova, O. S.; Gvazava, I. G.; Kalistratova, E. N.; Vasiliev, A. V.

    2016-01-01

    Diabetes affects over 350 million people worldwide, with the figure projected to rise to nearly 500 million over the next 20 years, according to the World Health Organization. Insulin-dependent diabetes mellitus (type 1 diabetes) is an endocrine disorder caused by an autoimmune reaction that destroys insulin-producing β-cells in the pancreas, which leads to insulin deficiency. Administration of exogenous insulin remains at the moment the treatment mainstay. This approach helps to regulate blood glucose levels and significantly increases the life expectancy of patients. However, type 1 diabetes is accompanied by long-term complications associated with the systemic nature of the disease and metabolic abnormalities having a profound impact on health. Of greater impact would be a therapeutic approach which would overcome these limitations by better control of blood glucose levels and prevention of acute and chronic complications. The current efforts in the field of regenerative medicine are aimed at finding such an approach. In this review, we discuss the time-honored technique of donor islets of Langerhans transplantation. We also focus on the use of pluripotent stem and committed cells and cellular reprogramming. The molecular mechanisms of pancreatic differentiation are highlighted. Much attention is devoted to the methods of grafts delivery and to the materials used during its creation.

  6. Molecular aspects of glucose homeostasis in skeletal muscle--A focus on the molecular mechanisms of insulin resistance.

    PubMed

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2015-12-01

    Among all the varied actions of insulin, regulation of glucose homeostasis is the most critical and intensively studied. With the availability of glucose from nutrient metabolism, insulin action in muscle results in increased glucose disposal via uptake from the circulation and storage of excess, thereby maintaining euglycemia. This major action of insulin is executed by redistribution of the glucose transporter protein, GLUT4 from intracellular storage sites to the plasma membrane and storage of glucose in the form of glycogen which also involves modulation of actin dynamics that govern trafficking of all the signal proteins of insulin signal transduction. The cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance are largely enigmatic, and this review provides a consolidated overview of the various molecular mechanisms involved in insulin-dependent glucose homeostasis in skeletal muscle, as insulin resistance at this major peripheral site impacts whole body glucose homeostasis.

  7. NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise.

    PubMed Central

    Price, T B; Perseghin, G; Duleba, A; Chen, W; Chase, J; Rothman, D L; Shulman, R G; Shulman, G I

    1996-01-01

    To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to approximately 25% of resting concentration. After approximately 20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 +/- 1.3 mM/hr and CON, 15.8 +/- 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 +/- 0.5 mM/hr and CON, 2.9 +/- 0.2 mM/hr; (P < or = 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal. PMID:8643574

  8. Effect of caffeine and ethanolic extract of kolanut on glucose uptake in the canine hindlimb at rest and during contraction.

    PubMed

    Salahdeen, H M; Alada, A R A

    2009-06-01

    The study investigated the effects of caffeine and ethanolic extract of kolanut (EEK) on glucose uptake in the canine hindlimb at rest and during contraction. Thirty male anaesthetized mongrel dogs [11-13 kg] were divided into six groups [5 dogs/group] Caffeine [6 mg/kg], EEK [5 mg/kg], or normal saline [control] was administered intravenously to each group at rest. Arterial and venous blood samples were collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 minutes after drug administration. Blood glucose was measured by glucose oxidase method. Arteriovenous [A-V] glucose difference was calculated and venous blood flow [VBF] was measured during the sampling period. Hindlimb glucose uptake [HGU] was calculated as the product of [A-V] glucose and blood flow. After sampling at rest, the experiments were repeated with the right femoral nerve stimulated using electrical stimulator at 5 Hz. At rest, A-V glucose increased significantly [P<0.05] from 4.2+/-0.2 mg/dl to 29.8+/-8.6, and 24.4+/-2.6 for caffeine and EEK respectively. VBF decreased to 2.0+/-0.9 and 6.0+/-0.6 ml/min for caffeine and EEK respectively. However, HGU significantly increased from 34.8+/-0.1 mg/min to 74.5+/-3.2 mg/min and 175.8+/-3.4 mg/min for caffeine and EEK, respectively. Contraction of the hindlimb muscle alone significantly increased the [A-V] glucose [68%], VBF [26%] and HGU [120%] when compared with the control. During contraction, [A-V] glucose increased from 4.3 +/-1.5 mg/dl to 35.6+/-3.0 mg/dl, and 27.0+/-2.2 mg/dl for caffeine and EEK respectively. VBF also increased from 8.4+/-0.3 ml/min to 12.8+/-0.3 ml/min for EEK. Although, contraction improves VBF [7.3+/-0.5 ml/min] to the hindlimb in response to caffeine, the value was significantly [P<0.05] lower than that of control [8.4+/-0.5 ml/min]. Contraction also significantly increased HGU from 35.8+/-3.6 mg/min to 249.0+/-3.3 and 286.72+/-2.0 mg/min for caffeine and EEK, respectively. The results showed that caffeine and EEK

  9. AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B.

    PubMed

    Bertrand, Luc; Ginion, Audrey; Beauloye, Christophe; Hebert, Alexandre D; Guigas, Bruno; Hue, Louis; Vanoverschelde, Jean-Louis

    2006-07-01

    Diabetic hearts are known to be more susceptible to ischemic disease. Biguanides, like metformin, are known antidiabetic drugs that lower blood glucose concentrations by decreasing hepatic glucose production and increasing glucose disposal in muscle. Part of these metabolic effects is thought to be mediated by the activation of AMP-activated protein kinase (AMPK). In this work, we studied the relationship between AMPK activation and glucose uptake stimulation by biguanides and oligomycin, another AMPK activator, in both insulin-sensitive and insulin-resistant cardiomyocytes. In insulin-sensitive cardiomyocytes, insulin, biguanides and oligomycin were able to stimulate glucose uptake with the same efficiency. Stimulation of glucose uptake by insulin or biguanides was correlated to protein kinase B (PKB) or AMPK activation, respectively, and were additive. In insulin-resistant cardiomyocytes, where insulin stimulation of glucose uptake was greatly reduced, biguanides or oligomycin, in the absence of insulin, induced a higher stimulation of glucose uptake than that obtained in insulin-sensitive cells. This stimulation was correlated with the activation of both AMPK and PKB and was sensitive to the phosphatidylinositol-3-kinase/PKB pathway inhibitors. Finally, an adenoviral-mediated expression of a constitutively active form of AMPK increased both PKB phosphorylation and glucose uptake in insulin-resistant cardiomyocytes. We concluded that AMPK activators, like biguanides and oligomycin, are able to restore glucose uptake stimulation, in the absence of insulin, in insulin-resistant cardiomyocytes via the additive activation of AMPK and PKB. Our results suggest that AMPK activation could restore normal glucose metabolism in diabetic hearts and could be a potential therapeutic approach to treat insulin resistance.

  10. Uptake and metabolism of glucose, alanine and lactate by red blood cells of the American eel Anguilla rostrata

    PubMed

    Soengas; Moon

    1995-01-01

    The uptake and metabolism of glucose, alanine and lactate were assessed in red blood cells (RBCs) of the American eel Anguilla rostrata. l-Lactate was metabolized at the highest rates as assessed by O2 consumption and CO2 production, followed by glucose and alanine (rates were approximately half of those observed for lactate). A saturable (Km 10.36±0.60 mmol l-1, Jmax 27.42±2.16 µmol 3-OMG l-1 cell water min-1), sodium-independent but cytochalasin-B-sensitive carrier for d-glucose was observed, which was stereospecific and inhibited by other hexoses. These characteristics are in agreement with those reported for the GLUT-1 glucose carrier of human and Japanese eel erythrocytes. These cells also contained a saturable carrier for l-lactate in the concentration range 0­10 mmol l-1 (Km 6.74±0.36 mmol l-1, Jmax 2.29±0.09 mmol lactate l-1 cell water min-1) whereas, at higher concentrations (10­40 mmol l-1), transport occurred by simple diffusion. The carrier was stereospecific, sodium-independent, fully inhibited by alpha-cyano-4-hydroxycinnamate, DIDS and pyruvate, but less sensitive to SITS, IBCLA and pCMBS. We suggest that this carrier is similar to the H+/monocarboxylate carrier found in mammalian RBCs. Despite the fact that l-alanine transport did not saturate, transport was stereospecific because it was inhibited by d-alanine. These experiments do not, therefore, exclude the existence of an alanine carrier in the eel RBC. The rates of substrate uptake exceeded the ability of the RBC to metabolize the substrate (using 1 mmol l-1 extracellular concentration), with uptake rate/metabolic rate ratios being 2 for alanine, 5 for glucose and 151 for lactate. These experiments indicate that uptake does not limit the ability of the American eel RBC to utilize glucose, alanine or lactate, but that the mechanism(s) of substrate uptake is species-specific.

  11. Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome

    PubMed Central

    Brown, Audrey E.; Jones, David E.; Walker, Mark; Newton, Julia L.

    2015-01-01

    Background Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects. Methods Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise. Results In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured. Conclusion EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets. PMID:25836975

  12. Expression of a dominant-negative Ras mutant does not affect stimulation of glucose uptake and glycogen synthesis by insulin.

    PubMed

    Dorrestijn, J; Ouwens, D M; Van den Berghe, N; Bos, J L; Maassen, J A

    1996-05-01

    It has previously been shown that insulin-induced stimulation of glucose uptake and glycogen synthesis requires activation of phosphatidylinositol-3-kinase (PI3kinase). Insulin also induces formation of RasGTP in cells and various studies have yielded inconsistent data with respect to the contribution of signalling pathways activated by RasGTP, to insulin-stimulated glucose uptake and glycogen synthesis. We have examined the requirement of RasGTP-mediated signalling for these insulin responses by expression of a dominant negative mutant of Ras (RasN17) in cells by vaccinia virus mediated gene transfer. This Ras-mutant abrogates the signalling pathways mediated by endogenous RasGTP. Subsequently, the ability of insulin to stimulate 2-deoxyglucose uptake and glycogen was examined. We observed that expression of RasN17 in 3T3L1 adipocytes did not affect the stimulation of hexose uptake by insulin. Similarly, expression of RasN17 in A14 cells, an NIH 3T3-derived cell line with high expression of insulin receptors, did not affect insulin-induced stimulation of glycogen synthesis. In both cell lines, insulin-induced phosphorylation of Mapkinase (Erk1,2) was abrogated after expression of RasN17, demonstrating the functional interference by RasN17 with signalling mediated by endogenous RasGTP. Wortmannin, an inhibitor of PI3kinase, abolished dose-dependently the insulin-induced stimulation of hexose uptake and glycogen synthesis without an effect on RasGTP levels in both cell types. We conclude that stimulation of glucose transport and glycogen synthesis by insulin occurs independently of RasGTP-mediated signalling.

  13. DNAJB3/HSP-40 cochaperone improves insulin signaling and enhances glucose uptake in vitro through JNK repression

    PubMed Central

    Abu-Farha, Mohamed; Cherian, Preethi; Al-Khairi, Irina; Tiss, Ali; Khadir, Abdelkrim; Kavalakatt, Sina; Warsame, Samia; Dehbi, Mohammed; Behbehani, Kazem; Abubaker, Jehad

    2015-01-01

    Heat shock response (HSR) is an essential host-defense mechanism that is dysregulated in obesity-induced insulin resistance and type 2 diabetes (T2D). Our recent data demonstrated that DNAJB3 was downregulated in obese human subjects and showed negative correlation with inflammatory markers. Nevertheless, DNAJB3 expression pattern in diabetic subjects and its mode of action are not yet known. In this study, we showed reduction in DNAJB3 transcript and protein levels in PBMC and subcutaneous adipose tissue of obese T2D compared to obese non-diabetic subjects. Overexpression of DNAJB3 in HEK293 and 3T3-L1 cells reduced JNK, IRS-1 Ser-307 phosphorylation and enhanced Tyr-612 phosphorylation suggesting an improvement in IRS-1 signaling. Furthermore, DNAJB3 mediated the PI3K/AKT pathway activation through increasing AKT and AS160 phosphorylation. AS160 mediates the mobilization of GLUT4 transporter to the cell membrane and thereby improves glucose uptake. Using pre-adipocytes cells we showed that DNAJB3 overexpression caused a significant increase in the glucose uptake, possibly through its phosphorylation of AS160. In summary, our results shed the light on the possible role of DNAJB3 in improving insulin sensitivity and glucose uptake through JNK repression and suggest that DNAJB3 could be a potential target for therapeutic treatment of obesity-induced insulin resistance. PMID:26400768

  14. Elevated postmortem ethanol concentrations in an insulin-dependent diabetic.

    PubMed

    Collison, Ines B

    2005-10-01

    A 54-year-old woman (165 cm, 37 kg) was found dead in her home during a welfare check after not having been seen for at least three days. The body showed clear evidence of decomposition. Her head was in what appeared to be a pool of blood. The residence was clean, neat, and showed no evidence of violence. Insulin was found in the refrigerator, and syringes were in the kitchen cabinet. In agreement with these physical findings, her clinical history indicated that she suffered insulin-dependent diabetes mellitus. Autolytic changes were noticed at autopsy, and no obvious cause of death was demonstrated. The autopsy heart blood sample screened negative for cocaine and/or metabolite (benzoylecgonine), phenethylamines, opiates, and barbiturates by radioimmunoassay. The alcohol concentration was 0.51 g/dL in the blood, 0.04 g/dL in the brain, 0.08 g/dL in the liver, and 0.05 g/dL in the urine, and acetone levels were 42 mg/dL, 53 mg/dL, 14 mg/dL, and 19 mg/dL, respectively. Isopropanol was also present in all samples analyzed. The cause of death was ruled as metabolic acidosis due to diabetes mellitus. Possible bacterial postmortem production of ethanol is considered as an explanation for the increased concentration of ethanol found in the postmortem heart blood.

  15. Effects of maternal ethanol ingestion on uptake of glucose alanine analogs in fetal rats

    SciTech Connect

    Snyder, A.K.; Singh, S.P.; Pullen, G.L.

    1986-05-01

    The distribution of maternally-derived glucose and alanine has been studied in selected tissues of fetuses from ethanol-fed (EF) rats (30% of caloric intake throughout gestation). Controls received diet without ethanol by pair-feeding (PF) or ad libitum (AF). On the 22nd day of gestation, 2 ..mu..Ci /sup 3/H 2-deoxyglucose (DG) and 1 ..mu..Ci /sup 14/C ..cap alpha..-aminoisobutyric acid (AIB) were administered i.v. to each rat. One hour later, maternal blood, placenta, and fetal blood, liver, lung and brain were sampled for /sup 3/H and /sup 14/C activities. When compared to either control group, the mean /sup 14/C AIB activities of tissues from EF animals were reduced from 19 to 46%, with the greatest effect seen in the brain (3.7 +/- 0.1, 7.2 +/- 0.3 and 6.9 +/- 1.3 dpm/mg in EF, PF and AF fetuses respectively). In addition, the ratios of tissue:plasma /sup 14/C were reduced (p < 0.01 or lower) in the EF fetal tissues and placenta. Maternal ethanol ingestion reduced the /sup 3/H 2-DG content of placenta (p < 0.05) and of brain (38.6 + 1.2, 48.1 +/- 1.2 and 47.2 +/- 1.2 in EF, PF and AF, p < 0.001). Brain weight showed significant positive correlations with AIB content (r = 0.466, p < 0.001) and with 2-DG content (r = 0.267, p < 0.01). Impaired uptake of maternally-derived nutrients may play a significant role in the effects of ethanol in utero.

  16. A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes

    PubMed Central

    Karunanithi, Sheelarani; Xiong, Tingting; Uhm, Maeran; Leto, Dara; Sun, Jingxia; Chen, Xiao-Wei; Saltiel, Alan R.

    2014-01-01

    Insulin-stimulated glucose uptake in fat and muscle is mediated by the major facilitative glucose transporter Glut4. Insulin controls the trafficking of Glut4 to the plasma membrane via regulation of a series of small G proteins, including RalA and Rab10. We demonstrate here that Rab10 is a bona fide target of the GTPase-activating protein AS160, which is inhibited after phosphorylation by the protein kinase Akt. Once activated, Rab10 can increase the GTP binding of RalA by recruiting the Ral guanyl nucleotide exchange factor, Rlf/Rgl2. Rab10 and RalA reside in the same pool of Glut4-storage vesicles in untreated cells, and, together with Rlf, they ensure maximal glucose transport. Overexpression of membrane-tethered Rlf compensates for the loss of Rab10 in Glut4 translocation, suggesting that Rab10 recruits Rlf to membrane compartments for RalA activation and that RalA is downstream of Rab10. Together these studies identify a new G protein cascade in the regulation of insulin-stimulated Glut4 trafficking and glucose uptake. PMID:25103239

  17. 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. PMID:26553070

  18. Identification of mannose uptake and catabolism genes in Corynebacterium glutamicum and genetic engineering for simultaneous utilization of mannose and glucose.

    PubMed

    Sasaki, Miho; Teramoto, Haruhiko; Inui, Masayuki; Yukawa, Hideaki

    2011-03-01

    Here, focus is on Corynebacterium glutamicum mannose metabolic genes with the aim to improve this industrially important microorganism's ability to ferment mannose present in mixed sugar substrates. cgR_0857 encodes C. glutamicum's protein with 36% amino acid sequence identity to mannose 6-phosphate isomerase encoded by manA of Escherichia coli. Its deletion mutant did not grow on mannose and exhibited noticeably reduced growth on glucose as sole carbon sources. In effect, C. glutamicum manA is not only essential for growth on mannose but also important in glucose metabolism. A double deletion mutant of genes encoding glucose and fructose permeases (ptsG and ptsF, respectively) of the phosphoenolpyruvate-dependent phosphotransferase system (PTS) was not able to grow on mannose unlike the respective single deletion mutants with mannose utilization ability. A mutant deficient in ptsH, a general PTS gene, did not utilize mannose. These indicate that the glucose-PTS and fructose-PTS are responsible for mannose uptake in C. glutamicum. When cultured with a glucose and mannose mixture, mannose utilization of manA-overexpressing strain CRM1 was significantly higher than that of its wild-type counterpart, but with a strong preference for glucose. ptsF-overexpressing strain CRM2 co-utilized mannose and glucose, but at a total sugar consumption rate much lower than that of the wild-type strain and CRM1. Strain CRM3 overexpressing both manA and ptsF efficiently co-utilized mannose and glucose. Under oxygen-deprived conditions, high volumetric productivity of organic acids concomitant with the simultaneous consumption of the mixed sugars was achieved by the densely packed growth-arrested CRM3 cells.

  19. Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus.

    PubMed

    Meyerovitch, J; Rothenberg, P; Shechter, Y; Bonner-Weir, S; Kahn, C R

    1991-04-01

    We have studied the effects of oral administration of vanadate, an insulinometic agent and a potent inhibitor of phosphotyrosyl protein phosphatase (PTPase) in vitro, on blood glucose and PTPase action, in two hyperinsulinemic rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of vanadate (0.25 mg/ml in the drinking water) to ob/ob mice for 3 wk lowered blood glucose level from 236 +/- 4 to 143 +/- 2 mg/dl without effect on body weight. Administration of vanadate to db/db mice produced a similar effect. Electron microscopic examination revealed no signs of hepatotoxicity after 47 d of treatment. There was a slight reduction in insulin receptor autophosphorylation when tested by immunoblotting with antiphosphotyrosine antibody after in vivo stimulation, and the phosphorylation of the endogenous substrate of the insulin receptor, pp185, was markedly decreased in the ob/ob mice. Both cytosolic and particulate PTPase activities in liver of ob/ob mice measured by dephosphorylation of a 32P-labeled peptide corresponding to the major site of insulin receptor autophosphorylation were decreased by approximately 50% (P less than 0.01). In db/db diabetic mice, PTPase activity in the cytosolic fraction was decreased to 53% of control values (P less than 0.02) with no significant difference in the particulate PTPase activity. Treatment with vanadate did not alter hepatic PTPase activity as assayed in vitro, or receptor and substrate phosphorylation as assayed in vivo, in ob/ob mice despite its substantial effect on blood glucose. These data indicate that vanadate is an effective oral hypoglycemic treatment in NIDDM states and suggest that its major effects occurs distal to the insulin receptor tyrosine kinase.

  20. Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways.

    PubMed

    Hsieh, Chi-Fen; Tsuei, Yi-Wei; Liu, Chi-Wei; Kao, Chung-Cheng; Shih, Li-Jane; Ho, Low-Tone; Wu, Liang-Yi; Wu, Chi-Peng; Tsai, Pei-Hua; Chang, Hsin-Huei; Ku, Hui-Chen; Kao, Yung-Hsi

    2010-10-01

    Insulin and (-)-epigallocatechin gallate (EGCG) are reported to regulate obesity and fat accumulation, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated glucose uptake in 3T3-L1 and C3H10T1/2 adipocytes. EGCG inhibited insulin stimulation of adipocyte glucose uptake in a dose- and time-dependent manner. The concentration of EGCG that decreased insulin-stimulated glucose uptake by 50-60% was approximately 5-10 µM for a period of 2 h. At 10 µM, EGCG and gallic acid were more effective than (-)-epicatechin, (-)-epigallocatechin, and (-)-epicatechin 3-gallate. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and extended the findings for this study to clarify whether EGCG-induced changes in insulin-stimulated glucose uptake in adipocytes could be mediated through the 67LR. Pretreatment of adipocytes with a 67LR antibody, but not normal rabbit immunoglobulin, prevented the effects of EGCG on insulin-increased glucose uptake. This suggests that the 67LR mediates the effect of EGCG on insulin-stimulated glucose uptake in adipocytes. Moreover, pretreatment with an AMP-activated protein kinase (AMPK) inhibitor, such as compound C, but not with a glutathione (GSH) activator, such as N-acetyl-L-cysteine (NAC), blocked the antiinsulin effect of EGCG on adipocyte glucose uptake. These data suggest that EGCG exerts its anti-insulin action on adipocyte glucose uptake via the AMPK, but not the GSH, pathway. The results of this study possibly support that EGCG mediates fat content.

  1. Risk factors for development of microalbuminuria in insulin dependent diabetic patients: a cohort study. Microalbuminuria Collaborative Study Group, United Kingdom.

    PubMed Central

    1993-01-01

    OBJECTIVE--To investigate the risk factors for the development of persistent microalbuminuria in insulin dependent diabetic patients. DESIGN--Four year follow up of a cohort of diabetic patients. SETTING--Outpatient departments of teaching and district general hospitals in England. SUBJECTS--148 non-microalbuminuric, non-hypertensive insulin dependent diabetic patients. MAIN OUTCOME MEASURES--Urinary albumin excretion rate and arterial blood pressure. RESULTS--137 patients completed four year follow up, of whom 11 developed persistent microalbumin-uria (albumin excretion rate > or = 30 micrograms/min on at least two consecutive occasions), giving a cumulative frequency of 8%. 103 remained normoalbuminuric and 23 exhibited intermittent microalbuminuria. At baseline the persistent microalbuminuric group had had significantly raised blood pressure (mean 137.9 (SD 14.9)/82.3 (7.6) v 123.5 (13.2)/72.8 (9.1) mm Hg), glycated haemoglobin concentration 10.4% (2.0%) v 8-9% (2.0%), and albumin excretion rate (median (interquartile range) 17.5 (13.0-22.3) v 4.8 (3.7-6.7) micrograms/min) (p < 0.05 for all) compared with the normo-albuminuric group. Blood pressure and glycated haemoglobin remained significantly higher in the persistent microalbuminuric group throughout the study (p < 0.05). Multiple regression analysis showed initial albumin excretion rate, blood pressure, and smoking to be significant determinants of persistent microalbuminuria (p < 0.02). CONCLUSION--In insulin dependent diabetic patients with poor glucose control, which may initially increase albumin excretion rate, an early rise of arterial pressure and smoking are implicated in the development of persistent microalbuminuria. Images p1237-a PMID:8499853

  2. Does apical membrane GLUT2 have a role in intestinal glucose uptake?

    PubMed Central

    Naftalin, Richard J

    2014-01-01

    It has been proposed that the non-saturable component of intestinal glucose absorption, apparent following prolonged exposure to high intraluminal glucose concentrations, is mediated via the low affinity glucose and fructose transporter, GLUT2, upregulated within the small intestinal apical border. The evidence that the non-saturable transport component is mediated via an apical membrane sugar transporter is that it is inhibited by phloretin, after exposure to phloridzin. Since the other apical membrane sugar transporter, GLUT5, is insensitive to inhibition by either cytochalasin B, or phloretin, GLUT2 was deduced to be the low affinity sugar transport route. As in its uninhibited state, polarized intestinal glucose absorption depends both on coupled entry of glucose and sodium across the brush border membrane and on the enterocyte cytosolic glucose concentration exceeding that in both luminal and submucosal interstitial fluids, upregulation of GLUT2 within the intestinal brush border will usually stimulate downhill glucose reflux to the intestinal lumen from the enterocytes; thereby reducing, rather than enhancing net glucose absorption across the luminal surface. These states are simulated with a computer model generating solutions to the differential equations for glucose, Na and water flows between luminal, cell, interstitial and capillary compartments. The model demonstrates that uphill glucose transport via SGLT1 into enterocytes, when short-circuited by any passive glucose carrier in the apical membrane, such as GLUT2, will reduce transcellular glucose absorption and thereby lead to increased paracellular flow. The model also illustrates that apical GLUT2 may usefully act as an osmoregulator to prevent excessive enterocyte volume change with altered luminal glucose concentrations. PMID:25671087

  3. Insulin Signaling and Glucose Uptake in the Soleus Muscle of 30-Month-Old Rats After Calorie Restriction With or Without Acute Exercise.

    PubMed

    Wang, Haiyan; Sharma, Naveen; Arias, Edward B; Cartee, Gregory D

    2016-03-01

    Exercise and calorie restriction (CR) can each improve insulin sensitivity in older individuals, but benefits of combining these treatments on skeletal muscle insulin signaling and glucose uptake are poorly understood, especially in predominantly slow-twitch muscles (eg, soleus). Accordingly, our purpose was to determine independent and combined effects of prior acute exercise and CR (beginning at 14 weeks old) on insulin signaling and glucose uptake in insulin-stimulated soleus muscles of 30-month-old rats. CR alone (but not exercise alone) versus ad libitum sedentary controls induced greater insulin-stimulated glucose uptake. There was a main effect of diet (CR > ad libitum) for insulin-stimulated Akt(Ser473) and Akt(Thr308) phosphorylation. CR alone versus ad libitum sedentary increased Akt substrate of 160 kDa (AS160) Ser(588) phosphorylation and TBC1D1 Thr(596), but not AS160 Thr(642) phosphorylation or abundance of GLUT4, GLUT1, or hexokinase II proteins. Combined CR and exercise versus CR alone did not further increase insulin-stimulated glucose uptake although phosphorylation of Akt(Ser473), Akt(Thr308), TBC1D1(Thr596), and AMPK(Thr172) for the combined group exceeded values for CR and/or exercise alone. These results revealed that although the soleus was highly responsive to a CR-induced enhancement of insulin-stimulated glucose uptake, the exercise protocol did not elevate insulin-stimulated glucose uptake, either alone or when combined with CR.

  4. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81.

    PubMed

    Ahmed, Kashan; Tunaru, Sorin; Tang, Cong; Müller, Michaela; Gille, Andreas; Sassmann, Antonia; Hanson, Julien; Offermanns, Stefan

    2010-04-01

    Lactate is an important metabolic intermediate released by skeletal muscle and other organs including the adipose tissue, which converts glucose into lactate under the influence of insulin. Here we show that lactate activates the G protein-coupled receptor GPR81, which is expressed in adipocytes and mediates antilipolytic effects through G(i)-dependent inhibition of adenylyl cyclase. Using GPR81-deficient mice, we demonstrate that the receptor is not involved in the regulation of lipolysis during intensive exercise. However, insulin-induced inhibition of lipolysis and insulin-induced decrease in adipocyte cAMP levels were strongly reduced in mice lacking GPR81, although insulin-dependent release of lactate by adipocytes was comparable between wild-type and GPR81-deficient mice. Thus, lactate and its receptor GPR81 unexpectedly function in an autocrine and paracrine loop to mediate insulin-induced antilipolytic effects. These data show that lactate can directly modulate metabolic processes in a hormone-like manner, and they reveal a new mechanism underlying the antilipolytic effects of insulin.

  5. Effect of Solanum surattense on mitochondrial enzymes in diabetic rats and in vitro glucose uptake activity in L6 myotubes

    PubMed Central

    Sridevi, Muruhan; Kalaiarasi, Pannerselvam; Pugalendi, Kodukkur Viswanathan

    2015-01-01

    Background: S. surattense is widely used in Siddha medicine for various ailments. Objective: The aim was to evaluate the impact of alcoholic leaf-extract of S. surattense on mitochondrial enzymes in streptozotocin (STZ) induced diabetic rats and to study the in vitro muscle glucose uptake activity on L6 myotubes. Materials and Methods: The male albino Wistar rats were randomly divided into five groups of six animals each. Diabetes was induced by intraperitoneal injection of STZ (40 mg/kg body weight). After being confirmed the diabetic rats were treated with alcoholic leaf-extract of S. surattense (100 mg/kg body weight) for 45 days. The biochemical estimations (liver mitochondrial enzymes, antioxidants, thiobarbituric acid reactive substances [TBARS]) and histopathological studies were performed. Further, the in vitro muscle glucose uptake activity in L6 myotubes and messenger RNA (mRNA) expression of glucose transporter-4 (GLUT-4) was performed. Results: In diabetic rats, the activities of liver mitochondrial enzymes were found to be significantly lowered. The mitochondrial TBARS level increased, whereas the activities/level of enzymatic and non-enzymatic antioxidants decreased in diabetic rats. Administration of S. surattense to diabetic rats significantly reversed the above parameters toward normalcy. Furthermore in diabetic rats, the histopathological studies showed growth of adipose tissue and shrinkage of islets in the pancreas, liver showed fatty change with mild inflammation of portal triad, and kidney showed messangial capillary proliferation of glomeruli and fatty infiltration of tubules. Treatment with S. surattense brought back these changes to near normalcy. The extract was analyzed for in vitro muscle glucose uptake activity in L6 myotubes and mRNA expression of GLUT-4 by semi-quantitative reverse transcriptase-polymerase chain reaction. One nano gram per millilitre of S. surattense leaf-extract gave 115% glucose uptake on L6 myotubes. It also showed

  6. Involvement of functional groups on the surface of carboxyl group-terminated polyamidoamine dendrimers bearing arbutin in inhibition of Na⁺/glucose cotransporter 1 (SGLT1)-mediated D-glucose uptake.

    PubMed

    Sakuma, Shinji; Kanamitsu, Shun; Teraoka, Yumi; Masaoka, Yoshie; Kataoka, Makoto; Yamashita, Shinji; Shirasaka, Yoshiyuki; Tamai, Ikumi; Muraoka, Masahiro; Nakatsuji, Yohji; Kida, Toshiyuki; Akashi, Mitsuru

    2012-04-01

    A carboxyl group-terminated polyamidoamine dendrimer (generation: 3.0) bearing arbutin, which is a substrate of Na⁺/glucose cotransporter 1 (SGLT1), via a nonbiodegradable ω-amino triethylene glycol linker (PAMAM-ARB), inhibits SGLT1-mediated D-glucose uptake, as does phloridzin, which is a typical SGLT1 inhibitor. Here, since our previous research revealed that the activity of arbutin was dramatically improved through conjugation with the dendrimer, we examined the involvement of functional groups on the dendrimer surface in inhibition of SGLT1-mediated D-glucose uptake. PAMAM-ARB, with a 6.25% arbutin content, inhibited in vitro D-glucose uptake most strongly; the inhibitory effect decreased as the arbutin content increased. In vitro experiments using arbutin-free original dendrimers indicated that dendrimer-derived carboxyl groups actively participated in SGLT1 inhibition. However, the inhibitory effect was much less than that of PAMAM-ARB and was equal to that of glucose moiety-free PAMAM-ARB. Data supported that the glucose moiety of arbutin was essential for the high activity of PAMAM-ARB in SGLT1 inhibition. Analysis of the balance of each domain further suggested that carboxyl groups anchored PAMAM-ARB to SGLT1, and the subsequent binding of arbutin-derived glucose moieties to the target sites on SGLT1 resulted in strong inhibition of SGLT1-mediated D-glucose uptake.

  7. Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway.

    PubMed

    Gandhi, Gopalsamy Rajiv; Jothi, Gnanasekaran; Antony, Poovathumkal James; Balakrishna, Kedike; Paulraj, Michael Gabriel; Ignacimuthu, Savarimuthu; Stalin, Antony; Al-Dhabi, Naif Abdullah

    2014-12-15

    In this study, the therapeutic efficacy of gallic acid from Cyamopsis tetragonoloba (L.) Taub. (Fabaceae) beans was examined against high-fat diet fed-streptozotocin-induced experimental type 2 diabetic rats. Molecular-dockings were done to determine the putative binding modes of gallic acid into the active sites of key insulin-signaling markers. Gallic acid (20 mg/kg) given to high-fat diet fed-streptozotocin-induced rats lowered body weight gain, fasting blood glucose and plasma insulin in diabetic rats. It further restored the alterations of biochemical parameters to near normal levels in diabetic treated rats along with cytoprotective action on pancreatic β-cell. Histology of liver and adipose tissues supported the biochemical findings. Gallic acid significantly enhanced the level of peroxisome proliferator-activated receptor γ (PPARγ) expression in the adipose tissue of treated rat compared to untreated diabetic rat; it also slightly activated PPARγ expressions in the liver and skeletal muscle. Consequently, it improved insulin-dependent glucose transport in adipose tissue through translocation and activation of glucose transporter protein 4 (GLUT4) in phosphatidylinositol 3-kinase (PI3K)/phosphorylated protein kinase B (p-Akt) dependent pathway. Gallic acid docked with PPARγ; it exhibited promising interactions with the GLUT4, glucose transporter protein 1 (GLUT1), PI3K and p-Akt. These findings provided evidence to show that gallic acid could improve adipose tissue insulin sensitivity, modulate adipogenesis, increase adipose glucose uptake and protect β-cells from impairment. Hence it can be used in the management of obesity-associated type 2 diabetes mellitus.

  8. Mechanism of action of the stimulatory effect of apigenin-6-C-(2''-O-alpha-l-rhamnopyranosyl)-beta-L-fucopyranoside on 14C-glucose uptake.

    PubMed

    Cazarolli, Luisa Helena; Folador, Poliane; Moresco, Henrique Hunger; Brighente, Inês Maria Costa; Pizzolatti, Moacir Geraldo; Silva, Fátima Regina Mena Barreto

    2009-05-15

    There has been a growing interest in hypoglycemic agents from natural products, particularly those derived from plants. Flavonoids are naturally occurring phenolic compounds with a broad range of biological activities and the beneficial effects of flavonoids have been studied in relation to diabetes mellitus, either through their capacity to avoid glucose absorption or to improve glucose tolerance. The purpose of this study was to investigate the mechanism of action of the stimulatory effect of apigenin-6-C-(2''-O-alpha-L-rhamnopyranosyl)-beta-L-fucopyranoside (1), isolated from Averrhoa carambola L. (Oxalidaceae) leaves, on (14)C-glucose uptake. This compound (1) was found to have an acute effect on blood glucose lowering in diabetic rats and stimulated glucose-induced insulin secretion after oral treatment in hyperglycemic rats. A significant stimulatory effect of compound 1 on (14)C-glucose uptake was observed at 50 and 100 microM. The effect of compound 1 on glucose uptake was completely nullified by wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), RO318220, an inhibitor of protein kinase C (PKC), PD98059, a specific inhibitor of mitogen-activated protein kinase (MEK), cycloheximide, an inhibitor of protein synthesis, and colchicine, a microtubule-depolymerizing agent. Compound 1 (100 microM) and insulin (10 nM) did not show any synergistic effect on glucose uptake. These results suggest that the flavonoid may have a dual target of action, as an insulin-secretagogue and also as an insulin-mimetic agent.

  9. Diastereomeric mixture of calophyllic acid and isocalophyllic acid stimulates glucose uptake in skeletal muscle cells: involvement of PI-3-kinase- and ERK1/2-dependent pathways.

    PubMed

    Prasad, Janki; Maurya, Chandan Kumar; Pandey, Jyotsana; Jaiswal, Natasha; Madhur, Gaurav; Srivastava, Arvind Kumar; Narender, Tadigoppula; Tamrakar, Akhilesh Kumar

    2013-05-01

    The diastereomeric mixture of calophyllic acid and isocalophyllic acid (F015) isolated from the leaves of Calophyllum inophyllum was investigated for the metabolic effect on glucose transport in skeletal muscle cells. In L6 myotubes, F015 dose-dependently stimulated glucose uptake by increasing translocation of glucose transporter4 (GLUT4) to plasma membrane without affecting their gene expression. The effects on glucose uptake were additive to insulin. Inhibitors analyses revealed that F015-induced glucose uptake was dependent on the activation of phosphatidylinositol-3-kinase (PI-3-K) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), while independent to the activation of 5'AMP-activated kinase (AMPK). F015 significantly increased the phosphorylation of AKT, AS160 and ERK1/2, account for the augmented glucose transport capacity in L6 myotubes. Furthermore, F015 improved glucose tolerance and enhanced insulin sensitivity in skeletal muscle of dexamethasone-induced insulin resistant mice. Our findings demonstrate that F015 activates glucose uptake in skeletal muscle cells through PI-3-K- and EKR1/2-dependent mechanisms and can be a potential lead for the management of diabetes and obesity.

  10. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease.

    PubMed

    Cunnane, Stephen C; Courchesne-Loyer, Alexandre; St-Pierre, Valérie; Vandenberghe, Camille; Pierotti, Tyler; Fortier, Mélanie; Croteau, Etienne; Castellano, Christian-Alexandre

    2016-03-01

    Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed. PMID:26766547

  11. Role for the microtubule cytoskeleton in GLUT4 vesicle trafficking and in the regulation of insulin-stimulated glucose uptake.

    PubMed Central

    Fletcher, L M; Welsh, G I; Oatey, P B; Tavaré, J M

    2000-01-01

    Insulin stimulates glucose uptake into adipocytes by promoting the translocation of the glucose transporter isoform 4 (GLUT4) from intracellular vesicles to the plasma membrane. In 3T3-L1 adipocytes GLUT4 resides both in an endosomal pool, together with transferrin receptors, and in a unique pool termed 'GLUT4 storage vesicles' (GSVs), which excludes endosomal proteins. The trafficking of GLUT4 vesicles was studied in living 3T3-L1 adipocytes by time-lapse confocal microscopy of GLUT4 tagged with green fluorescent protein. GLUT4 vesicles exhibited two types of motion: rapid vibrations around a point and short (generally less than 10 microm) linear movements. The linear movements were completely blocked by incubation of the cells in the presence of microtubule-depolymerizing agents. This suggests that a subpopulation of GLUT4 vesicles can exhibit motor-driven movements along microtubules. Upon further examination, microtubule depolymerization inhibited insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane by approx. 40%, but had no effect on insulin-induced translocation of the transferrin receptor to the plasma membrane from endosomes. We propose that an intact microtubule cytoskeleton may be required for optimal trafficking of GLUT4 present in the GSV pool, but not that resident in the endosomal pool. PMID:11085918

  12. The cholesterol-lowering agent methyl-β-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice.

    PubMed

    Llanos, Paola; Contreras-Ferrat, Ariel; Georgiev, Tihomir; Osorio-Fuentealba, Cesar; Espinosa, Alejandra; Hidalgo, Jorge; Hidalgo, Cecilia; Jaimovich, Enrique

    2015-02-15

    Insulin stimulates glucose uptake in adult skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the transverse tubule (T-tubule) membranes, which have particularly high cholesterol levels. We investigated whether T-tubule cholesterol content affects insulin-induced glucose transport. Feeding mice a high-fat diet (HFD) for 8 wk increased by 30% the T-tubule cholesterol content of triad-enriched vesicular fractions from muscle tissue compared with triads from control mice. Additionally, isolated muscle fibers (flexor digitorum brevis) from HFD-fed mice showed a 40% decrease in insulin-stimulated glucose uptake rates compared with fibers from control mice. In HFD-fed mice, four subcutaneous injections of MβCD, an agent reported to extract membrane cholesterol, improved their defective glucose tolerance test and normalized their high fasting glucose levels. The preincubation of isolated muscle fibers with relatively low concentrations of MβCD increased both basal and insulin-induced glucose uptake in fibers from controls or HFD-fed mice and decreased Akt phosphorylation without altering AMPK-mediated signaling. In fibers from HFD-fed mice, MβCD improved insulin sensitivity even after Akt or CaMK II inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, prevented the stimulatory effects of MβCD on glucose uptake. Addition of MβCD elicited ryanodine receptor-mediated calcium signals in isolated fibers, which were essential for glucose uptake. Our findings suggest that T-tubule cholesterol content exerts a critical regulatory role on insulin-stimulated GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may represent a useful strategy to counteract insulin resistance.

  13. Enhancement of glucose uptake in skeletal muscle L6 cells and insulin secretion in pancreatic hamster-insulinoma-transfected cells by application of non-thermal plasma jet

    NASA Astrophysics Data System (ADS)

    Kumar, Naresh; Kaushik, Nagendra K.; Park, Gyungsoon; Choi, Eun H.; Uhm, Han S.

    2013-11-01

    Type-II diabetes Mellitus is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue, and liver and pancreatic beta cells. Since the skeletal muscle accounts for approximately 75% of insulin-stimulated glucose-uptake in our body, impaired insulin secretion from defected beta cell plays a major role in the afflicted glucose homoeostasis. It was shown that the intracellular reactive oxygen species and nitric oxide level was increased by non-thermal-plasma treatment in ambient air. These increased intracellular reactive species may enhance glucose uptake and insulin secretion through the activation of intracellular calcium (Ca+) and cAMP production.

  14. 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

  15. Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding.

    PubMed

    Coate, Katie C; Kraft, Guillaume; Moore, Mary Courtney; Smith, Marta S; Ramnanan, Christopher; Irimia, Jose M; Roach, Peter J; Farmer, Ben; Neal, Doss W; Williams, Phil; Cherrington, Alan D

    2014-07-15

    In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3-4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg(-1)·min(-1)) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg(-1)·min(-1) in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.

  16. FGT-1-mediated glucose uptake is defective in insulin/IGF-like signaling mutants in Caenorhabditis elegans.

    PubMed

    Kitaoka, Shun; Morielli, Anthony D; Zhao, Feng-Qi

    2016-06-01

    Insulin signaling plays a central role in the regulation of facilitative glucose transporters (GLUTs) in humans. To establish Caenorhabditis elegans (C. elegans) as a model to study the mechanism underlying insulin regulation of GLUT, we identified that FGT-1 is most likely the only functional GLUT homolog in C. elegans and is ubiquitously expressed. The FGT-1-mediated glucose uptake was almost completely defective in insulin/IGF-like signaling (IIS) mutants daf-2 and age-1, and this defect mainly resulted from the down-regulated FGT-1 protein expression. However, glycosylation may also be involved because OGA-1, an O-GlcNAcase, was essential for the function of FGT-1. Thus, our study showed that C. elegans can be a new powerful model system to study insulin regulation of GLUT. PMID:27419060

  17. APPL1 promotes glucose uptake in response to mechanical stretch via the PKCζ-non-muscle myosin IIa pathway in C2C12 myotubes.

    PubMed

    Saito, Tsugumichi; Okada, Shuichi; Shimoda, Yoko; Tagaya, Yuko; Osaki, Aya; Yamada, Eijiro; Shibusawa, Ryo; Nakajima, Yasuyo; Ozawa, Atsushi; Satoh, Tetsurou; Mori, Masatomo; Yamada, Masanobu

    2016-11-01

    Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCζ was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCζ co-immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCζ co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCζ translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCζ, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes. PMID:27478065

  18. Effects of melatonin on 2-deoxy-(1-/sup 14/C)glucose uptake within rat suprachiasmatic nucleus

    SciTech Connect

    Cassone, V.M.; Roberts, M.H.; Moore, R.Y.

    1988-08-01

    Previously, we have demonstrated that metabolic activity, shown by autoradiographic determination of 2-deoxy-(1-/sup 14/C)glucose (2-DG) uptake, within the rat hypothalamic suprachiasmatic nuclei (SCN) was inhibited by subcutaneous injection of 1 mg/kg melatonin. To determine whether this effect was specific to a particular time of day, the effects of melatonin on 2-DG uptake were studied in several hypothalamic areas, including the SCN, supraoptic nuclei (SON), lateral hypothalamic area (LHA), and anterior hypothalamic area (AHA) every 4 h throughout the circadian day. In a second experiment, the effects of different melatonin doses were studied at the time of day at which melatonin had its maximal effect to determine the dose-response relationship of melatonin-induced inhibition of SCN 2-DG uptake. The data indicate that melatonin inhibited 2-DG uptake in the SCN alone at one time of day, primarily at circadian time (CT) 6 and CT10, 2-6 h before subjective dusk, and secondarily at CT22, just before subjective dawn. This effect was dose dependent with a 50% effective dose of 1.49 +/- 2.30 micrograms/kg. The temporal and dose-response characteristics of these effects are similar to those characterizing the entraining effects of melatonin on circadian patterns of locomotion and drinking.

  19. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity

    PubMed Central

    Lobo, Rebecca C.; Hubbard, Neil E.; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L.; Go, Aiza C.; Anderson, Steve E.; Cala, Peter M.; Borowsky, Alexander D.

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2′,7′-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings

  20. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity

    PubMed Central

    Lobo, Rebecca C.; Hubbard, Neil E.; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L.; Go, Aiza C.; Anderson, Steve E.; Cala, Peter M.; Borowsky, Alexander D.

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2′,7′-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings

  1. Glucose Uptake and Intracellular pH in a Mouse Model of Ductal Carcinoma In situ (DCIS) Suggests Metabolic Heterogeneity.

    PubMed

    Lobo, Rebecca C; Hubbard, Neil E; Damonte, Patrizia; Mori, Hidetoshi; Pénzváltó, Zsófia; Pham, Cindy; Koehne, Amanda L; Go, Aiza C; Anderson, Steve E; Cala, Peter M; Borowsky, Alexander D

    2016-01-01

    Mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma remain unclear. Previously we showed that the transition to invasiveness in the mammary intraepithelial neoplastic outgrowth (MINO) model of DCIS does not correlate with its serial acquisition of genetic mutations. We hypothesized instead that progression to invasiveness depends on a change in the microenvironment and that precancer cells might create a more tumor-permissive microenvironment secondary to changes in glucose uptake and metabolism. Immunostaining for glucose transporter 1 (GLUT1) and the hypoxia marker carbonic anhydrase 9 (CAIX) in tumor, normal mammary gland and MINO (precancer) tissue showed differences in expression. The uptake of the fluorescent glucose analog dye, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG), reflected differences in the cellular distributions of glucose uptake in normal mammary epithelial cells (nMEC), MINO, and Met1 cancer cells, with a broad distribution in the MINO population. The intracellular pH (pHi) measured using the fluorescent ratio dye 2',7'-bis(2-carboxyethyl)-5(6)-155 carboxyfluorescein (BCECF) revealed expected differences between normal and cancer cells (low and high, respectively), and a mixed distribution in the MINO cells, with a subset of cells in the MINO having an increased rate of acidification when proton efflux was inhibited. Invasive tumor cells had a more alkaline baseline pHi with high rates of proton production coupled with higher rates of proton export, compared with nMEC. MINO cells displayed considerable variation in baseline pHi that separated into two distinct populations: MINO high and MINO low. MINO high had a noticeably higher mean acidification rate compared with nMEC, but relatively high baseline pHi similar to tumor cells. MINO low cells also had an increased acidification rate compared with nMEC, but with a more acidic pHi similar to nMEC. These findings demonstrate

  2. The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake.

    PubMed

    Isakoff, S J; Taha, C; Rose, E; Marcusohn, J; Klip, A; Skolnik, E Y

    1995-10-24

    Recent experimental evidence has focused attention to the role of two molecules, insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3-kinase (PI3-kinase), in linking the insulin receptor to glucose uptake; IRS-1 knockout mice are insulin resistant, and pharmacological inhibitors of PI3-kinase block insulin-stimulated glucose uptake. To investigate the role of PI3-kinase and IRS-1 in insulin-stimulated glucose uptake we examined whether stimulation of insulin-sensitive cells with platelet-derived growth factor (PDGF) or with interleukin 4 (IL-4) stimulates glucose uptake; the activated PDGF receptor (PDGFR) directly binds and activates PI3-kinase, whereas the IL-4 receptor (IL-4R) activates PI3-kinase via IRS-1 or the IRS-1-related molecule 4PS. We found that stimulation of 3T3-L1 adipocytes with PDGF resulted in tyrosine phosphorylation of the PDGFR and activation of PI3-kinase in these cells. To examine whether IL-4 stimulates glucose uptake, L6 myoblasts were engineered to overexpress GLUT4 as well as both chains of the IL-4R (L6/IL-4R/GLUT4); when these L6/IL-4R/GLUT4 myoblasts were stimulated with IL-4, IRS-1 became tyrosine phosphorylated and associated with PI3-kinase. Although PDGF and IL-4 can activate PI3-kinase in the respective cell lines, they do not possess insulin's ability to stimulate glucose uptake and GLUT4 translocation to the plasma membrane. These findings indicate that activation of PI3-kinase is not sufficient to stimulate GLUT4 translocation to the plasma membrane. We postulate that activation of a second signaling pathway by insulin, distinct from PI3-kinase, is necessary for the stimulation of glucose uptake in insulin-sensitive cells.

  3. Hypoglycemic and hypolipidemic effects of processed Aloe vera gel in a mouse model of non-insulin-dependent diabetes mellitus.

    PubMed

    Kim, Kwanghee; Kim, Hyunyul; Kwon, Jeunghak; Lee, Sungwon; Kong, Hyunseok; Im, Sun-A; Lee, Young-Hee; Lee, Young-Ran; Oh, Sun-Tack; Jo, Tae Hyung; Park, Young In; Lee, Chong-Kil; Kim, Kyungjae

    2009-09-01

    The effects of processed Aloe vera gel (PAG) on the course of established diet-induced non-insulin-dependent diabetes mellitus (NIDDM) were studied in C57BL/6J mice. NIDDM was induced in C57BL/6J mice by feeding them a high-fat diet. Mice exhibiting diet-induced obesity (DIO) with blood glucose levels above 180mg/dl were selected to examine the antidiabetic effects of PAG. Oral administration of PAG for 8 weeks reduced circulating blood glucose concentrations to a normal level in these DIO mice. In addition, the administration of PAG significantly decreased plasma insulin. The antidiabetic effects of PAG were also confirmed by intraperitoneal glucose tolerance testing. PAG appeared to lower blood glucose levels by decreasing insulin resistance. The administration of PAG also lowered triacylglyceride levels in liver and plasma. Histological examinations of periepididymal fat pad showed that PAG reduced the average size of adipocytes. These results demonstrate that the oral administration of PAG prevents the progression of NIDDM-related symptoms in high-fat diet-fed mice, and suggest that PAG could be useful for treating NIDDM.

  4. Muscle-tendon glucose uptake in Achilles tendon rupture and tendinopathy before and after eccentric rehabilitation: Comparative case reports.

    PubMed

    Masood, Tahir; Kalliokoski, Kari; Bojsen-Møller, Jens; Finni, Taija

    2016-09-01

    Achilles tendon rupture (ATR) is the most common tendon rupture injury. The consequences of ATR on metabolic activity of the Achilles tendon and ankle plantarflexors are unknown. Furthermore, the effects of eccentric rehabilitation on metabolic activity patterns of Achilles tendon and ankle plantarflexors in ATR patients have not been reported thus far. We present a case study demonstrating glucose uptake (GU) in the Achilles tendon, the triceps surae, and the flexor hallucis longus of a post-surgical ATR patient before and after a 5-month eccentric rehabilitation. At baseline, three months post-surgery, all muscles and Achilles tendon displayed much higher GU in the ATR patient compared to a healthy individual despite lower plantarflexion force. After the rehabilitation, plantarflexion force increased in the operated leg while muscle GU was considerably reduced. The triceps surae muscles showed similar values to the healthy control. When compared to the healthy or a matched patient with Achilles tendon pain after 12 weeks of rehabilitation, Achilles tendon GU levels of ATR patient remained greater after the rehabilitation. Past studies have shown a shift in the metabolic fuel utilization towards glycolysis due to immobilization. Further research, combined with immuno-histological investigation, is needed to fully understand the mechanism behind excessive glucose uptake in ATR cases. PMID:27428528

  5. Signaling of the p21-activated kinase (PAK1) coordinates insulin-stimulated actin remodeling and glucose uptake in skeletal muscle cells.

    PubMed

    Tunduguru, Ragadeepthi; Chiu, Tim T; Ramalingam, Latha; Elmendorf, Jeffrey S; Klip, Amira; Thurmond, Debbie C

    2014-11-15

    Skeletal muscle accounts for ∼ 80% of postprandial glucose clearance, and skeletal muscle glucose clearance is crucial for maintaining insulin sensitivity and euglycemia. Insulin-stimulated glucose clearance/uptake entails recruitment of glucose transporter 4 (GLUT4) to the plasma membrane (PM) in a process that requires cortical F-actin remodeling; this process is dysregulated in Type 2 Diabetes. Recent studies have implicated PAK1 as a required element in GLUT4 recruitment in mouse skeletal muscle in vivo, although its underlying mechanism of action and requirement in glucose uptake remains undetermined. Toward this, we have employed the PAK1 inhibitor, IPA3, in studies using L6-GLUT4-myc muscle cells. IPA3 fully ablated insulin-stimulated GLUT4 translocation to the PM, corroborating the observation of ablated insulin-stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1(-/-) knockout mice. IPA3-treatment also abolished insulin-stimulated glucose uptake into skeletal myotubes. Mechanistically, live-cell imaging of myoblasts expressing the F-actin biosensor LifeAct-GFP treated with IPA3 showed blunting of the normal insulin-induced cortical actin remodeling. This blunting was underpinned by a loss of normal insulin-stimulated cofilin dephosphorylation in IPA3-treated myoblasts. These findings expand upon the existing model of actin remodeling in glucose uptake, by placing insulin-stimulated PAK1 signaling as a required upstream step to facilitate actin remodeling and subsequent cofilin dephosphorylation. Active, dephosphorylated cofilin then provides the G-actin substrate for continued F-actin remodeling to facilitate GLUT4 vesicle translocation for glucose uptake into the skeletal muscle cell.

  6. Regulation of myosin IIA and filamentous actin during insulin-stimulated glucose uptake in 3T3-L1 adipocytes

    SciTech Connect

    Stall, Richard; Ramos, Joseph; Kent Fulcher, F.; Patel, Yashomati M.

    2014-03-10

    Insulin stimulated glucose uptake requires the colocalization of myosin IIA (MyoIIA) and the insulin-responsive glucose transporter 4 (GLUT4) at the plasma membrane for proper GLUT4 fusion. MyoIIA facilitates filamentous actin (F-actin) reorganization in various cell types. In adipocytes F-actin reorganization is required for insulin-stimulated glucose uptake. What is not known is whether MyoIIA interacts with F-actin to regulate insulin-induced GLUT4 fusion at the plasma membrane. To elucidate the relationship between MyoIIA and F-actin, we examined the colocalization of MyoIIA and F-actin at the plasma membrane upon insulin stimulation as well as the regulation of this interaction. Our findings demonstrated that MyoIIA and F-actin colocalized at the site of GLUT4 fusion with the plasma membrane upon insulin stimulation. Furthermore, inhibition of MyoII with blebbistatin impaired F-actin localization at the plasma membrane. Next we examined the regulatory role of calcium in MyoIIA-F-actin colocalization. Reduced calcium or calmodulin levels decreased colocalization of MyoIIA and F-actin at the plasma membrane. While calcium alone can translocate MyoIIA it did not stimulate F-actin accumulation at the plasma membrane. Taken together, we established that while MyoIIA activity is required for F-actin localization at the plasma membrane, it alone is insufficient to localize F-actin to the plasma membrane. - Highlights: • Insulin induces colocalization of MyoIIA and F-actin at the cortex in adipocytes. • MyoIIA is necessary but not sufficient to localize F-actin at the cell cortex. • MyoIIA-F-actin colocalization is regulated by calcium and calmodulin.

  7. Linking cytoarchitecture to metabolism: sarcolemma-associated plectin affects glucose uptake by destabilizing microtubule networks in mdx myofibers

    PubMed Central

    2013-01-01

    Background Duchenne muscular dystrophy (DMD) is one of the most frequent forms of muscular disorders. It is caused by the absence of dystrophin, a core component of the sarcolemma-associated junctional complex that links the cytoskeleton to the extracellular matrix. We showed previously that plectin 1f (P1f), one of the major muscle-expressed isoforms of the cytoskeletal linker protein plectin, accumulates at the sarcolemma of DMD patients as well as of mdx mice, a widely studied animal model for DMD. Based on plectin’s dual role as structural protein and scaffolding platform for signaling molecules, we speculated that the dystrophic phenotype observed after loss of dystrophin was caused, at least to some extent, by excess plectin. Thus, we hypothesized that elimination of plectin expression in mdx skeletal muscle, while probably resulting in an overall more severe phenotype, may lead to a partial phenotype rescue. In particular, we wanted to assess whether excess sarcolemmal plectin contributes to the dysregulation of sugar metabolism in mdx myofibers. Methods We generated plectin/dystrophin double deficient (dKO) mice by breeding mdx with conditional striated muscle-restricted plectin knockout (cKO) mice. The phenotype of these mice was comparatively analyzed with that of mdx, cKO, and wild-type mice, focusing on structural integrity and dysregulation of glucose metabolism. Results We show that the accumulation of plectin at the sarcolemma of mdx muscle fibers hardly compensated for their loss of structural integrity. Instead, it led to an additional metabolic deficit by impairing glucose uptake. While dKO mice suffered from an overall more severe form of muscular dystrophy compared to mdx or plectin-deficient mice, sarcolemmal integrity as well as glucose uptake of their myofibers were restored to normal levels upon ablation of plectin. Furthermore, microtubule (MT) networks in intact dKO myofibers, including subsarcolemmal areas, were found to be more robust

  8. An Outer Membrane Protein Involved in the Uptake of Glucose Is Essential for Cytophaga hutchinsonii Cellulose Utilization

    PubMed Central

    Zhou, Hong; Wang, Xia; Yang, Tengteng; Zhang, Weixin; Chen, Guanjun

    2016-01-01

    Cytophaga hutchinsonii specializes in cellulose digestion by employing a collection of novel cell-associated proteins. Here, we identified a novel gene locus, CHU_1276, that is essential for C. hutchinsonii cellulose utilization. Disruption of CHU_1276 in C. hutchinsonii resulted in complete deficiency in cellulose degradation, as well as compromised assimilation of cellobiose or glucose at a low concentration. Further analysis showed that CHU_1276 was an outer membrane protein that could be induced by cellulose and low concentrations of glucose. Transcriptional profiling revealed that CHU_1276 exerted a profound effect on the genome-wide response to both glucose and Avicel and that the mutant lacking CHU_1276 displayed expression profiles very different from those of the wild-type strain under different culture conditions. Specifically, comparison of their transcriptional responses to cellulose led to the identification of a gene set potentially regulated by CHU_1276. These results suggest that CHU_1276 plays an essential role in cellulose utilization, probably by coordinating the extracellular hydrolysis of cellulose substrate with the intracellular uptake of the hydrolysis product in C. hutchinsonii. PMID:26773084

  9. Selaginellin and biflavonoids as protein tyrosine phosphatase 1B inhibitors from Selaginella tamariscina and their glucose uptake stimulatory effects.

    PubMed

    Nguyen, Phi-Hung; Ji, Da-Jung; Han, Yu-Ran; Choi, Jae-Sue; Rhyu, Dong-Young; Min, Byung-Sun; Woo, Mi-Hee

    2015-07-01

    As part of an ongoing search for new antidiabetic agents from medicinal plants, the methanol extract of the aerial parts of Selaginella tamariscina was found to possess stimulatory effect on glucose uptake in 3T3-L1 adipocyte cells. Thus, bioassay-guided isolation of this active extract yielded two new compounds (1 and 2) along with five known biflavonoids (3-7). Their structures were elucidated by extensive analysis of spectroscopic and physicochemical data. The absolute configuration of compound 2 was determined by specific rotation and CD data analysis. All isolates exhibited potent inhibitory effects on PTP1B enzyme with IC50 values ranging from 4.5±0.1 to 13.2±0.8μM. Furthermore, the isolates (1-7) showed significant stimulatory effects on 2-NBDG uptake in 3T3-L1 adipocyte cells. Of these, compounds (1, 6, and 7) which exhibited mixed-competitive inhibition modes against PTP1B, showed potent stimulatory effects on 2-NBDG uptake. This result indicated the potential of these biflavonoids as lead molecules for development of antidiabetic agents and the beneficial use of S. tamariscina against hyperglycemia.

  10. Selaginellin and biflavonoids as protein tyrosine phosphatase 1B inhibitors from Selaginella tamariscina and their glucose uptake stimulatory effects.

    PubMed

    Nguyen, Phi-Hung; Ji, Da-Jung; Han, Yu-Ran; Choi, Jae-Sue; Rhyu, Dong-Young; Min, Byung-Sun; Woo, Mi-Hee

    2015-07-01

    As part of an ongoing search for new antidiabetic agents from medicinal plants, the methanol extract of the aerial parts of Selaginella tamariscina was found to possess stimulatory effect on glucose uptake in 3T3-L1 adipocyte cells. Thus, bioassay-guided isolation of this active extract yielded two new compounds (1 and 2) along with five known biflavonoids (3-7). Their structures were elucidated by extensive analysis of spectroscopic and physicochemical data. The absolute configuration of compound 2 was determined by specific rotation and CD data analysis. All isolates exhibited potent inhibitory effects on PTP1B enzyme with IC50 values ranging from 4.5±0.1 to 13.2±0.8μM. Furthermore, the isolates (1-7) showed significant stimulatory effects on 2-NBDG uptake in 3T3-L1 adipocyte cells. Of these, compounds (1, 6, and 7) which exhibited mixed-competitive inhibition modes against PTP1B, showed potent stimulatory effects on 2-NBDG uptake. This result indicated the potential of these biflavonoids as lead molecules for development of antidiabetic agents and the beneficial use of S. tamariscina against hyperglycemia. PMID:25907369

  11. Boehmeria nivea Stimulates Glucose Uptake by Activating Peroxisome Proliferator-Activated Receptor Gamma in C2C12 Cells and Improves Glucose Intolerance in Mice Fed a High-Fat Diet

    PubMed Central

    Kim, Sung Hee; Sung, Mi Jeong; Park, Jae Ho; Yang, Hye Jeong; Hwang, Jin-Taek

    2013-01-01

    We examined the antidiabetic property of Boehmeria nivea (L.) Gaud. Ethanolic extract of Boehmeria nivea (L.) Gaud. (EBN) increased the uptake of 2-[N-(nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose in C2C12 myotubes. To examine the mechanisms underlying EBN-mediated increase in glucose uptake, we examined the transcriptional activity and expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a pivotal target for glucose metabolism in C2C12 myotubes. We found that the EBN increased both the transcriptional activity and mRNA expression levels of PPAR-γ. In addition, we measured phosphorylation and expression levels of other targets of glucose metabolism, such as AMP-activated protein kinase (AMPK) and protein kinase B (Akt/PKB). We found that EBN did not alter the phosphorylation or expression levels of these proteins in a time- or dose-dependent manner, which suggested that EBN stimulates glucose uptake through a PPAR-γ-dependent mechanism. Further, we investigated the antidiabetic property of EBN using mice fed a high-fat diet (HFD). Administration of 0.5% EBN reduced the HFD-induced increase in body weight, total cholesterol level, and fatty liver and improved the impaired fasting glucose level, blood insulin content, and glucose intolerance. These results suggest that EBN had an antidiabetic effect in cell culture and animal systems and may be useful for preventing diabetes. PMID:23690860

  12. Cinnamon extract enhances glucose uptake in 3T3-L1 adipocytes and C2C12 myocytes by inducing LKB1-AMP-activated protein kinase signaling.

    PubMed

    Shen, Yan; Honma, Natsumi; Kobayashi, Katsuya; Jia, Liu Nan; Hosono, Takashi; Shindo, Kazutoshi; Ariga, Toyohiko; Seki, Taiichiro

    2014-01-01

    We previously demonstrated that cinnamon extract (CE) ameliorates type 1 diabetes induced by streptozotocin in rats through the up-regulation of glucose transporter 4 (GLUT4) translocation in both muscle and adipose tissues. This present study was aimed at clarifying the detailed mechanism(s) with which CE increases the glucose uptake in vivo and in cell culture systems using 3T3-L1 adipocytes and C2C12 myotubes in vitro. Specific inhibitors of key enzymes in insulin signaling and AMP-activated protein kinase (AMPK) signaling pathways, as well as small interference RNA, were used to examine the role of these kinases in the CE-induced glucose uptake. The results showed that CE stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase. An AMPK inhibitor and LKB1 siRNA blocked the CE-induced glucose uptake. We also found for the first time that insulin suppressed AMPK activation in the adipocyte. To investigate the effect of CE on type 2 diabetes in vivo, we further performed oral glucose tolerance tests and insulin tolerance tests in type 2 diabetes model rats administered with CE. The CE improved glucose tolerance in oral glucose tolerance tests, but not insulin sensitivity in insulin tolerance test. In summary, these results indicate that CE ameliorates type 2 diabetes by inducing GLUT4 translocation via the AMPK signaling pathway. We also found insulin antagonistically regulates the activation of AMPK. PMID:24551069

  13. Molecular mechanisms of enhanced [18F] fluorodeoxy glucose (FDG) uptake in isochemically injured myocardium: the role of glucose transporter and hexokinase expression. Final technical report for period August 1, 1993--November 30, 1997

    SciTech Connect

    Brosius, F.C. III

    1999-08-01

    We determined that there were no regional differences in GLUT1 or GLUT4 expression in normal dog heart. We demonstrated that glucose uptake was relatively enhanced in regions of severe ischemia in this model. We showed that GLUT1 mRNA and polypeptide expression but not GLUT4 expression were substantially and significantly increased in both ischemic and nonischemic myocardial regions after 6 hours. We also found that GLUT4 translocation and glucose uptake induced by ischemia in perfused rat hearts were not inhibited by Wortmannin, a PI3 kinase inhibitor, whereas insulin-stimulatd increases in GLUT4 translocation and glucose uptake were inhibited. To determine whether some of the same phenomena occurred in humans with chronic myocardial ischemia, we investigated myocardial GLUT mRNA expression in 11 patients who underwent coronary artery bypass surgery. We have cultured neonatal rat cardiomyocytes and tested the effects of several factors including hypoxia and insulin.

  14. Influence of Boron Nutrition on Net Uptake and Efflux of (32)P and (14)C-Glucose in Helianthus annuus Roots and Cell Cultures of Daucus carota.

    PubMed

    Goldbach, H

    1985-04-01

    (32)P and (14)C-glucose uptake were reduced under B deficiency in both Daucus cell suspensions and Helianthus roots. Similarly, efflux rates were found to be smaller in B deficient material. Efflux rates tended to be more affected than net uptake of both (32)P and glucose. This may explain why sunflower roots showed a higher glucose net uptake immediately after transferring from a B sufficient to a B deficient nutrient solution. The data confirm earlier findings of B as an essential element for membrane function and integrity. B-deficiency effects could be reversed by the addition of B within less than one hour. Cell suspensions reacted similarly to roots with respect to B deficiency and may thus be suitable for further research on B deficiency effects.

  15. Natural vanadium-containing Jeju ground water stimulates glucose uptake through the activation of AMP-activated protein kinase in L6 myotubes.

    PubMed

    Hwang, Seung-Lark; Chang, Hyeun Wook

    2012-01-01

    The aim of this study was to elucidate the effects of natural vanadium-containing Jeju ground water on glucose uptake in L6 myotubes and adipogensesis in 3T3 L1 cells. The Jeju ground water samples containing vanadium components were designated as S1 (8.0 ± 0.9 μg/l), S2 (24.0 ± 2.0 μg/l), and S3 (26.0 ± 2.0 μg/l), respectively. To investigate the effects of the Jeju ground water on glucose uptake in L6 myotubes, L6 cells were differentiated in media containing deionized distilled water (DDW group) and the water samples (S1, S2, and S3 groups). After daily changes in cultured media containing the Jeju ground water samples for 1 week, all samples had increased glucose uptake compared to the DDW group and the order of glucose uptake increased in parallel with vanadium content (S3 > S2 > S1). In addition, S3 significantly stimulated the phosphorylation of the Thr-172 residue of the AMP-activated protein kinase-α subunit and the Ser-79 subunit of acetyl-CoA carboxylase compared to the DDW group. The effect of glucose uptake by S3 was reversed by pretreatment with Compound C, an AMPK inhibitor. Interestingly, vanadium pentoxide also increased glucose uptake and activated AMPK activity in a dose-dependent manner. Furthermore, as compared to the DDW treated group, S3 treatment inhibited adipogenesis of 3T3-L1 cells by down regulation of expressions of adipogenic transcription factors. Taken together, these findings suggest that S3 displays beneficial effects in the treatment of diabetes, at least in part through the activation of AMPK activity.

  16. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states.

    PubMed

    Naftalin, Richard J

    2016-01-01

    A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP

  17. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states

    PubMed Central

    Naftalin, Richard J.

    2016-01-01

    A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD), non-alcoholic steatohepatitis, (NASH) and type 2 diabetes mellitus, (T2DM) demonstrates how when glucagon-like peptide-1, (GLP-1) is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA) blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU). When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic implications on GLP

  18. Hydroxylamine enhances glucose uptake in C2C12 skeletal muscle cells through the activation of insulin receptor substrate 1.

    PubMed

    Kimura, Taro; Kato, Eisuke; Machikawa, Tsukasa; Kimura, Shunsuke; Katayama, Shinji; Kawabata, Jun

    2014-02-28

    Diabetes mellitus is a global disease, and the number of patients with it is increasing. Of various agents for treatment, those that directly act on muscle are currently attracting attention because muscle is one of the main tissues in the human body, and its metabolism is decreased in type II diabetes. In this study, we found that hydroxylamine (HA) enhances glucose uptake in C2C12 myotubes. Analysis of HA's mechanism revealed the involvement of IRS1, PI3K and Akt that is related to the insulin signaling pathway. Further investigation about the activation mechanism of insulin receptor or IRS1 by HA may provide a way to develop a novel anti-diabetic agent alternating to insulin.

  19. Glucose Metabolism Gene Expression Patterns and Tumor Uptake of {sup 18}F-Fluorodeoxyglucose After Radiation Treatment

    SciTech Connect

    Wilson, George D.; Thibodeau, Bryan J.; Fortier, Laura E.; Pruetz, Barbara L.; Galoforo, Sandra; Baschnagel, Andrew M.; Chunta, John; Oliver Wong, Ching Yee; Yan, Di; Marples, Brian; Huang, Jiayi

    2014-11-01

    Purpose: To investigate whether radiation treatment influences the expression of glucose metabolism genes and compromises the potential use of {sup 18}F-fluorodeoxyglucose positron emission tomography (FDG-PET) as a tool to monitor the early response of head and neck cancer xenografts to radiation therapy (RT). Methods and Materials: Low passage head and neck squamous cancer cells (UT14) were injected to the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm{sup 3} they were treated with either sham RT or 15 Gy in 1 fraction. At different time points, days 3, 9, and 16 for controls and days 4, 7, 12, 21, 30, and 40 after irradiation, 2 to 3 mice were assessed with dynamic FDG-PET acquisition over 2 hours. Immediately after the FDG-PET the tumors were harvested for global gene expression analysis and immunohistochemical evaluation of GLUT1 and HK2. Different analytic parameters were used to process the dynamic PET data. Results: Radiation had no effect on key genes involved in FDG uptake and metabolism but did alter other genes in the HIF1α and glucose transport–related pathways. In contrast to the lack of effect on gene expression, changes in the protein expression patterns of the key genes GLUT1/SLC2A1 and HK2 were observed after radiation treatment. The changes in GLUT1 protein expression showed some correlation with dynamic FDG-PET parameters, such as the kinetic index. Conclusion: {sup 18}F-fluorodeoxyglucose positron emission tomography changes after RT would seem to represent an altered metabolic state and not a direct effect on the key genes regulating FDG uptake and metabolism.

  20. Glucose uptake heterogeneity of the leg muscles is similar between patients with multiple sclerosis and healthy controls during walking

    PubMed Central

    Kindred, John H.; Ketelhut, Nathaniel B.; Rudroff, Thorsten

    2014-01-01

    Background Difficulties in ambulation are one of the main problems reported by patients with multiple sclerosis. A previous study by our research group showed increased recruitment of muscle groups during walking but the influence of skeletal muscle properties, such as muscle fiber activity, has not been fully elucidated. The purpose of this investigation was to use the novel method of calculating glucose uptake heterogeneity in the leg muscles of patients with multiple sclerosis and compare these results to healthy controls. Methods Eight patients with multiple sclerosis (4 men) and 8 healthy controls (4 men) performed 15 min of treadmill walking at a comfortable self-selected speed following muscle strength tests. Participants were injected with ≈8 millicuries of [18F]-Fluorodeoxyglucose during walking after which positron emission tomography/computed tomography imaging was performed. Findings No differences in muscle strength were detected between multiple sclerosis and control groups (P > 0.27). Within the multiple sclerosis group differences in muscle volume existed between the stronger and weaker legs in the vastus lateralis, semitendinosus, and semimembranosus (P < 0.03). Glucose uptake heterogeneity between the groups was not different for any muscle group or individual muscle of the legs (P > 0.16, P ≥ 0.05). Interpretations Patients with multiple sclerosis and healthy controls showed similar muscle fiber activity during walking. Interpretations of these results, with respect to our previous study, suggest that walking difficulties in patients with multiple sclerosis may be more associated with altered central nervous system motor patterns rather than alterations in skeletal muscle properties. PMID:25541392

  1. Cyclic AMP and its functional relationship in Tetrahymena: a comparison between phagocytosis and glucose uptake.

    PubMed

    Csaba, G; Nagy, S U; Lantos, T

    1978-01-01

    In Tetrahymena, an increase in the level of cAMP is accompanied by an increased phagocytotic rate, whereas increased sugar uptake is parallelled by a decreased cAMP level. The increase in cAMP level seems to be decisive with respect to phagocytosis as a basic phenomenon of life. In the action of epinephrine, however, some mechanism other than cAMP mediation may be involved. Depending on concentration, one hormone may provoke either an increase or a decrease in cAMP level, and this in turn triggers the corresponding function.

  2. P-LAP/IRAP-induced cell proliferation and glucose uptake in endometrial carcinoma cells via insulin receptor signaling

    PubMed Central

    Shibata, Kiyosumi; Kajiyama, Hiroaki; Ino, Kazuhiko; Nawa, Akihiro; Nomura, Seiji; Mizutani, Shigehiko; Kikkawa, Fumitaka

    2007-01-01

    Background Hyperglycemia or hyperinsulinemia contributes to poorer endometrial cancer survival. It was shown that P-LAP/IRAP translocates to the plasma membrane in response to insulin stimulation. Recently, we demonstrated that P-LAP/IRAP is associated with a poor prognosis in endometrial adenocarcinoma patients. The aim of this study was to examine whether the malignant potential of endometrial cancer enhanced by P-LAP/IRAP is due to increased glucose uptake via the P-LAP/IRAP-mediated activation of insulin signaling. Methods We transfected P-LAP/IRAP cDNA into A-MEC cells (endometrial adenocarcinoma cell line), and A-MEC-LAP cells expressed a remarkably high level of GLUT4 proteins. Results 3H-2-deoxyglucose uptake which responds to insulin in A-MEC-LAP cells was significantly higher than that of A-MEC-pc cells. A-MEC-LAP cells exhibited a significant growth-stimulatory effect compared to A-MEC-pc cells. A-MEC-LAP cells expressed a remarkably high level of p85PI3K protein compared to A-MEC-pc cells, and showed a higher degree of AKT phosphorylation by insulin stimulation. Conclusion In summary, P-LAP/IRAP was involved in the increasing malignant potential of endometrial cancer mediated by insulin. P-LAP/IRAP was suggested to be a potential new target of molecular-targeted therapy for endometrial cancer. PMID:17233921

  3. Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2.

    PubMed

    Zhang, Shihai; Yang, Qing; Ren, Man; Qiao, Shiyan; He, Pingli; Li, Defa; Zeng, Xiangfang

    2016-08-01

    Knowledge of regulation of glucose transport contributes to our understanding of whole-body glucose homoeostasis and human metabolic diseases. Isoleucine has been reported to participate in regulation of glucose levels in many studies; therefore, this study was designed to examine the effect of isoleucine on intestinal and muscular GLUT expressions. In an animal experiment, muscular GLUT and intestinal GLUT were determined in weaning pigs fed control or isoleucine-supplemented diets. Supplementation of isoleucine in the diet significantly increased piglet average daily gain, enhanced GLUT1 expression in red muscle and GLUT4 expression in red muscle, white muscle and intermediate muscle (P<0·05). In additional, expressions of Na+/glucose co-transporter 1 and GLUT2 were up-regulated in the small intestine when pigs were fed isoleucine-supplemented diets (P<0·05). C2C12 cells were used to examine the expressions of muscular GLUT and glucose uptake in vitro. In C2C12 cells supplemented with isoleucine in the medium, cellular 2-deoxyglucose uptake was increased (P<0·05) through enhancement of the expressions of GLUT4 and GLUT1 (P<0·05). The effect of isoleucine was greater than that of leucine on glucose uptake (P<0·05). Compared with newborn piglets, 35-d-old piglets have comparatively higher GLUT4, GLUT2 and GLUT5 expressions. The results of this study demonstrated that isoleucine supplementation enhanced the intestinal and muscular GLUT expressions, which have important implications that suggest that isoleucine could potentially increase muscle growth and intestinal development by enhancing local glucose uptake in animals and human beings. PMID:27464458

  4. [Diet therapy in non-insulin dependent diabetes mellitus (NIDDM)].

    PubMed

    Cavallo-Perin, P; Bodoni, P; Marena, S

    1997-12-01

    The main approach in NIDDM therapy is diet. Most patients present insulin resistance characterized by overweight, VLDL increase, minimal increase of LDL, decrease of HDL cholesterol, and hypertension. The overall goals of nutrition therapy are the maintenance of near normal glucose levels, and the achievement of optimal serum lipid levels with adequate calories for maintaining or attaining a reasonable body weight. In presence of obesity and hypertension even a slightly weight loss could achieve an improvement in metabolic control and in hypertension with a better life expectance. General-ly carbohydrate intake would represent the 50-60% of total caloric amount (with preference to those with low glycemic index), and lipids no more than 35% (less than 10% of these 10-15% from monounsaturated fats with less than 300 mg/day of cholesterol). If elevated very low density lipoproteins level is the primary problem, a beneficial approach is 10% of total caloric intake from saturated fats, 10% from polyunsaturated, and 15-20% from monounsaturated fats with less than 200 mg/day of cholesterol and 40% of carbohydrates. A large amount of fructose (20% of calories) may increase LDL levels but sweeteners as saccarine or aspartame are approved and determine a better diet compliance. Daily consumpion of 20-35 g of dietary fibres from food sources is recommended for metabolic control. Protein intake would be of about 10% of total caloric amount especially in presence of diabetic nepropathy. Alcohol would not exceed 30 g/day for men and 20 g/day for women keeping in mild that alcohol may worsen metabolic control, diet compliance, and may be dangerous itself. For people with hypertension a decrease of dietary sodium intake is recommended. Nutritional recommendations are developed to meet treatment goals and desired outcomes. Monitoring metabolic parameters, blood pressure, and body weight is very important to ensure successful outcomes.

  5. Whole body glucose kinetics in type I diabetes studied with (6,6-/sup 2/H) and (U-/sup 13/C)-glucose and the artificial B-cell

    SciTech Connect

    Darmaun, D.; Cirillo, D.; Koziet, J.; Chauvet, D.; Young, V.R.; Robert, J.J.

    1988-05-01

    Dynamic aspects of whole body glucose metabolism were assessed in ten young adult insulin-dependent (type I) diabetic men. Using a primed, continuous intravenous infusion of (6,6-/sup 2/H)glucose and (U-/sup 13/C)glucose, endogenous production, tissue uptake, carbon recycling, and oxidation of glucose were measured in the postabsorptive state. These studies were undertaken after blood glucose had been maintained overnight at 5.9 +/- 0.4 mmol/L (n = 10), and on another night at 10.5 +/- 0.4 mmol/L (n = 4) or 15.2 +/- 0.6 mmol/L (n = 6). In the normoglycemic state, endogenous glucose production averaged 2.15 +/- 0.13 mg x kg-1 x min-1. This value, as well as the rate of glucose carbon recycling (0.16 +/- 0.04 mg x kg-1 x min-1) and glucose oxidation (1.52 +/- 0.16 mg x kg-1 x min-1) are comparable to those found in nondiabetic controls. In the hyperglycemic states at 10 or 15 mmol/L, endogenous glucose production was increased by 11% (P less than .01) and 60% (P less than .01) compared to the normoglycemic states, respectively. Glucose carbon recycling contributed only a small percentage to this variation in glucose production (15% at the 15 mmol/L glucose level). This suggests that if gluconeogenesis participates in the increased glucose output, it is not dependent on a greater systemic supply of three-carbon precursors. The increased rate of glucose production in the hyperglycemic state was quantitatively offset by a rise in urinary glucose excretion. Glucose tissue uptake, as well as glucose oxidation, did not vary between normoglycemic and hyperglycemic states.

  6. First-pass uptake and oxidation of glucose by the splanchnic tissue in young goats fed soy protein-based milk diets with or without amino acid supplementation: glucose metabolism in goat kids after soy feeding.

    PubMed

    Schönhusen, U; Junghans, P; Flöter, A; Steinhoff-Wagner, J; Görs, S; Schneider, F; Metges, C C; Hammon, H M

    2013-04-01

    The study was designed to examine whether feeding soy protein isolate as partial replacement of casein (CN) affects glucose metabolism in young goats and whether effects may be ameliorated by supplementation of those AA known to be lower concentrated in soy than in CN. Goat kids (d 20 of age) were fed comparable milk protein diets, in which 50% of the crude protein was either CN (control, CON), soy protein isolate (SPI), or soy protein isolate supplemented with AA (SPIA) for 43 d (n=8 per group). On d 62 of age, a single bolus dose of d-[(13)C6]glucose (10mg/kg of BW) was given with the morning diet, and simultaneously, a single bolus dose of d-[6,6-(2)H2]glucose (5mg/kg of BW) was injected into a jugular vein. Blood samples were collected between -30 and +420 min relative to the tracer administration to measure the (13)C and (2)H enrichments of plasma glucose and the (13)C enrichment of blood CO2. Glucose first-pass uptake by the splanchnic tissues was calculated from the rate of appearance of differentially labeled glucose tracer in plasma. Glucose oxidation was calculated from (13)C enrichment in blood CO2. In addition, plasma concentrations of triglycerides, nonesterified fatty acids, glucose, insulin, and glucagon were measured. On d 63 of age, kids were killed and jejunal mucosa and liver samples were collected to measure lactase mRNA levels and lactase and maltase activities in the jejunum and activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK) in the liver. Basal plasma glucose concentration tended to be higher in the CON than the SPIA group, whereas basal insulin was higher in the CON group than the SPI and SPIA groups, and glucagon was higher in the CON than the SPIA group. Plasma glucose and insulin concentrations increased during the first hour after feeding, whereas plasma glucagon increased immediately after feeding and after 1h of feeding. First-pass uptake and glucose oxidation were not affected by diet. Maltase

  7. Screening of medicinal plants for PPPAR-alpha and PPAR-gamma activation and evaluation of their effects on glucose uptake and 3T3-L1 adipogenesis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Medicinal plants are a rich source of ligands for nuclear receptors. The present study was aimed to screen a collection of plant extracts for PPAR-alpha/gamma activating properties and identify the active extract that can stimulate cellular glucose uptake without enhancing the adipogenesis. A report...

  8. α-Mangostin Improves Glucose Uptake and Inhibits Adipocytes Differentiation in 3T3-L1 Cells via PPARγ, GLUT4, and Leptin Expressions

    PubMed Central

    Taher, Muhammad; Mohamed Amiroudine, Mohamed Zaffar Ali; Tengku Zakaria, Tengku Muhamad Faris Syafiq; Ichwan, Solachuddin J. A.; Kaderi, Mohd Arifin; Ahmed, Qamar Uddin; Zakaria, Zainul Amiruddin

    2015-01-01

    Obesity has been often associated with the occurrence of cardiovascular diseases, type 2 diabetes, and cancer. The development of obesity is also accompanied by significant differentiation of preadipocytes into adipocytes. In this study, we investigated the activity of α-mangostin, a major xanthone component isolated from the stem bark of G. malaccensis, on glucose uptake and adipocyte differentiation of 3T3-L1 cells focusing on PPARγ, GLUT4, and leptin expressions. α-Mangostin was found to inhibit cytoplasmic lipid accumulation and adipogenic differentiation. Cells treated with 50 μM of α-mangostin reduced intracellular fat accumulation dose-dependently up to 44.4% relative to MDI-treated cells. Analyses of 2-deoxy-D-[3H] glucose uptake activity showed that α-mangostin significantly improved the glucose uptake (P < 0.05) with highest activity found at 25 μM. In addition, α-mangostin increased the amount of free fatty acids (FFA) released. The highest glycerol release level was observed at 50 μM of α-mangostin. qRT-PCR analysis showed reduced lipid accumulation via inhibition of PPARγ gene expression. Induction of glucose uptake and free fatty acid release by α-mangostin were accompanied by increasing mRNA expression of GLUT4 and leptin. These evidences propose that α-mangostin might be possible candidate for the effective management of obesity in future. PMID:25873982

  9. Evidence for compromised metabolic function and limited glucose uptake in spermatozoa from the teratospermic domestic cat (Felis catus) and cheetah (Acinonyx jubatus).

    PubMed

    Terrell, Kimberly A; Wildt, David E; Anthony, Nicola M; Bavister, Barry D; Leibo, Stanley P; Penfold, Linda M; Marker, Laurie L; Crosier, Adrienne E

    2010-11-01

    Cheetahs and certain other felids consistently ejaculate high proportions (≥ 60%) of malformed spermatozoa, a condition known as teratospermia, which is prevalent in humans. Even seemingly normal spermatozoa from domestic cat teratospermic ejaculates have reduced fertilizing capacity. To understand the role of sperm metabolism in this phenomenon, we conducted a comparative study in the normospermic domestic cat versus the teratospermic cat and cheetah with the general hypothesis that sperm metabolic function is impaired in males producing predominantly pleiomorphic spermatozoa. Washed ejaculates were incubated in chemically defined medium containing glucose and pyruvate. Uptake of glucose and pyruvate and production of lactate were assessed using enzyme-linked fluorescence assays. Spermatozoa from domestic cats and cheetahs exhibited similar metabolic profiles, with minimal glucose metabolism and approximately equimolar rates of pyruvate uptake and lactate production. Compared to normospermic counterparts, pyruvate and lactate metabolism were reduced in teratospermic cat and cheetah ejaculates, even when controlling for sperm motility. Rates of pyruvate and lactate (but not glucose) metabolism were correlated positively with sperm motility, acrosomal integrity, and normal morphology. Collectively, our findings reveal that pyruvate uptake and lactate production are reliable, quantitative indicators of sperm quality in these two felid species and that metabolic function is impaired in teratospermic ejaculates. Furthermore, patterns of substrate utilization are conserved between these species, including the unexpected lack of exogenous glucose metabolism. Because glycolysis is required to support sperm motility and capacitation in certain other mammals (including dogs), the activity of this pathway in felid spermatozoa is a target for future investigation.

  10. SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway.

    PubMed

    Cliffe, Simon T; Kramer, Jamie M; Hussain, Khalid; Robben, Joris H; de Jong, Eiko K; de Brouwer, Arjan P; Nibbeling, Esther; Kamsteeg, Erik-Jan; Wong, Melanie; Prendiville, Julie; James, Chela; Padidela, Raja; Becknell, Charlie; van Bokhoven, Hans; Deen, Peter M T; Hennekam, Raoul C M; Lindeman, Robert; Schenck, Annette; Roscioli, Tony; Buckley, Michael F

    2009-06-15

    Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome is a recently described autosomal recessive disorder associated with predominantly antibody negative, insulin-dependent diabetes mellitus. In order to identify the genetic basis of PHID and study its relationship with glucose metabolism, we performed homozygosity mapping in five unrelated families followed by candidate gene sequencing. Five loss-of-function mutations were identified in the SLC29A3 gene which encodes a member of a highly conserved protein family that transports nucleosides, nucleobases and nucleoside analogue drugs, hENT3. We show that PHID is allelic with a related syndrome without diabetes mellitus, H syndrome. The interaction of SLC29A3 with insulin signaling pathways was then studied using an established model in Drosophila melanogaster. Ubiquitous knockdown of the Drosophila ortholog of hENT3, dENT1 is lethal under stringent conditions; whereas milder knockdown induced scutellar bristle phenotypes similar to those previously reported in the knockdown of the Drosophila ortholog of the Islet gene. A cellular growth assay showed a reduction of cell size/number which could be rescued or enhanced by manipulation of the Drosophila insulin receptor and its downstream signaling effectors, dPI3K and dAkt. In summary, inactivating mutations in SLC29A3 cause a syndromic form of insulin-dependent diabetes in humans and in Drosophila profoundly affect cell size/number through interactions with the insulin signaling pathway. These data suggest that further investigation of the role of SLC29A3 in glucose metabolism is a priority for diabetes research.

  11. The edible red alga, Gracilaria verrucosa, inhibits lipid accumulation and ROS production, but improves glucose uptake in 3T3-L1 cells.

    PubMed

    Woo, Mi-Seon; Choi, Hyeon-Son; Lee, Ok-Hwan; Lee, Boo-Yong

    2013-07-01

    Gracilaria verrucosa is a red alga that is widely distributed in seaside areas of many countries. We examined the effect of G. verrucosa extract on adipogenesis, reactive oxygen species (ROS) production, and glucose uptake in 3T3-L1 cells. Oil red O staining and a nitroblue tetrazolium assay showed that G. verrucosa extract inhibited lipid accumulation and ROS production, respectively. mRNA levels of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha, as well as of their target gene, adipocyte protein 2, were reduced upon treatment with G. verrucosa extract. However, G. verrucosa extract increased glucose uptake, glucose transporter-4 expression, and AMP-activated protein kinaseα (AMPKα) phosphorylation compared to the control. Our results suggest that the anti-adipogenic and insulin-sensitive effects of G. verrucosa extract can be recapitulated to activation of AMPKα.

  12. Uptake of locally applied deoxyglucose, glucose and lactate by axons and Schwann cells of rat vagus nerve

    PubMed Central

    Véga, Céline; Martiel, Jean-Louis; Drouhault, Delphine; Burckhart, Marie-France; Coles, Jonathan A

    2003-01-01

    We asked whether, in a steady state, neurons and glial cells both take up glucose sufficient for their energy requirements, or whether glial cells take up a disproportionate amount and transfer metabolic substrate to neurons. A desheathed rat vagus nerve was held crossways in a laminar flow perfusion chamber and stimulated at 2 Hz. 14C-labelled substrate was applied from a micropipette for 5 min over a < 0.6 mm band of the surface of the nerve. After 10-55 min incubation, the nerve was lyophilized and the longitudinal distribution of radioactivity measured. When the weakly metabolizable analogue of glucose, 2-deoxy-[U-14C]d-glucose (*DG), was applied, the profiles of the radioactivity broadened with time, reaching distances several times the mean length of the Schwann cells (0.32 mm; most of the Schwann cells are non-myelinating). The profiles were well fitted by curves calculated for diffusion in a single compartment, the mean diffusion coefficient being 463 ± 34 μm2 s−1 (± s.e.m., n = 16). Applications of *DG were repeated in the presence of the gap junction blocker, carbenoxolone (100 μm). The profiles were now narrower and better fitted with two compartments. One compartment had a coefficient not significantly different from that in the absence of the gap junction blocker (axons), the other compartment had a coefficient of 204 ± 24 μm2 s−1, n = 4. Addition of the gap junction blocker 18-α-glycyrrhetinic acid, or blocking electrical activity with TTX, also reduced longitudinal diffusion. Ascribing the compartment in which diffusion was reduced by these treatments to non-myelinating Schwann cells, we conclude that 78.0 ± 3.6 % (n = 9) of the uptake of *DG was into Schwann cells. This suggests that there was transfer of metabolic substrate from Schwann cells to axons. Local application of [14C]glucose or [14C]lactate led to variable labelling along the length of the nerve, but with both substrates narrow peaks were often present at the application site

  13. Effects of arecoline on adipogenesis, lipolysis, and glucose uptake of adipocytes-A possible role of betel-quid chewing in metabolic syndrome

    SciTech Connect

    Hsu, Hsin-Fen; Tsou, Tsui-Chun; Chao, How-Ran; Shy, Cherng-Gueih; Kuo, Ya-Ting; Tsai, Feng-Yuan; Yeh, Szu-Ching; Ko, Ying-Chin

    2010-06-15

    To investigate the possible involvement of betel-quid chewing in adipocyte dysfunction, we determined the effects of arecoline, a major alkaloid in areca nuts, on adipogenic differentiation (adipogenesis), lipolysis, and glucose uptake by fat cells. Using mouse 3T3-L1 preadipocytes, we showed that arecoline inhibited adipogenesis as determined by oil droplet formation and adipogenic marker gene expression. The effects of arecoline on lipolysis of differentiated 3T3-L1 adipocytes were determined by the glycerol release assay, indicating that arecoline induced lipolysis in an adenylyl cyclase-dependent manner. The diabetogenic effects of arecoline on differentiated 3T3-L1 adipocytes were evaluated by the glucose uptake assay, revealing that {>=} 300 {mu}M arecoline significantly attenuated insulin-induced glucose uptake; however, no marked effect on basal glucose uptake was detected. Moreover, using 94 subjects that were randomly selected from a health check-up, we determined the association of betel-quid chewing with hyperlipidemia and its related risk factors. Hyperlipidemia frequency and serum triglyceride levels of betel-quid chewers were significantly higher than those of non-betel-quid chewers. In this study, we demonstrated that arecoline inhibits adipogenic differentiation, induces adenylyl cyclase-dependent lipolysis, and interferes with insulin-induced glucose uptake. Arecoline-induced fat cell dysfunction may lead to hyperlipidemia and hyperglycemia/insulin-resistance. These findings provide the first in vitro evidence of betel-quid chewing modulation of adipose cell metabolism that could contribute to the explanation of the association of this habit with metabolic syndrome disorders.

  14. Glycaemic responses to different types of bread in insulin-dependent diabetic subjects (IDDM): studies at constant insulinaemia.

    PubMed

    Rasmussen, O; Winther, E; Hermansen, K

    1991-02-01

    To study the glycaemic effect of various Danish bread types in insulin-dependent diabetic subjects (IDDM) we looked at the incremental blood glucose areas after isocaloric meals of grained wholemeal rye bread, wholemeal bread (graham bread) and white bread in seven C-peptide negative diabetic subjects. Furthermore, we evaluated the glycaemic potency of dried fruits by exchanging 40 per cent of the starch of grained wholemeal rye bread as dried figs. Prior to the meal intake the patients had attained normoglycaemia and isoinsulinaemia by means of the artificial pancreas. The four test meals containing 50 g of available carbohydrate were taken in random order. The postprandial blood glucose response areas after whole-meal bread (1037 +/- 113 mM X 180 min) and white bread (1021 +/- 100 mM X 180 min) were significantly higher than that to grained wholemeal rye bread (786 +/- 66 mM X 180 min, P less than 0.05). Exchange of 40 per cent of the complex carbohydrate as grained wholemeal rye bread with simple sugars, such as figs, had no influence on the blood glucose response (786 +/- 66 mM X 180 min vs. 766 +/- 56 mM X 180 min). Constant and identical serum-free insulin levels at 30 mU/l and similar amounts of glucose lost in the urine were found after the four test meals. In conclusion, the difference in extraction rate of wheat in the form of white flour (0, 7) and wholemeal flour (1, 0) was not reflected in the glycaemic responses in IDDM subjects. Grained wholemeal rye bread is a fibre-rich, cheap nutrient which elicits a significantly lower glycaemic response compared to wholemeal and white bread and can be recommended to diabetic subjects.

  15. Food Purchase Decision-Making Typologies of Women with Non-Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Miller, Carla; Warland, Rex; Achterberg, Cheryl

    1997-01-01

    Food selection is a key factor in the nutritional management of diabetes. Criteria that influence point-of-purchase decision making in women with non-insulin-dependent diabetes mellitus were identified. Four types of shoppers were distinguished from interviews; cluster analysis was used to confirm the analysis. Usefulness in patient education is…

  16. Psychoeducational Characteristics of Children and Adolescents with Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Rovet, Joanne F.; And Others

    1993-01-01

    This literature review considers the frequency and consistency of general and specific neurocognitive deficits in pediatric patients with insulin-dependent diabetes mellitus and the impact of these deficits on school achievement and learning disabilities. Findings are discussed in terms of the impact of the adequacy of diabetes control on specific…

  17. Pediatrics Residents' Attitudes about Insulin-Dependent Diabetes Mellitus and Children with Diabetes.

    ERIC Educational Resources Information Center

    Ingersoll, Gary M.; And Others

    1990-01-01

    Comparison of the beliefs and attitudes of a sample of pediatric residents (n=56) and practicing physicians (n=1,500) concerning children with insulin-dependent Diabetes Mellitus and the disease itself found residents in their second and third years of training considerably more negative about both than physicians or first-year residents.…

  18. Cognitive Functioning and Academic Achievement in Children with Insulin-Dependent Diabetes Mellitus (IDDM).

    ERIC Educational Resources Information Center

    Holmes, Clarissa S.; And Others

    1995-01-01

    Consistent evidence relates insulin dependent diabetes mellitus (IDDM) to lower intellectual functioning in children, although performance is still in the average range. Children with IDDM have received specialized classroom assistance at school. Boys with diabetes appear at greater risk for learning problems than girls. Evidence suggests both…

  19. Parent-Child Relationships and the Management of Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Miller-Johnson, Shari; And Others

    1994-01-01

    Examined dimensions of parent-child relationships as predictors of adherence to treatment and metabolic control in study of 88 children/adolescents with insulin-dependent diabetes mellitus. Ratings of parent-child discipline, warmth, and behavioral support were not significantly associated with diabetes outcome, but parent-child conflict was…

  20. EFFECTS OF ADMINISTRATION ROUTE, DIETARY CONDITION, AND BLOOD GLUCOSE LEVEL ON KINETICS AND UPTAKE OF 18F-FDG IN MICE

    PubMed Central

    Wong, Koon-Pong; Sha, Wei; Zhang, Xiaoli; Huang, Sung-Cheng

    2011-01-01

    The effects of dietary condition and blood glucose level on the kinetics and uptake of 18F-FDG in mice were systematically investigated using intraperitoneal and tail-vein injection. Methods Dynamic PET was performed for 60 min on 23 isoflurane-anesthetized male C57BL/6 mice after intravenous (n = 11) or intraperitoneal (n = 12) injection of 18F-FDG. Five and 6 mice in the intravenous and intraperitoneal groups, respectively, were kept fasting overnight (18 ± 2 h), and the others were fed ad libitum. Serial blood samples were collected from the femoral artery to measure 18F-FDG and glucose concentrations. Image data were reconstructed using filtered backprojection with CT-based attenuation correction. The standardized uptake value (SUV) was estimated from the 45- to 60-min image. The metabolic rate of glucose (MRGlu) and 18F-FDG uptake constant (Ki) were derived by Patlak graphical analysis. Results In the brain, SUV and Ki were significantly higher in fasting mice with intraperitoneal injection, but MRGlu did not differ significantly under different dietary states and administration routes. Cerebral Ki was inversely related to elevated blood glucose levels, irrespective of administration route or dietary state. In myocardium, SUV, Ki, and MRGlu were significantly lower in fasting than in nonfasting mice for both routes of injection. Myocardial SUV and Ki were strongly dependent on the dietary state, and Ki did not correlate with the blood glucose level. Similar results were obtained for skeletal muscle, although the differences were not as pronounced. Conclusions Intraperitoneal injection is a valid alternative route, providing pharmacokinetic data equivalent to data from tail-vein injection for small-animal 18F-FDG PET. Cerebral Ki varies inversely with blood glucose level, but the measured cerebral MRGlu does not correlate with blood glucose level or dietary condition. Conversely, the Ki values of the myocardium and skeletal muscle are strongly dependent on

  1. Frequent interruptions of sedentary time modulates contraction- and insulin-stimulated glucose uptake pathways in muscle: Ancillary analysis from randomized clinical trials.

    PubMed

    Bergouignan, Audrey; Latouche, Celine; Heywood, Sarah; Grace, Megan S; Reddy-Luthmoodoo, Medini; Natoli, Alaina K; Owen, Neville; Dunstan, David W; Kingwell, Bronwyn A

    2016-01-01

    Epidemiological studies have observed associations between frequent interruptions of sitting time with physical activity bouts and beneficial metabolic outcomes, even in individuals who regularly exercise. Frequent interruptions to prolonged sitting reduce postprandial plasma glucose. Here we studied potential skeletal muscle mechanisms accounting for this improved control of glycemia in overweight adults under conditions of one day uninterrupted sitting and sitting interrupted with light-intensity or moderate-intensity walking every 20-min (n = 8); and, after three days of either uninterrupted sitting or light-intensity walking interruptions (n = 5). Contraction- and insulin-mediated glucose uptake signaling pathways as well as changes in oxidative phosphorylation proteins were examined. We showed that 1) both interventions reduce postprandial glucose concentration, 2) acute interruptions to sitting over one day stimulate the contraction-mediated glucose uptake pathway, 3) both acute interruptions to sitting with moderate-intensity activity over one day and light-intensity activity over three days induce a transition to modulation of the insulin-signaling pathway, in association with increased capacity for glucose transport. Only the moderate-intensity interruptions resulted in greater capacity for glycogen synthesis and likely for ATP production. These observations contribute to a mechanistic explanation of improved postprandial glucose metabolism with regular interruptions to sitting time, a promising preventive strategy for metabolic diseases. PMID:27554943

  2. Frequent interruptions of sedentary time modulates contraction- and insulin-stimulated glucose uptake pathways in muscle: Ancillary analysis from randomized clinical trials

    PubMed Central

    Bergouignan, Audrey; Latouche, Celine; Heywood, Sarah; Grace, Megan S.; Reddy-Luthmoodoo, Medini; Natoli, Alaina K.; Owen, Neville; Dunstan, David W.; Kingwell, Bronwyn A.

    2016-01-01

    Epidemiological studies have observed associations between frequent interruptions of sitting time with physical activity bouts and beneficial metabolic outcomes, even in individuals who regularly exercise. Frequent interruptions to prolonged sitting reduce postprandial plasma glucose. Here we studied potential skeletal muscle mechanisms accounting for this improved control of glycemia in overweight adults under conditions of one day uninterrupted sitting and sitting interrupted with light-intensity or moderate-intensity walking every 20-min (n = 8); and, after three days of either uninterrupted sitting or light-intensity walking interruptions (n = 5). Contraction- and insulin-mediated glucose uptake signaling pathways as well as changes in oxidative phosphorylation proteins were examined. We showed that 1) both interventions reduce postprandial glucose concentration, 2) acute interruptions to sitting over one day stimulate the contraction-mediated glucose uptake pathway, 3) both acute interruptions to sitting with moderate-intensity activity over one day and light-intensity activity over three days induce a transition to modulation of the insulin-signaling pathway, in association with increased capacity for glucose transport. Only the moderate-intensity interruptions resulted in greater capacity for glycogen synthesis and likely for ATP production. These observations contribute to a mechanistic explanation of improved postprandial glucose metabolism with regular interruptions to sitting time, a promising preventive strategy for metabolic diseases. PMID:27554943

  3. Insulin binding and glucose uptake of adipocytes in rats adapted to hypergravitational force

    NASA Technical Reports Server (NTRS)

    Kobayashi, M.; Mondon, C. E.; Oyama, J.

    1980-01-01

    Rats were exposed to 4.15 g for 1 yr and weight and age matched, and lean noncentrifuged rats were used as control groups. Rats exposed to chronic hypergravity (hypergravic rats) were found to show lower ambient insulin levels, greater food intake with smaller body weight gain, and decreased size of isolated adipocytes. The ability of adipocytes from the hypergravic rats to bind insulin was increased. With Scatchard analysis, both number and affinity of receptors were increased. In contrast to the increased binding, glucose transport was found to be decreased in adipocytes from these animals. However, when the data were expressed as a percentage of maximal effect, the half maximal insulin effect for both the hypergravic and lean control groups was produced at an insulin concentration of 0.23 + or - 0.02 ng/ml, which was lower than the insulin concentration of 0.31 + or - 0.02 ng/ml for the weight-matched control group (P less than 0.05). This increased insulin sensitivity in the hypergravic group was accounted for by an increased number of receptors.

  4. Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer's disease-related regions after glucose loading.

    PubMed

    Ishibashi, Kenji; Kawasaki, Keiichi; Ishiwata, Kiichi; Ishii, Kenji

    2015-08-01

    Increased plasma glucose levels are known to reduce fluorine-18-labeled fluorodeoxyglucose ((18)F-FDG) uptake in Alzheimer's disease (AD)-related regions, resulting in the appearance of an AD-like pattern. However, the relationships of its appearance with cerebral blood flow and insulin levels are uncertain. We performed (18)F-FDG and oxygen-15-labeled water ((15)O-H2O) positron emission tomography in the fasting and glucose-loading conditions on nine young healthy volunteers with no cognitive impairments. Measurement of plasma glucose and insulin levels confirmed that all subjects were free of insulin resistance, and that glucose loading significantly increased plasma glucose and insulin levels. Fluorine-18-labeled fluorodeoxyglucose and (15)O-H2O images were compared between the two conditions, focusing on AD-related regions: precuneus/posterior cingulate (PP), lateral parietal cortex (LPC), and frontal cortex (FC). Volume-of-interest analyses showed significantly lower uptake of both (18)F-FDG and (15)O-H2O in PP, LPC, and FC after glucose loading (P<0.05). Whole-brain voxel-wise analyses also revealed the PP, LPC, and FC areas where uptake of both (18)F-FDG and (15)O-H2O decreased (P<0.05, familywise error rate-corrected). We concluded that increased plasma glucose and insulin levels can cause the appearance of the AD-like pattern in both (18)F-FDG and (15)O-H2O images, and this phenomenon can occur even in subjects without insulin resistance. PMID:26058692

  5. Xanthohumol impairs glucose uptake by a human first-trimester extravillous trophoblast cell line (HTR-8/SVneo cells) and impacts the process of placentation.

    PubMed

    Correia-Branco, Ana; Azevedo, Cláudia F; Araújo, João R; Guimarães, João T; Faria, Ana; Keating, Elisa; Martel, Fátima

    2015-10-01

    In this study, we aimed to investigate modulation of glucose uptake by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line by a series of compounds and to study its consequences upon cell proliferation, viability and migration. We observed that uptake of (3)H-deoxy-d-glucose ((3)H-DG; 10 nM) was time-dependent, saturable, inhibited by cytochalasin B (50 and 100 µM), phloretin (0.5 mM) and phloridzin (1 mM), insulin-insensitive and sodium-independent. In the short term (30 min), neither 5-HT (100-1000 µM), melatonin (10 nM) nor the drugs of abuse ethanol (100 mM), nicotine (100 µM), cocaine (25 µM), amphetamine (10-25 µM) and 3,4-methylenedioxy-N-methamphetamine (10 µM) affected (3)H-DG uptake, while dexamethasone (100-1000 µM), fluoxetine (100-300 µM), quercetin, epigallocatechin-3-gallate (30-1000 µM), xanthohumol (XH) and resveratrol (1-500 µM) decreased it. XH was the most potent inhibitor [IC50 = 3.55 (1.37-9.20) µM] of (3)H-DG uptake, behaving as a non-competitive inhibitor of (3)H-DG uptake, both after short- and long-term (24 h) treatment. The effect of XH (5 µM; 24 h) upon (3)H-DG uptake involved mammalian target of rapamycin, tyrosine kinases and c-Jun N-terminal kinases intracellular pathways. Moreover, XH appeared to decrease cellular uptake of lactate due to inhibition of the monocarboxylate transporter 1. Additionally, XH (24 h; 5 µM) decreased cell viability, proliferation, culture growth and migration. The effects of XH upon cell viability and culture growth, but not the antimigratory effect, were mimicked by low extracellular glucose conditions and reversed by high extracellular glucose conditions. We thus suggest that XH, by inhibiting glucose cellular uptake and impairing HTR-8/SVneo cell viability and proliferation, may have a deleterious impact in the process of placentation. PMID:26194608

  6. Biological correlation between glucose transporters, Ki-67 and 2-deoxy-2-[18F]-fluoro-D-glucose uptake in diffuse large B-cell lymphoma and natural killer/T-cell lymphoma.

    PubMed

    Liu, Y M; Zhai, X M; Wu, Y W

    2016-01-01

    The purpose of this study was to investigate the association between cellular 2-deoxy-2-[18F]-fluoro-D-glucose ((18)F-FDG) uptake and the expression of several subtypes of glucose transporters (GLUT) and Ki-67 in diffuse large B-cell lymphoma (DLBCL) and natural killer (NK)/T-cell lymphoma (NKTCL). Cell lines were histologically determined to be DLBCL (Raji cells) and NKTCL (Daudi cells), and uptake after pretreatment with (18)F-FDG was determined. Real-time polymerase chain reaction was performed to detect the expression levels of GLUTs 1, 2, 3, 4, and 7 and Ki-67, and to evaluate their association with (18)F-FDG uptake in DLBCL and NKTCL cells. The uptake rates of (18)F-FDG ranged from 18 to 46% (average 30 ± 10.20%) in Raji cells and 25 to 48% (average 35.6 ± 7.57%) in Daudi cells. In DLBCL cells, the expression levels of GLUTs 1, 3, and 7 were significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rank correlation coefficient of 0.667, 0.516, and 0.468, respectively; P < 0.05). In NKTCL cells, the expression levels of GLUTs 1 and 3 were observed to be significantly correlated with cellular (18)F-FDG uptake rates (Spearman's rho of 0.756 and 0.498, respectively; P < 0.05). Ki-67 played no role in (18)F-FDG uptake in Raji or Daudi cells. In conclusion, the data acquired through this preliminary study indicate that GLUT 1 and GLUT 3 contribute to 18F-FDG uptake in DLBCL and NKTCL. PMID:27173341

  7. Anti-obesity actions of green tea: possible involvements in modulation of the glucose uptake system and suppression of the adipogenesis-related transcription factors.

    PubMed

    Ashida, Hitoshi; Furuyashiki, Takashi; Nagayasu, Hironobu; Bessho, Hiroaki; Sakakibara, Hiroyuki; Hashimoto, Takashi; Kanazawa, Kazuki

    2004-01-01

    To investigate mechanisms of the anti-obesity actions of green tea in vivo, rats were given green tea instead of drinking water for 3 weeks. It was confirmed that green tea reduced adipose tissue weight without any change in body weight, other tissue weights, and food and water intakes. Green tea also significantly reduced the plasma levels of cholesterols and free fatty acids. Certain catechins existed in the plasma at 0.24 microM under our experimental conditions, though most of them existed as conjugated forms. For mechanisms of the anti-obesity actions, green tea significantly reduced glucose uptake accompanied by a decrease in translocation of glucose transporter 4 (GLUT4) in adipose tissue, while it significantly stimulated the glucose uptake with GLUT4 translocation in skeletal muscle. Moreover, green tea suppressed the expression of peroxisome proliferator-activated receptor gamma and the activation of sterol regulatory element binding protein-1 in adipose tissue. In conclusion, green tea modulates the glucose uptake system in adipose tissue and skeletal muscle and suppresses the expression and/or activation of adipogenesis-related transcription factors, as the possible mechanisms of its anti-obesity actions.

  8. Structural Elucidation of a Novel Polysaccharide from Pseudostellaria heterophylla and Stimulating Glucose Uptake in Cells and Distributing in Rats by Oral.

    PubMed

    Chen, Jinlong; Pang, Wensheng; Shi, Wentao; Yang, Bin; Kan, Yongjun; He, Zhaodong; Hu, Juan

    2016-01-01

    The semi-refined polysaccharide of Pseudostellaria heterophylla is a complex polysaccharide that exhibits significantly hypoglycemic activities. A novel homogeneous polysaccharide, named as H-1-2, was isolated from the semi-refined polysaccharide. The mean molecular weight of H-1-2 was 1.4 × 10⁴ Da and it was only composed of d-glucose monosaccharide. Structure elucidation indicated that H-1-2 contains pyranride, and has the characteristics of the α-iso-head configuration, a non-reducing end (T-), 4-, 1,6-, and 1,4,6-connection, in all four ways to connect glucose. H-1-2 was a type of glucan, where chemical combination exists in the main chain between 1→4 linked glucose, and contains a small amount of 1,6-linked glucose, which was in the branched chain. In vitro HepG2, 3T3-L1, and L6 cells were used to assess cellular glucose consumption and cellular glucose uptake by glucose oxidase, and the transport of 2-NBDG fluorescence probe results showed that H-1-2 could clearly increase glucose uptake and utilization in muscle and adipose cells, which is beneficial to screen for in the discovery of anti-diabetes lead compounds. H-1-2 was labeled with radioisotopes ((99m)Tc-pertechnetate). (99m)Tc-labeled-H-1-2 was performed by SPECT/CT analysis images after oral administration in rats. At 4 h post ingestion, about 50% of the radioactivity was observed in the intestine. No significant radioactivity was found in the heart, liver, and kidney, conjecturing that absorption of (99m)Tc-labeled H-1-2 might, via intestinal mucosa, be absorbed into systemic circulation. This problem, as to whether the polysaccharide is absorbed orally, will need further examination. PMID:27649122

  9. Impact of keratin intermediate filaments on insulin-mediated glucose metabolism regulation in the liver and disease association.

    PubMed

    Roux, Alexandra; Gilbert, Stéphane; Loranger, Anne; Marceau, Normand

    2016-02-01

    In all cells, a tight regulation exists between glucose uptake and utilization to prevent diseases related to its perturbed metabolism. In insulin-targeted cells, such as hepatocytes, proper glucose utilization requires an elaborate interplay between the insulin receptor, the glucose transporter, and mitochondria that involves the participation of actin microfilaments and microtubules. In addition, there is increasing evidence of an involvement of the third cytoskeletal network provided by intermediate filaments (IFs). Keratins belong to the multigene family of IF proteins, coordinately expressed as distinct pairs within the context of epithelial cell differentiation. Hepatocyte IFs are made up of the [keratin (K)8/K18] pair only, whereas pancreatic β-cell IFs additionally include small amounts of K7. There are accumulating examples of K8/K18 involvement in the glucose-insulin cross-talk, including the modulation of plasma glucose levels, insulin release from pancreatic β-cells, and insulin-mediated glucose uptake and glycogen production in hepatocytes after a K8/K18 loss. This review integrates the mechanistic features that support such an impact of K8/K18 IFs on insulin-dependent glucose metabolism regulation in liver and its implication in glucose- or insulin-associated diseases.

  10. Concentrations of lipids and apolipoproteins in patients with clinically well-controlled insulin-dependent and non-insulin-dependent diabetes.

    PubMed

    Joven, J; Vilella, E; Costa, B; Turner, P R; Richart, C; Masana, L

    1989-05-01

    The triglyceride and cholesterol content of total, very-low-, intermediate-, low-, and high-density lipoproteins, and of apolipoproteins (apo) Al, All, B, Cll, Clll, and E were determined in plasma from 107 patients with clinically well-controlled diabetes and from 66 age- and weight-matched healthy normal subjects. The diabetic patients were separated into two groups: those with insulin-dependent diabetes mellitus (IDDM, type 1, n = 24) and those with non-insulin-dependent diabetes mellitus (NIDDM, type 2, n = 83). The latter group contained two subgroups: those treated by diet (type 2d, n = 42) or by insulin (type 2i, n = 41). High-density lipoprotein cholesterol was increased in IDDM patients, and decreased in NIDDM patients relative to control subjects. Mean apo Al values in IDDM patients were higher than in their respective controls and in NIDDM patients. Concentrations of apo B, Clll, and E were higher in all diabetic patients than in the healthy controls, but those of apo Cll did not differ statistically between diabetics and nondiabetics. Although total plasma cholesterol and triglyceride concentrations were apparently near normal values in patients with good glycemic control, we found a persistent increase of intermediate-density lipoproteins (remnants) in all the diabetic groups studied. This factor may be related to the perceived increased cardiovascular risk in these individuals.

  11. Protein-tyrosine phosphatase activity in human adipocytes is strongly correlated with insulin-stimulated glucose uptake and is a target of insulin-induced oxidative inhibition.

    PubMed

    Wu, Xiangdong; Hardy, V Elise; Joseph, Jeffrey I; Jabbour, Serge; Mahadev, Kalyankar; Zhu, Li; Goldstein, Barry J

    2003-06-01

    Protein-tyrosine phosphatases (PTPases), in particular PTP1B, have been shown to modulate insulin signal transduction in liver and skeletal muscle in animal models; however, their role in human adipose tissue remains unclear. The uptake of (14)C-D-glucose in response to 10 or 100 nmol/L insulin was measured in isolated subcutaneous adipocytes from subjects with a mean age of 44 years (range, 26 to 58) and mean body mass index (BMI) of 35.6 (range, 29.7 to 45.5). The endogenous activity of total PTPases and specifically of PTP1B in immunoprecipitates was measured in cell lysates under an inert atmosphere with and without added reducing agents. Using nonlinear regression analysis, higher BMI was significantly correlated with lower adipocyte glucose uptake (r = 0.73, P =.01) and with increased endogenous total PTPase activity (r = 0.64, P =.04). Correlation with waist circumference gave similar results. The endogenous total PTPase activity also strongly correlated with insulin-stimulated glucose uptake (R =.89, P <.0001); however, the activity of PTP1B was unrelated to the level of glucose uptake. Consistent with the insulin-stimulated oxidative inhibition of thiol-dependent PTPases reported for 3T3-L1 adipocytes and hepatoma cells, treatment of human adipocytes with 100 nmol/L insulin for 5 minutes lowered endogenous PTPase activity to 37% of control (P <.001), which was increased 25% by subsequent treatment with dithiothreitol in vitro. Cellular treatment with diphenyleneiodonium (DPI), an NADPH oxidase inhibitor that blocks the cellular generation of H(2)O(2) and reduces the insulin-induced reduction of cellular PTPase activity, also diminished insulin-stimulated glucose uptake by 82% (P =.001). These data suggest that total cellular PTPase activity, but not the activity of PTP1B, is higher in more obese subjects and is negatively associated with insulin-stimulated glucose transport. The insulin-stimulated oxidative inhibition of PTPases may also have an important

  12. Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes.

    PubMed

    Tan, X C; Chua, K H; Ravishankar Ram, M; Kuppusamy, U R

    2016-04-01

    Various strategies have been adopted to combat complications caused by Type 2 diabetes mellitus and controlled diet is one of them. Monoterpenes, major constituents of essential oils, are synthesized and widely used as artificial food flavors. A series of twelve monoterpenes were assessed in the present study. Monoterpenes, exhibited low 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity even at high concentrations. Some monoterpenes inhibited α-amylase and α-glucosidase activity and stimulated glucose uptake and lipolysis. Monoterpenes such as (R)-(+)-limonene stimulated both glucose uptake (17.4%) and lipolysis (17.7%); the mRNA expression of glucose transporter 1 (GLUT1) was upregulated but glucose transporter 4 (GLUT4) was unaffected, and adipose triglyceride lipase (ATGL) was suppressed. Taken together, the selected monoterpenes may not confer strong protection against free radicals but nevertheless, their positive influence on lipid and glucose metabolism may have potential in the control of obesity and Type 2 diabetes mellitus. PMID:26593489

  13. Monoterpenes: Novel insights into their biological effects and roles on glucose uptake and lipid metabolism in 3T3-L1 adipocytes.

    PubMed

    Tan, X C; Chua, K H; Ravishankar Ram, M; Kuppusamy, U R

    2016-04-01

    Various strategies have been adopted to combat complications caused by Type 2 diabetes mellitus and controlled diet is one of them. Monoterpenes, major constituents of essential oils, are synthesized and widely used as artificial food flavors. A series of twelve monoterpenes were assessed in the present study. Monoterpenes, exhibited low 2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity even at high concentrations. Some monoterpenes inhibited α-amylase and α-glucosidase activity and stimulated glucose uptake and lipolysis. Monoterpenes such as (R)-(+)-limonene stimulated both glucose uptake (17.4%) and lipolysis (17.7%); the mRNA expression of glucose transporter 1 (GLUT1) was upregulated but glucose transporter 4 (GLUT4) was unaffected, and adipose triglyceride lipase (ATGL) was suppressed. Taken together, the selected monoterpenes may not confer strong protection against free radicals but nevertheless, their positive influence on lipid and glucose metabolism may have potential in the control of obesity and Type 2 diabetes mellitus.

  14. The distinctive role of positron emission tomography/computed tomography in breast carcinoma with brown adipose tissue 2-fluoro-2-deoxy-d-glucose uptake.

    PubMed

    Heiba, Sherif I; Bernik, Stephanie; Raphael, Barbara; Sandella, Nick; Cholewinski, Witold; Klein, Paula

    2005-01-01

    The diagnostic power of an integrated positron emission tomography/computed tomography (PET/CT) system for whole-body 2-fluoro-2-deoxy-d-glucose (FDG) imaging is clearly demonstrated in this case report. The precise anatomic localization of FDG uptake with CT in a PET/CT scan of a patient with known breast carcinoma helped identify a contralateral breast tumor with axillary lymph node metastasis despite the presence of extensive physiologic brown fat FDG uptake. Accordingly, the patient received appropriate surgical management and pathologic confirmation of the disease.

  15. The distinctive role of positron emission tomography/computed tomography in breast carcinoma with brown adipose tissue 2-fluoro-2-deoxy-d-glucose uptake.

    PubMed

    Heiba, Sherif I; Bernik, Stephanie; Raphael, Barbara; Sandella, Nick; Cholewinski, Witold; Klein, Paula

    2005-01-01

    The diagnostic power of an integrated positron emission tomography/computed tomography (PET/CT) system for whole-body 2-fluoro-2-deoxy-d-glucose (FDG) imaging is clearly demonstrated in this case report. The precise anatomic localization of FDG uptake with CT in a PET/CT scan of a patient with known breast carcinoma helped identify a contralateral breast tumor with axillary lymph node metastasis despite the presence of extensive physiologic brown fat FDG uptake. Accordingly, the patient received appropriate surgical management and pathologic confirmation of the disease. PMID:16297092

  16. Insulin-dependent regulation of GLAST/EAAT1 in Bergmann glial cells.

    PubMed

    Poblete-Naredo, Irais; Angulo, Carla; Hernández-Kelly, Luisa; López-Bayghen, Esther; Aguilera, José; Ortega, Arturo

    2009-02-20

    Glutamate is the major excitatory neurotransmitter in the central nervous system. Ionotropic and metabotropic glutamate receptors are present in neurons and glial cells and are involved in gene expression regulation. A family of sodium-dependent glutamate transporters carries out the removal of the neurotransmitter from the synaptic cleft. In the cerebellum, the bulk of glutamate transport is mediated through the excitatory amino acids transporter 1 (EAAT1/GLAST) expressed in Bergmann glial cells. Proper transporter function is critical for glutamate cycling and glucose turnover, as well as prevention of excitotoxic insult to Purkinje cells. In order to gain insight into the regulatory signals that modify this uptake activity, we investigated the effects of insulin exposure. Using the well-defined chick cerebellar Bergmann glial cell culture model, we observed a time and dose-dependent decrease in [(3)H]-d-aspartate uptake. As expected, this effect is mimicked by the tyrosine phosphatase inhibitor sodium orthovanadate, suggesting a receptor-mediated effect. Equilibrium [(3)H]-d-aspartate binding experiments as well as a reverse transcriptase/polymerase chain reaction strategy demonstrated that the decrease in the uptake activity is related to reduced numbers of transporter molecules in the plasma membrane. Accordingly, the transcriptional activity of the chick glast promoter diminished upon insulin treatment. The present findings suggest the involvement of insulin in neuronal/glial coupling in the cerebellum.

  17. D-Xylose as a sugar complement regulates blood glucose levels by suppressing phosphoenolpyruvate carboxylase (PEPCK) in streptozotocin-nicotinamide-induced diabetic rats and by enhancing glucose uptake in vitro

    PubMed Central

    Kim, Eunju; Kim, Yoo-Sun; Kim, Kyung-Mi; Jung, Sangwon; Yoo, Sang-Ho

    2016-01-01

    BACKGROUND/OBJECTIVES Type 2 diabetes (T2D) is more frequently diagnosed and is characterized by hyperglycemia and insulin resistance. D-Xylose, a sucrase inhibitor, may be useful as a functional sugar complement to inhibit increases in blood glucose levels. The objective of this study was to investigate the anti-diabetic effects of D-xylose both in vitro and stretpozotocin (STZ)-nicotinamide (NA)-induced models in vivo. MATERIALS/METHODS Wistar rats were divided into the following groups: (i) normal control; (ii) diabetic control; (iii) diabetic rats supplemented with a diet where 5% of the total sucrose content in the diet was replaced with D-xylose; and (iv) diabetic rats supplemented with a diet where 10% of the total sucrose content in the diet was replaced with D-xylose. These groups were maintained for two weeks. The effects of D-xylose on blood glucose levels were examined using oral glucose tolerance test, insulin secretion assays, histology of liver and pancreas tissues, and analysis of phosphoenolpyruvate carboxylase (PEPCK) expression in liver tissues of a STZ-NA-induced experimental rat model. Levels of glucose uptake and insulin secretion by differentiated C2C12 muscle cells and INS-1 pancreatic β-cells were analyzed. RESULTS In vivo, D-xylose supplementation significantly reduced fasting serum glucose levels (P < 0.05), it slightly reduced the area under the glucose curve, and increased insulin levels compared to the diabetic controls. D-Xylose supplementation enhanced the regeneration of pancreas tissue and improved the arrangement of hepatocytes compared to the diabetic controls. Lower levels of PEPCK were detected in the liver tissues of D-xylose-supplemented rats (P < 0.05). In vitro, both 2-NBDG uptake by C2C12 cells and insulin secretion by INS-1 cells were increased with D-xylose supplementation in a dose-dependent manner compared to treatment with glucose alone. CONCLUSIONS In this study, D-xylose exerted anti-diabetic effects in vivo by

  18. Model-Based Quantification of the Systemic Interplay between Glucose and Fatty Acids in the Postprandial State

    PubMed Central

    Sips, Fianne L. P.; Nyman, Elin; Adiels, Martin; Hilbers, Peter A. J.; Strålfors, Peter; van Riel, Natal A. W.; Cedersund, Gunnar

    2015-01-01

    In metabolic diseases such as Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, the systemic regulation of postprandial metabolite concentrations is disturbed. To understand this dysregulation, a quantitative and temporal understanding of systemic postprandial metabolite handling is needed. Of particular interest is the intertwined regulation of glucose and non-esterified fatty acids (NEFA), due to the association between disturbed NEFA metabolism and insulin resistance. However, postprandial glucose metabolism is characterized by a dynamic interplay of simultaneously responding regulatory mechanisms, which have proven difficult to measure directly. Therefore, we propose a mathematical modelling approach to untangle the systemic interplay between glucose and NEFA in the postprandial period. The developed model integrates data of both the perturbation of glucose metabolism by NEFA as measured under clamp conditions, and postprandial time-series of glucose, insulin, and NEFA. The model can describe independent data not used for fitting, and perturbations of NEFA metabolism result in an increased insulin, but not glucose, response, demonstrating that glucose homeostasis is maintained. Finally, the model is used to show that NEFA may mediate up to 30–45% of the postprandial increase in insulin-dependent glucose uptake at two hours after a glucose meal. In conclusion, the presented model can quantify the systemic interactions of glucose and NEFA in the postprandial state, and may therefore provide a new method to evaluate the disturbance of this interplay in metabolic disease. PMID:26356502

  19. Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer’s disease

    PubMed Central

    Willette, Auriel A.; Bendlin, Barbara B.; Starks, Erika J.; Birdsill, Alex C.; Johnson, Sterling C.; Christian, Bradley T.; Okonkwo, Ozioma C.; La Rue, Asenath; Hermann, Bruce P.; Koscik, Rebecca L.; Jonaitis, Erin M.; Sager, Mark A.; Asthana, Sanjay

    2015-01-01

    Importance Converging evidence suggests that Alzheimer’s disease (AD) involves insulin signaling impairment. AD patients and people at risk for AD show reduced glucose metabolism, as indexed by F18-fluorodeoxyglucose positron emission tomography ([F18]FDG-PET). Objective To determine if insulin resistance (IR) predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD. A secondary objective was to examine if IR-predicted variation in regional glucose metabolism was associated with worse cognitive performance. Setting A general community sample enriched for AD family history. Participants Population-based, cross-sectional study of 150 cognitively normal, late middle-aged (mean=60.67 years) adults from the Wisconsin Registry for Alzheimer’s Prevention. Design Participants underwent cognitive testing, fasting blood draw, and an [F18]FDG-PET scan at baseline. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was used to assess peripheral insulin resistance. Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. A voxel-wise analysis was used to determine if HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, Apolipoprotein E genotype, AD family history status, and a reference region used to normalize regional uptake. Main Outcome Measures Regional glucose uptake determined using [F18]FDG-PET, and neuropsychological factors. Results Higher HOMA-IR was associated with lower global glucose metabolism (β=−0.29, p<.01) and lower regional glucose metabolism across large portions of frontal, lateral parietal, lateral temporal, and medial temporal lobe (MTL; p<.05, family-wise error corrected). The association was especially robust in left MTL (R2=0.178). Lower left MTL glucose metabolism predicted by HOMA-IR was significantly

  20. Influence of 3 months endurance training on red cell deformability in non insulin dependent type 2 diabetes mellitus patients.

    PubMed

    Ahmad, B; Opitz, D; Bloch, W; Brixius, K

    2013-08-01

    The main purpose of the study was to examine if 3 months of bicycle endurance training alters the red cell deformability in non insulin dependent type 2 diabetes mellitus men.The red cell deformability was measured with the Laser assisted optical rotational cell analyzer. The maximal elongation index and the semimaximal shear stress were measured with the Lineweaver Burke model.At the beginning and the end of the intervention the patients passed a bicycle ergometry test. As a reference group, 13 males without diabetes passed the same testing procedure. Blood samplings were taken before testing, immediately after physical exhaustion and after a 30 min recovery phase.After the training period diabetic patients could significantly reduce BMI, fasting glucose and HbA1c. The reference group had significantly higher elongation indices than the diabetes patients independent from training status. After the training period the basal values of the maximal elongation index did not change significantly. However, maximal elongation indices were significantly reduced after physical examination and in resting time.The semimaximal shear stress of diabetes patients did not alter during the training period. In comparison to the reference group semimaximal shear stress was significantly reduced at all measurement times.This pilot study proves that the maximal elongation index is significantly decreased in diabetes mellitus patients. After 3 months endurance training the red cells become more rigid while the semimaximal shear stress remains constant. Further interventions are required to analyze the exact cause of the presented findings.

  1. The Hygiene Hypothesis: An Explanation for the Increased Frequency of Insulin-Dependent Diabetes

    PubMed Central

    Bach, Jean-François; Chatenoud, Lucienne

    2012-01-01

    The steadily increasing frequency of insulin-dependent diabetes in several countries is best explained today by the decline of infections. Epidemiologic and animal data support this conclusion, which, however, requires confirmation by intervention trials in man. The mechanisms of the protective effect of infections on diabetes onset are diverse including competition for homeostatic factors and stimulation of regulatory T cells and of Toll-like receptors. These considerations might have interesting therapeutic applications for the prevention of the disease. PMID:22355800

  2. Involvement of the Niacin Receptor GPR109a in the LocalControl of Glucose Uptake in Small Intestine of Type 2Diabetic Mice.

    PubMed

    Wong, Tung Po; Chan, Leo Ka Yu; Leung, Po Sing

    2015-09-08

    Niacin is a popular nutritional supplement known to reduce the risk of cardiovascular diseases by enhancing high-density lipoprotein levels. Despite such health benefits, niacin impairs fasting blood glucose. In type 2 diabetes (T2DM), an increase in jejunal glucose transport has been well documented; however, this is intriguingly decreased during niacin deficient state. In this regard, the role of the niacin receptor GPR109a in T2DM jejunal glucose transport remains unknown. Therefore, the effects of diabetes and high-glucose conditions on GPR109a expression were studied using jejunal enterocytes of 10-week-old m+/db and db/db mice, as well as Caco-2 cells cultured in 5.6 or 25.2 mM glucose concentrations. Expression of the target genes and proteins were quantified using real-time polymerase chain reaction (RT-PCR) and Western blotting. Glucose uptake in Caco-2 cells and everted mouse jejunum was measured using liquid scintillation counting. 10-week T2DM increased mRNA and protein expression levels of GPR109a in jejunum by 195.0% and 75.9%, respectively, as compared with the respective m+/db control; high-glucose concentrations increased mRNA and protein expression of GPR109a in Caco-2 cells by 130.2% and 69.0%, respectively, which was also confirmed by immunohistochemistry. In conclusion, the enhanced GPR109a expression in jejunal enterocytes of T2DM mice and high-glucose treated Caco-2 cells suggests that GPR109a is involved in elevating intestinal glucose transport observed in diabetes.

  3. Fucoxanthin exerts differing effects on 3T3-L1 cells according to differentiation stage and inhibits glucose uptake in mature adipocytes

    SciTech Connect

    Kang, Seong-Il; Ko, Hee-Chul; Shin, Hye-Sun; Kim, Hyo-Min; Hong, Youn-Suk; Lee, Nam-Ho; Kim, Se-Jae

    2011-06-17

    Highlights: {yields} Fucoxanthin enhances 3T3-L1 adipocyte differentiation at an early stage. {yields} Fucoxanthin inhibits 3T3-L1 adipocyte differentiation at intermediate and late stages. {yields} Fucoxanthin attenuates glucose uptake by inhibiting the phosphorylation of IRS in mature 3T3-L1 adipocytes. {yields} Fucoxanthin exerts its anti-obesity effect by inhibiting the differentiation of adipocytes at both intermediate and late stages, as well as glucose uptake in mature adipocytes. -- Abstract: Progression of 3T3-L1 preadipocyte differentiation is divided into early (days 0-2, D0-D2), intermediate (days 2-4, D2-D4), and late stages (day 4 onwards, D4-). In this study, we investigated the effects of fucoxanthin, isolated from the edible brown seaweed Petalonia binghamiae, on adipogenesis during the three differentiation stages of 3T3-L1 preadipocytes. When fucoxanthin was applied during the early stage of differentiation (D0-D2), it promoted 3T3-L1 adipocyte differentiation, as evidenced by increased triglyceride accumulation. At the molecular level, fucoxanthin increased protein expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), CCAAT/enhancer-binding protein {alpha} (C/EBP{alpha}), sterol regulatory element-binding protein 1c (SREBP1c), and aP2, and adiponectin mRNA expression, in a dose-dependent manner. However, it reduced the expression of PPAR{gamma}, C/EBP{alpha}, and SREBP1c during the intermediate (D2-D4) and late stages (D4-D7) of differentiation. It also inhibited the uptake of glucose in mature 3T3-L1 adipocytes by reducing the phosphorylation of insulin receptor substrate 1 (IRS-1). These results suggest that fucoxanthin exerts differing effects on 3T3-L1 cells of different differentiation stages and inhibits glucose uptake in mature adipocytes.

  4. Background Colonic 18F-Fluoro-2-Deoxy-D-Glucose Uptake on Positron Emission Tomography Is Associated with the Presence of Colorectal Adenoma

    PubMed Central

    Lee, Ko Eun; Yoon, Hai-Jeon; Chang, Ji Young; Son, Hyo Moon; Ryu, Min Sun; Kim, Seong-Eun; Shim, Ki-Nam; Jung, Hye-Kyung; Jung, Sung-Ae

    2016-01-01

    18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan is used to evaluate various kinds of tumors. While most studies on PET findings of the colon focus on the colonic uptake pattern, studies regarding background colonic uptake on PET scan are rare. The purpose of this study was to identify the association between the background colonic uptake and the presence of colorectal adenoma (CRA), which is a frequent precancerous lesion. We retrospectively reviewed the medical records of 241 patients with gynecologic malignancy who had received PET or PET/computed tomography (CT) scan and colonoscopy at the same period as a baseline evaluation. Background colonic 18F-FDG uptake was visually graded and the maximal standardized uptake values (SUVmax) of 7 different bowel segments were averaged. In univariate analysis, older age at diagnosis (≥ 50 years, p = 0.034), overweight (BMI ≥ 23 kg/m², p = 0.010), hypercholesterolemia (≥ 200 mg/dL, p = 0.027), and high grade background colonic uptake (p = 0.009) were positively associated with the prevalence of CRA. By multiple logistic regression, high grade background colonic uptake was independently predictive of CRA (odds ratio = 2.25, p = 0.021). The proportion of CRA patients significantly increased as background colonic uptake grade increased from 1 to 4 (trend p = 0.015). Out of the 138 patients who underwent PET/CT, the proportion of CRA patients in the group with high SUVmax (> 2.25) was significantly higher than in the low SUVmax group (27.5% vs. 11.6%, p = 0.031). In conclusion, high grade of background colonic 18F-FDG uptake is significantly associated with the prevalence of CRA. PMID:27509022

  5. Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes

    SciTech Connect

    Serri, O.; Beauregard, H.; Brazeau, P.; Abribat, T.; Lambert, J.; Harris, A.; Vachon, L. Sandoz Canada Inc., Dorval, Quebec )

    1991-02-20

    To determine whether treatment with a somatostatin analogue can reduce kidney hyperfiltration and hypertrophy in insulin-dependent diabetes mellitus, the authors studied 11 patients with insulin-dependent diabetes mellitus and glomerular hyperfiltration. The patients were assigned randomly to receive continuous subcutaneous infusion of either octreotide, 300 {mu}g/24 h (five patients) or placebo (six patients) for 12 weeks. At baseline, mean glomerular filtration rate and mean total kidney volume were not significantly different in the two groups. However, after 12 weeks of treatment, the mean glomerular filtration rate was significantly lower in the octreotide group than in the placebo group. Furthermore, the mean total kidney volume was significantly lower after treatment in the octreotide group than in the placebo group. Glycemic control did not change significantly in either group. They conclude that subcutaneous infusion of octreotide for 12 weeks reduces increased glomerular filtration rate and kidney size in patients with insulin-dependent diabetes mellitus despite the fact that glycemic control remains unchanged.

  6. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

    SciTech Connect

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  7. Propionic acid and butyric acid inhibit lipolysis and de novo lipogenesis and increase insulin-stimulated glucose uptake in primary rat adipocytes.

    PubMed

    Heimann, Emilia; Nyman, Margareta; Degerman, Eva

    2015-01-01

    Fermentation of dietary fibers by colonic microbiota generates short-chain fatty acids (SCFAs), e.g., propionic acid and butyric acid, which have been described to have "anti-obesity properties" by ameliorating fasting glycaemia, body weight and insulin tolerance in animal models. In the present study, we therefore investigate if propionic acid and butyric acid have effects on lipolysis, de novo lipogenesis and glucose uptake in primary rat adipocytes. We show that both propionic acid and butyric acid inhibit isoproterenol- and adenosine deaminase-stimulated lipolysis as well as isoproterenol-stimulated lipolysis in the presence of a phosphodiesterase (PDE3) inhibitor. In addition, we show that propionic acid and butyric acid inhibit basal and insulin-stimulated de novo lipogenesis, which is associated with increased phosphorylation and thus inhibition of acetyl CoA carboxylase, a rate-limiting enzyme in fatty acid synthesis. Furthermore, we show that propionic acid and butyric acid increase insulin-stimulated glucose uptake. To conclude, our study shows that SCFAs have effects on fat storage and mobilization as well as glucose uptake in rat primary adipocytes. Thus, the SCFAs might contribute to healthier adipocytes and subsequently also to improved energy metabolism with for example less circulating free fatty acids, which is beneficial in the context of obesity and type 2 diabetes. PMID:26167409

  8. Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.

    PubMed

    Morland, Cecilie; Pettersen, Mi Nguyen; Hassel, Bjørnar

    2016-05-01

    Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia. PMID:26994581

  9. Hyperosmolar sodium chloride is toxic to cultured neurons and causes reduction of glucose metabolism and ATP levels, an increase in glutamate uptake, and a reduction in cytosolic calcium.

    PubMed

    Morland, Cecilie; Pettersen, Mi Nguyen; Hassel, Bjørnar

    2016-05-01

    Elevation of serum sodium, hypernatremia, which may occur during dehydration or treatment with sodium chloride, may cause brain dysfunction and damage, but toxic mechanisms are poorly understood. We found that exposure to excess NaCl, 10-100mmol/L, for 20h caused cell death in cultured cerebellar granule cells (neurons). Toxicity was due to Na(+), since substituting excess Na(+) with choline reduced cell death to control levels, whereas gluconate instead of excess Cl(-) did not. Prior to cell death from hyperosmolar NaCl, glucose consumption and lactate formation were reduced, and intracellular aspartate levels were elevated, consistent with reduced glycolysis or glucose uptake. Concomitantly, the level of ATP became reduced. Pyruvate, 10mmol/L, reduced NaCl-induced cell death. The extracellular levels of glutamate, taurine, and GABA were concentration-dependently reduced by excess NaCl; high-affinity glutamate uptake increased. High extracellular [Na(+)] caused reduction in intracellular free [Ca(2+)], but a similar effect was seen with mannitol, which was not neurotoxic. We suggest that inhibition of glucose metabolism with ensuing loss of ATP is a neurotoxic mechanism of hyperosmolar sodium, whereas increased uptake of extracellular neuroactive amino acids and reduced intracellular [Ca(2+)] may, if they occur in vivo, contribute to the cerebral dysfunction and delirium described in hypernatremia.

  10. Saponarin activates AMPK in a calcium-dependent manner and suppresses gluconeogenesis and increases glucose uptake via phosphorylation of CRTC2 and HDAC5.

    PubMed

    Seo, Woo-Duck; Lee, Ji Hae; Jia, Yaoyao; Wu, Chunyan; Lee, Sung-Joon

    2015-11-15

    This study investigated the molecular mechanism of saponarin, a flavone glucoside, in the regulation of insulin sensitivity. Saponarin suppressed the rate of gluconeogenesis and increased cellular glucose uptake in HepG2 and TE671 cells by regulating AMPK. Using an in vitro kinase assay, we showed that saponarin did not directly interact with the AMPK protein. Instead, saponarin increased intracellular calcium levels and induced AMPK phosphorylation, which was diminished by co-stimulation with STO-609, an inhibitor of CAMKKβ. Transcription of hepatic gluconeogenesis genes was upregulated by nuclear translocation of CRTC2 and HDAC5, coactivators of CREB and FoxO1 transcription factors, respectively. This nuclear translocation was inhibited by increased phosphorylation of CRTC2 and HDAC5 by saponarin-induced AMPK in HepG2 cells and suppression of CREB and FoxO1 transactivation activities in cells stimulated by saponarin. The results from a chromatin immunoprecipitation assay confirmed the reduced binding of CRTC2 on the PEPCK and G6Pase promoters. In TE671 cells, AMPK phosphorylated HDAC5, which suppressed nuclear penetration and upregulated GLUT4 transcription, leading to enhanced glucose uptake. Collectively, these results suggest that saponarin activates AMPK in a calcium-dependent manner, thus regulating gluconeogenesis and glucose uptake.

  11. Epinephrine-stimulated glycogen breakdown activates glycogen synthase and increases insulin-stimulated glucose uptake in epitrochlearis muscles.

    PubMed

    Kolnes, Anders J; Birk, Jesper B; Eilertsen, Einar; Stuenæs, Jorid T; Wojtaszewski, Jørgen F P; Jensen, Jørgen

    2015-02-01

    Epinephrine increases glycogen synthase (GS) phosphorylation and decreases GS activity but also stimulates glycogen breakdown, and low glycogen content normally activates GS. To test the hypothesis that glycogen content directly regulates GS phosphorylation, glycogen breakdown was stimulated in condition with decreased GS activation. Saline or epinephrine (0.02 mg/100 g rat) was injected subcutaneously in Wistar rats (∼130 g) with low (24-h-fasted), normal (normal diet), and high glycogen content (fasted-refed), and epitrochlearis muscles were removed after 3 h and incubated ex vivo, eliminating epinephrine action. Epinephrine injection reduced glycogen content in epitrochlearis muscles with high (120.7 ± 17.8 vs. 204.6 ± 14.5 mmol/kg, P < 0.01) and normal glycogen (89.5 ± 7.6 vs. 152 ± 8.1 mmol/kg, P < 0.01), but not significantly in muscles with low glycogen (90.0 ± 5.0 vs. 102.8 ± 7.8 mmol/kg, P = 0.17). In saline-injected rats, GS phosphorylation at sites 2+2a, 3a+3b, and 1b was higher and GS activity lower in muscles with high compared with low glycogen. GS sites 2+2a and 3a+3b phosphorylation decreased and GS activity increased in muscles where epinephrine decreased glycogen content; these parameters were unchanged in epitrochlearis from fasted rats where epinephrine injection did not decrease glycogen content. Incubation with insulin decreased GS site 3a+3b phosphorylation independently of glycogen content. Insulin-stimulated glucose uptake was increased in muscles where epinephrine injection decreased glycogen content. In conclusion, epinephrine stimulates glycogenolysis in epitrochlearis muscles with normal and high, but not low, glycogen content. Epinephrine-stimulated glycogenolysis decreased GS phosphorylation and increased GS activity. These data for the first time document direct regulation of GS phosphorylation by glycogen content.

  12. Higenamine 4'-O-β-d-glucoside in the lotus plumule induces glucose uptake of L6 cells through β2-adrenergic receptor.

    PubMed

    Kato, Eisuke; Inagaki, Yosuke; Kawabata, Jun

    2015-07-01

    Hypoglycemic effect is an efficient means to modulate elevated blood glucose levels in patients with diabetes. We found that the extract of lotus plumule (the germ of Nelumbo nucifera Gaertn. seed) showed potent glucose uptake enhancement activity against L6 myotubes, which results in a hypoglycemic effect. This activity was further investigated, and an active constituent was identified as a single bioactive compound, higenamine 4'-O-β-d-glucoside. Mechanistic studies employing phosphatidylinositol 3-kinase (PI3K) inhibitor, AMP-activated protein kinase (AMPK) inhibitor, or adrenergic receptor antagonist showed that the compound induced its activity through β2-adrenergic receptor. Patients with type II diabetes mellitus frequently develop insulin resistance. Owing to the differences between the mechanism of action of insulin and of the isolated compound, the compound or lotus plumule itself may have the possibility of modulating blood glucose levels in insulin-resistant patients effectively. PMID:25943853

  13. Higenamine 4'-O-β-d-glucoside in the lotus plumule induces glucose uptake of L6 cells through β2-adrenergic receptor.

    PubMed

    Kato, Eisuke; Inagaki, Yosuke; Kawabata, Jun

    2015-07-01

    Hypoglycemic effect is an efficient means to modulate elevated blood glucose levels in patients with diabetes. We found that the extract of lotus plumule (the germ of Nelumbo nucifera Gaertn. seed) showed potent glucose uptake enhancement activity against L6 myotubes, which results in a hypoglycemic effect. This activity was further investigated, and an active constituent was identified as a single bioactive compound, higenamine 4'-O-β-d-glucoside. Mechanistic studies employing phosphatidylinositol 3-kinase (PI3K) inhibitor, AMP-activated protein kinase (AMPK) inhibitor, or adrenergic receptor antagonist showed that the compound induced its activity through β2-adrenergic receptor. Patients with type II diabetes mellitus frequently develop insulin resistance. Owing to the differences between the mechanism of action of insulin and of the isolated compound, the compound or lotus plumule itself may have the possibility of modulating blood glucose levels in insulin-resistant patients effectively.

  14. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells.

    PubMed

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA-PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  15. Anti-diabetic effects of Caulerpa lentillifera: stimulation of insulin secretion in pancreatic β-cells and enhancement of glucose uptake in adipocytes

    PubMed Central

    Sharma, Bhesh Raj; Rhyu, Dong Young

    2014-01-01

    Objective To evaluate anti-diabetic effect of Caulerpa lentillifera (C. lentillifera). Methods The inhibitory effect of C. lentillifera extract on dipeptidyl peptidase-IV and α-glucosidase enzyme was measured in a cell free system. Then, interleukin-1β and interferon-γ induced cell death and insulin secretion were measured in rat insulinoma (RIN) cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ELISA kit, respectively. Glucose uptake and glucose transporter expression were measured by fluorometry and western blotting, using 3T3-L1 adipocytes. Results C. lentillifera extract significantly decreased dipeptidyl peptidase-IV and α-glucosidase enzyme activities, and effectively inhibited cell death and iNOS expression in interleukin-1β and interferon-γ induced RIN cells. Furthermore, C. lentillifera extract significantly enhanced insulin secretion in RIN cells and glucose transporter expression and glucose uptake in 3T3-L1 adipocytes. Conclusions Thus, our results suggest that C. lentillifera could be used as a potential anti-diabetic agent. PMID:25183280

  16. Antidiabetic Activity of Pterospermum acerifolium Flowers and Glucose Uptake Potential of Bioactive Fraction in L6 Muscle Cell Lines with Its HPLC Fingerprint

    PubMed Central

    Paramaguru, Rathinavelusamy; Sasmal, Dinakar

    2014-01-01

    The present study was designed to estimate the detailed antidiabetic activity of Pterospermum acerifolium (L.) Willd flowers. In vitro alpha amylase inhibition study was carried out on 50% ethanol extract of flowers (PAFEE) and its various fractions. The active ethyl acetate fraction (PAFEF) was subfractionated into three subfractions (PAFE1, PAFE2, and PAFE3) and subjected to acute toxicity studies followed by antidiabetic screening in vivo by streptozotocin-nicotinamide induced type II diabetes. Diabetic animals treated with PAFE2 (30 mg/kg) reduced the levels of fasting blood glucose, significantly (P < 0.001) compared to that of diabetic control animals. Histological studies on drug treated groups did not show remarkable positive changes in β-cells. PAFE2 showed 32.6 ± 1.93% glucose uptake over control and, in the presence of PI3K inhibitor wortmannin, declined to 13.7 ± 2.51%. HPLC analysis of PAFE2 reveals the presence of quercetin and apigenin as major constituents and both are inhibiting the glycogen phosphorylase enzyme in molecular modelling studies. The study evidenced strongly that the probable glucose lowering mechanism of action of active subfraction PAFE2 is by increasing the glucose uptake in peripheral tissues and by inhibition of gluconeogenesis. PMID:25401101

  17. The pivotal role of protein kinase C zeta (PKCzeta) in insulin- and AMP-activated protein kinase (AMPK)-mediated glucose uptake in muscle cells.

    PubMed

    Liu, Li-Zhong; Cheung, Stanley C K; Lan, Lin-Lin; Ho, Stanley K S; Chan, Juliana C N; Tong, Peter C Y

    2010-10-01

    Insulin and AMP-activated protein kinase (AMPK) signal pathways are involved in the regulation of glucose uptake. The integration of signals between these two pathways to maintain glucose homeostasis remains elusive. In this work, stimulation of insulin and berberine conferred a glucose uptake or surface glucose transporter 4 (GLUT4) translocation that was less than simple summation of their effects in insulin-sensitive muscle cells. Using specific inhibitors to key kinases of both pathways and PKCzeta small interference RNA, protein kinase C zeta (PKCzeta) was found to regulate insulin-stimulated protein kinase B (PKB) activation and inhibit AMPK activity on dorsal cell surface. In the presence of berberine, PKCzeta controlled AMPK activation and AMPK blocked PKB activity in perinuclear region. The inhibition effect of PKCzeta on AMPK activation or the arrestment of PKB activity by AMPK still existed in basal condition. These results suggest that there is antagonistic regulation between insulin and AMPK signal pathways, which is mediated by the switch roles of PKCzeta.

  18. Expression and regulation of facilitative glucose transporters in equine insulin-sensitive tissue: from physiology to pathology.

    PubMed

    Lacombe, Véronique A

    2014-01-01

    Glucose uptake is the rate-limiting step in glucose utilization in mammalians and is tightly regulated by a family of specialized proteins, called the facilitated glucose transporters (GLUTs/SLC2). GLUT4, the major isoform in insulin-responsive tissue, translocates from an intracellular pool to the cell surface and as such determines insulin-stimulated glucose uptake. However, despite intensive research over 50 years, the insulin-dependent and -independent pathways that mediate GLUT4 translocation are not fully elucidated in any species. Insulin resistance (IR) is one of the hallmarks of equine metabolic syndrome and is the most common metabolic predisposition for laminitis in horses. IR is characterized by the impaired ability of insulin to stimulate glucose disposal into insulin-sensitive tissues. Similar to other species, the functional capability of the insulin-responsive GLUTs is impaired in muscle and adipose tissue during IR in horses. However, the molecular mechanisms of altered glucose transport remain elusive in all species, and there is still much to learn about the physiological and pathophysiological functions of the GLUT family members, especially in regard to class III. Since GLUTs are key regulators of whole-body glucose homeostasis, they have received considerable attention as potential therapeutic targets to treat metabolic disorders in human and equine patients. PMID:24977043

  19. Acetylcholinesterase is associated with apoptosis in β cells and contributes to insulin-dependent diabetes mellitus pathogenesis.

    PubMed

    Zhang, Bao; Yang, Lei; Yu, Luyang; Lin, Bo; Hou, Yanan; Wu, Jun; Huang, Qin; Han, Yifan; Guo, Lihe; Ouyang, Qi; Zhang, Bo; Lu, Lu; Zhang, Xuejun

    2012-03-01

    Acetylcholinesterase (AChE) expression is pivotal during apoptosis. Indeed, AChE inhibitors partially protect cells from apoptosis. Insulin-dependent diabetes mellitus (IDDM) is characterized in part by pancreatic β-cell apoptosis. Here, we investigated the role of AChE in the development of IDDM and analyzed protective effects of AChE inhibitors. Multiple low-dose streptozotocin (MLD-STZ) administration resulted in IDDM in a mouse model. Western blot analysis, cytochemical staining, and immunofluorescence staining were used to detect AChE expression in MIN6 cells, primary β cells, and apoptotic pancreatic β cells of MLD-STZ-treated mice. AChE inhibitors were administered intraperitoneally to the MLD-STZ mice for 30 days. Blood glucose, plasma insulin, and creatine levels were measured, and glucose tolerance tests were performed. The effects of AChE inhibitors on MIN6 cells were also evaluated. AChE expression was induced in the apoptotic MIN6 cells and primary β cells in vitro and pancreatic islets in vivo when treated with STZ. Induction and progressive accumulation of AChE in the pancreatic islets were associated with apoptotic β cells during IDDM development. The administration of AChE inhibitors effectively decreased hyperglycemia and incidence of diabetes, and restored plasma insulin levels and plasma creatine clearance in the MLD-STZ mice. AChE inhibitors partially protected MIN6 cells from the damage caused by STZ treatment. Induction and accumulation of AChE in pancreatic islets and the protective effects of AChE inhibitors on the onset and development of IDDM indicate a close relationship between AChE and IDDM.

  20. Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus

    SciTech Connect

    Sakura, Hiroshi; Eto, Kazuhiro; Ueno, Hirohisa; Yazaki, Yoshio; Kadowaki, Takashi ); Kadowaki, Hiroko; Simokawa, Kotaro; Akanuma, Yasuo ); Koda, Naoya; Fukushima, Yoshimitsu )

    1992-12-01

    Glucokinase is thought to play a glucose-sensor role in the pancreas, and abnormalities in its structure, function, and regulation can induce diabetes. The authors isolated the human glucokinase gene, and determined its genomic structure including exon-intron boundaries. Structure of the glucokinase gene in human was very similar to that in rat. Then, by screening Japanese diabetic patients using polymerase chain reaction - single strand conformation polymorphism (PCR-SSCP) and direct-sequencing strategies, they identified a missense mutation substituting ariginine (AGG) for glycine (GGG) at position 261 in exon 7 of the glucokinase gene in a patient with early-onset non-insulin-dependent diabetes (NIDDM). 12 refs., 3 figs., 2 tabs.

  1. Combination therapy of dyslipidemia in non-insulin-dependent diabetes mellitus and the metabolic syndrome.

    PubMed

    Rembold, Christopher M

    2004-10-01

    Non-insulin-dependent diabetes mellitus (NIDDM) and the metabolic syndrome separately and additively increase the risk for atherosclerotic cardiovascular disease. Considering the high cardiovascular risk associated with NIDDM and the metabolic syndrome, aggressive therapy of dyslipidemia with tailored combination therapy should be considered given informed consent and discussion of risks. In addition to statins, niacin, and fibrates, therapies shown to decrease the risk for atherosclerotic cardiovascular disease include omega-3 fatty acids, diet, exercise, and optimal blood pressure control with thiazides and blockers of the renin-angiotensin system. These therapies should also be considered to reduce the high cardiovascular risk associated with NIDDM and the metabolic syndrome.

  2. Insulin-dependent diabetes mellitus and quality of life. A theoretical analysis.

    PubMed

    Hanestad, B R

    1989-01-01

    Insulin-dependent diabetes mellitus (IDDM) affects the overall life situation of the individual. The term "quality of life" means each individual person's estimation of what it means to have a good life. There are many aspects of diabetes which will influence to a greater or lesser extent each individual's degree of satisfaction with his/her life. This theoretical analysis shows that there is no direct connection between reduced quality of life and IDDM. There is a need, however, for empirical investigations which will provide a better understanding of the relationship between quality of life and IDDM. PMID:2814081

  3. Obesity, albuminuria and hypertension among Hong Kong Chinese with non-insulin-dependent diabetes mellitus (NIDDM).

    PubMed Central

    Chan, J. C.; Cheung, C. K.; Swaminathan, R.; Nicholls, M. G.; Cockram, C. S.

    1993-01-01

    A total of 412 Hong Kong Chinese diabetic patients were studied on at least two occasions 8-16 weeks apart. Although 28% were insulin-treated, only 3.6% had insulin-dependent diabetes (IDDM). In the remaining 397 patients with non-insulin-dependent diabetes (NIDDM), the mean (s.d.) body mass index (BMI) was 24.4 +/- 3.2 kg/m2 in females and 24.2 +/- 3.2 kg/m2 in males. Obesity was present in 17% of males (BMI > 27 kg/m2) and 40% of females (BMI > 25 kg/m2). Established hypertension was present in 49%. Abnormal albuminuria, defined as a mean urinary albumin/creatinine (UA/Cr) ratio greater than 5.4 mg/mmol based on two random spot urine samples, was present in 47%. On stepwise multiple regression analysis, UA/Cr ratio (R2 = 0.34, F = 65.4, P < 0.001) showed significant associations with systolic blood pressure (standardized regression coefficient beta = 0.40, P < 0.001), plasma creatinine concentration (beta = 0.27, P < 0.001) and glycosylated haemoglobin (beta = 0.20, P < 0.001). While the prevalence of hypertension increased with increasing severity of proteinuria, 40% of normoalbuminuric patients had hypertension. Among patients diagnosed before the age of 35 (n = 67), 52% were insulin-treated although only 10% were insulin-dependent. Among these NIDDM patients of young onset (n = 59), obesity was present in 25% of males and 56% of females. Overall, 18% of these patients had a blood pressure greater than 140/90 mmHg and 27% had abnormal albuminuria. In Hong Kong Chinese, diabetes mellitus is predominantly non-insulin-dependent even in the young. Obesity is more prevalent among females. Abnormal albuminuria is relatively common and is closely associated with hypertension and glycaemic control. In the light of increasing prevalence of diabetes among overseas Chinese, our findings may have important implications in the management of Chinese diabetic patients. PMID:8497435

  4. Association of sexual activity and bacteriuria in women with non-insulin-dependent diabetes mellitus.

    PubMed

    Pérez-Luque, E L; de la Luz Villalpando, M; Malacara, J M

    1992-01-01

    A group of 215 patients with non-insulin-dependent diabetes mellitus (NIDDM) (147 women and 68 men) were selected by home interview, and accepted to undergo clinical examination including urine culture, in order to determine the frequency of bacteriuria and its possible associations with clinical and laboratory findings. Bacteriuria was found in 17.7% of women and 1.5% of men. Univariate and multivariate analysis performed for the group of women revealed sexual intercourse and pyuria as the only factors associated with the frequency of bacteriuria. It was concluded that asymptomatic bacteriuria may be associated with sexual activity in women with NIDDM.

  5. Comparison of outcomes in patients with insulin-dependent versus non-insulin dependent diabetes mellitus receiving drug-eluting stents (from the first phase of the prospective multicenter German DES.DE registry).

    PubMed

    Akin, Ibrahim; Bufe, Alexander; Eckardt, Lars; Reinecke, Holger; Senges, Jochen; Richardt, Gert; Kuck, Karl-Heinz; Schneider, Steffen; Nienaber, Christoph A

    2010-11-01

    Drug-eluting stents have been effective in randomized controlled trials, but their safety and efficacy in patients with insulin-dependent diabetes has not been well studied. Baseline clinical and angiographic characteristics and in-hospital and follow-up events were recorded for enrolled patients. From October 2005 and October 2006, 581 patients with insulin-dependent diabetes and 1,078 with non-insulin-dependent diabetes treated with sirolimus- and paclitaxel-eluting stents were enrolled at 98 sites. The composite of death, myocardial infarction, and stroke, defined as major adverse cardiac and cerebrovascular events, as well as target vessel revascularization was used as the primary end point. Multiple logistic regression analysis was used to adjust for confounding parameters. Baseline clinical characteristics were more severe in patients with insulin-dependent diabetes, whereas descriptive characteristics were not unique. At 1-year follow-up, the comparison between the 2 groups revealed significantly higher rates of overall death (7.4% vs 4.6%, p <0.05), target vessel revascularization (15.1% vs 10.4%, p <0.05), and overall stent thrombosis (6.5% vs 4.1%, p <0.05) for insulin-dependent patients, while rates of major adverse cardiac and cerebrovascular events were not significantly different (12.8% vs 9.9%, p = 0.09). These results persisted even after risk adjustment for heterogenous baseline characteristics of the 2 groups. In conclusion, the data generated from the German Drug-Eluting Stent (DES.DE) registry revealed that even with drug-eluting stents, the annual risk for death, target vessel revascularization, and thrombotic events remains higher in patients with insulin-dependent diabetes compared to those with non-insulin-dependent diabetes.

  6. Ethanol extract of the Prunus mume fruits stimulates glucose uptake by regulating PPAR-γ in C2C12 myotubes and ameliorates glucose intolerance and fat accumulation in mice fed a high-fat diet.

    PubMed

    Shin, Eun Ju; Hur, Haeng Jeon; Sung, Mi Jeong; Park, Jae Ho; Yang, Hye Jeong; Kim, Myung Sunny; Kwon, Dae Young; Hwang, Jin-Taek

    2013-12-15

    In this study, we performed in vitro and in vivo studies to examine whether a 70% ethanol extract of Prunus mume fruits (EMS) exhibits anti-diabetic effects. Treatment with EMS increased glucose uptake in C2C12 myotubes, and also increased PPAR-γ activity or PPAR-γ mRNA expression. To confirm these in vitro results, we next conducted an animal experiment. A high-fat diet significantly increased the body weight, fat accumulation, and glucose levels in mice. Under the same conditions, 5% EMS attenuated the high-fat diet-induced increase in body weight and fat accumulation and improved the impaired fasting glucose level and glucose tolerance. High performance liquid chromatography analysis demonstrated that EMS contained chlorogenic acid, caffeic acid, rutin, luteolin-7-glucoside, naringin, apigenin-7-glucoside, and hesperidin. Taken together, these findings suggest that EMS exerts an anti-diabetic effect both in vitro and in vivo, which is mediated, at least in part, by the activation of PPAR-γ.

  7. Ethanol extract of the Prunus mume fruits stimulates glucose uptake by regulating PPAR-γ in C2C12 myotubes and ameliorates glucose intolerance and fat accumulation in mice fed a high-fat diet.

    PubMed

    Shin, Eun Ju; Hur, Haeng Jeon; Sung, Mi Jeong; Park, Jae Ho; Yang, Hye Jeong; Kim, Myung Sunny; Kwon, Dae Young; Hwang, Jin-Taek

    2013-12-15

    In this study, we performed in vitro and in vivo studies to examine whether a 70% ethanol extract of Prunus mume fruits (EMS) exhibits anti-diabetic effects. Treatment with EMS increased glucose uptake in C2C12 myotubes, and also increased PPAR-γ activity or PPAR-γ mRNA expression. To confirm these in vitro results, we next conducted an animal experiment. A high-fat diet significantly increased the body weight, fat accumulation, and glucose levels in mice. Under the same conditions, 5% EMS attenuated the high-fat diet-induced increase in body weight and fat accumulation and improved the impaired fasting glucose level and glucose tolerance. High performance liquid chromatography analysis demonstrated that EMS contained chlorogenic acid, caffeic acid, rutin, luteolin-7-glucoside, naringin, apigenin-7-glucoside, and hesperidin. Taken together, these findings suggest that EMS exerts an anti-diabetic effect both in vitro and in vivo, which is mediated, at least in part, by the activation of PPAR-γ. PMID:23993593

  8. Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians

    SciTech Connect

    Sakul, H.; Cardon, L.; Pratley, R.

    1997-03-01

    Susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) is largely genetically determined. In Pima Indians, obesity, insulin resistance, and a low acute insulin response (AIR) to an intravenous glucose infusion are each predictors of the disease. To ascertain whether these phenotypes are genetically determined, we estimated their familiarity in nondiabetic Pima Indians with a maximum-likelihood method. Percentage body fat (PFAT) was highly familial (h{sup 2} = .76), whereas waist/thigh circumference ratio (W/T ratio) was not significantly familial after controlling for PFAT (h{sup 2} = .16). AIR was also highly familial (h{sup 2} = .80 at 10 min), even after controlling for PFAT and insulin action (h{sup 2} = .70). Insulin action at physiologic plasma insulin concentrations was familial (h{sup 2} = .61) but less so after controlling for PFAT and W/T ratio (h{sup 2} = .38). At maximally stimulating insulin concentrations, insulin action was familial (h{sup 2} = .45) and was less influenced by controlling for PFAT and W/T ratio (h{sup 2} = .49). We conclude that in Pima Indians (1) PFAT and AIR are highly familial traits, (2) central distribution of fat is not a familial trait when controlled for PFAT, (3) 38%-49% of the variance in insulin action, independent of the effect of obesity, is familial, and (4) PFAT, AIR, and insulin action are useful traits to study genetic susceptibility to NIDDM. Because genetic parameter estimates are applicable only to the populations from which they were estimated, it is important to determine whether these estimates of familiarities in Pima Indians can be confirmed in other populations before the utility of these traits in searching for NIDDM susceptibility genes in those populations can be fully advocated. 31 refs., 3 tabs.

  9. Transient insulin-dependent diabetes mellitus in children with steroid-dependent idiopathic nephrotic syndrome during tacrolimus treatment.

    PubMed

    Dittrich, Katalin; Knerr, Ina; Rascher, Wolfgang; Dötsch, Jörg

    2006-07-01

    Despite the availability of immunosuppressive drugs such as prednisone, cyclophosphamide, cyclosporine A (CyA) and mycophenolate mofetil for the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS), medication-free remission is not achieved in a number of patients. To avoid excessive steroid toxicity, the use of tacrolimus (Tac) has been discussed. We report on five children diagnosed with SDNS on the histological basis of minimal change glomerulopathy or focal segmental glomerulosclerosis. Following the failure of other medications to achieve sustained remission, Tac was administered to these patients who varied in age from 10.5 to 13.5 years. Only one patient showed a substantial reduction in the number of relapses with the Tac treatment. Two boys, after 9 and 44 months on therapy, respectively, developed insulin-dependent diabetes mellitus (IDDM), necessitating the withdrawal of Tac and the daily use of insulin for 3 and 6 months. In both patients hyperglycemia had occurred during prednisone-based relapse therapy of SDNS. The patients had low serum protein concentrations, presumably increasing the free active Tac fraction, while trough levels of the drug remained unchanged. Both of the affected patients had additional risk factors for impaired glucose tolerance, such as morbid obesity (patient 1; BMI: 41.6 kg/m(2)) and African American origin (patient 2). Our case reports demonstrate that the use of Tac in patients with SDNS may be associated with an increased risk for IDDM, especially during relapse of NS, and particularly if additional risk factors are present. Moreover, Tac does not appear to substantially increase the success of treatment.

  10. Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

    PubMed

    Ohta, Mitsuhiro; Fujinami, Aya; Kobayashi, Norihiro; Amano, Akiko; Ishigami, Akihito; Tokuda, Harukuni; Suzuki, Nobutaka; Ito, Fumitake; Mori, Taisuke; Sawada, Morio; Iwasa, Koichi; Kitawaki, Jo; Ohnishi, Katsunori; Tsujikawa, Muneo; Obayashi, Hiroshi

    2015-07-01

    4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes. PMID:26077869

  11. Imaging of β-cell mass and insulitis in insulin-dependent (Type 1) diabetes mellitus.

    PubMed

    Di Gialleonardo, Valentina; de Vries, Erik F J; Di Girolamo, Marco; Quintero, Ana M; Dierckx, Rudi A J O; Signore, Alberto

    2012-12-01

    Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic β-cells, called insulitis, confirmed in pancreatic samples obtained at autopsy. The possibility to noninvasively quantify β-cell mass in vivo would provide important biological insights and facilitate aspects of diagnosis and therapy, including follow-up of islet cell transplantation. Moreover, the availability of a noninvasive tool to quantify the extent and severity of pancreatic insulitis could be useful for understanding the natural history of human insulin-dependent (type 1) diabetes mellitus, to early diagnose children at risk to develop overt diabetes, and to select patients to be treated with immunotherapies aimed at blocking the insulitis and monitoring the efficacy of these therapies. In this review, we outline the imaging techniques currently available for in vivo, noninvasive detection of β-cell mass and insulitis. These imaging techniques include magnetic resonance imaging, ultrasound, computed tomography, bioluminescence and fluorescence imaging, and the nuclear medicine techniques positron emission tomography and single-photon emission computed tomography. Several approaches and radiopharmaceuticals for imaging β-cells and lymphocytic insulitis are reviewed in detail.

  12. Factor B (Bf) and glyoxalase genes in insulin-dependent diabetes mellitus.

    PubMed

    Allannic, H; Fauchet, R; Gueguen, M; Pheng Savath, H; Dinh Knoi, T; Genetet, B

    1985-02-01

    The frequency distribution of alleles controlled by the factor B (Bf) and glyoxalase genes that are found close to the HLA system on chromosome 6 was studied in 170 insulin-dependent diabetic patients. The data were compared with those for HLA-A, -B and -DR antigens and were related to age of onset of diabetes. All the diabetics were ketosis prone and on permanent insulin therapy. A significant excess of BfF1 was seen in the diabetic patients (p less than 10(-4]. Glyoxalase frequency distribution showed no significant deviation from controls, whereas HLA-DR3 (p less than 10(-4] HLA-DR4 (p less than 10(-4] were increased. Breakdown of data by age of diagnosis of disease showed no increase in the frequency of BfF1 and GLO1-2 but an increase of HLA DR3 and DR4 in patients with early onset diabetes. The findings of the study are consistent with data reported by others investigators and support the notion that one or more genes mapping close to the HLA A. B and DR and to the Bf loci confer susceptibility to insulin dependent diabetes. PMID:3856541

  13. The importance of diabetes heredity in lean subjects on insulin secretion, blood lipids and oxygen uptake in the pathogenesis of glucose intolerance.

    PubMed

    Berntorp, K; Eriksson, K F; Lindgärde, F

    1986-06-01

    Insulin secretion, work capacity and plasma lipids were evaluated in 52 middle-aged men with impaired glucose tolerance (IGT), and the values were compared with those of 23 normoglycemic subjects with family histories of Type 2 diabetes and of 22 non-hereditary normoglycemic controls. All subjects were non-obese males of comparable age. Estimated maximal oxygen uptake was significantly lower (p less than 0.01) and triglyceride concentrations significantly higher (p less than 0.01) in IGT individuals than in subjects of the non-hereditary normoglycemic group, while no significant differences were noted in comparison with the hereditary group. IGT individuals showed an impaired insulin response to glucose with significantly lower absolute values of insulin and C-peptide during the early phase of the oral glucose tolerance test (OGTT) than in non-hereditary normoglycemic subjects, but not significantly lower than in the hereditary group. Similarly, at most time points of the OGTT the ratios of insulin and C-peptide to glucose were significantly lower in the IGT group than in the non-hereditary group, while these differences were less pronounced in comparison with the hereditary group. These findings suggest some similarities of metabolic disturbances in lean normoglycemics with positive family histories of Type 2 diabetes and in lean IGT individuals. Family history of diabetes (both first degree and second degree only) was significantly more prevalent among IGT individuals than among normals.

  14. Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in a Rat Model of Streptozotocine-Induced Insulin-Dependent Diabetes Mellitus

    PubMed Central

    Lee, Yu-Chen; Li, Te-Mao; Tzeng, Chung-Yuh; Chen, Ying-I; Ho, Wai-Jane; Lin, Jaung-Geng; Chang, Shih-Liang

    2011-01-01

    Animal studies have shown that electroacupuncture (EA) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints reduces plasma glucose concentrations in rats with type II diabetes. However, whether EA reduces plasma glucose levels in type I diabetes is still unknown. In this study, we explore the various non-insulin-dependent pathways involved in EA-induced lowering of plasma glucose. Streptozotocin (STZ) (60 mg kg−1, i.v.) was administered via the femoral vein to induce insulin-dependent diabetes in non-adrenalectomized and in adrenalectomomized rats. EA (15 Hz) was applied for 30 min to bilateral ST-36 acupoints after administration of Atropine (0.1 mg kg−1 i.p.), Eserine (0.01 mg kg−1 i.p.), or Hemicholinium-3 (5 μg kg−1 i.p.) in non-adrenalectomized rats. Rats administered acetylcholine (0.01 mg kg−1 i.v.) did not undergo EA. Adrenalectomized rats underwent EA at bilateral ST-36 acupoints without further treatment. Blood samples were drawn from all rats before and after EA to measure changes in plasma glucose levels. Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. Atropine and hemicholinium-3 completely blocked the plasma glucose lowering effects of EA, whereas eserine led to a significant hypoglycemic response. In addition, plasma glucose levels after administration of acetylcholine were significantly lower than the fasting glucose levels. In STZ-adrenalectomized rats, EA did not induce a hypoglycemic response. EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. Taken together, EA at the ST-36 acupoint reduces plasma glucose concentrations by stimulating the cholinergic nerves. PMID:21799686

  15. Electroacupuncture at the Zusanli (ST-36) Acupoint Induces a Hypoglycemic Effect by Stimulating the Cholinergic Nerve in a Rat Model of Streptozotocine-Induced Insulin-Dependent Diabetes Mellitus.

    PubMed

    Lee, Yu-Chen; Li, Te-Mao; Tzeng, Chung-Yuh; Chen, Ying-I; Ho, Wai-Jane; Lin, Jaung-Geng; Chang, Shih-Liang

    2011-01-01

    Animal studies have shown that electroacupuncture (EA) at Zusanli (ST-36) and Zhongwan (CV-12) acupoints reduces plasma glucose concentrations in rats with type II diabetes. However, whether EA reduces plasma glucose levels in type I diabetes is still unknown. In this study, we explore the various non-insulin-dependent pathways involved in EA-induced lowering of plasma glucose. Streptozotocin (STZ) (60 mg kg(-1), i.v.) was administered via the femoral vein to induce insulin-dependent diabetes in non-adrenalectomized and in adrenalectomomized rats. EA (15 Hz) was applied for 30 min to bilateral ST-36 acupoints after administration of Atropine (0.1 mg kg(-1) i.p.), Eserine (0.01 mg kg(-1) i.p.), or Hemicholinium-3 (5 μg kg(-1) i.p.) in non-adrenalectomized rats. Rats administered acetylcholine (0.01 mg kg(-1) i.v.) did not undergo EA. Adrenalectomized rats underwent EA at bilateral ST-36 acupoints without further treatment. Blood samples were drawn from all rats before and after EA to measure changes in plasma glucose levels. Expression of insulin signaling proteins (IRS1, AKT2) in atropine-exposed rats before and after EA was measured by western blot. Atropine and hemicholinium-3 completely blocked the plasma glucose lowering effects of EA, whereas eserine led to a significant hypoglycemic response. In addition, plasma glucose levels after administration of acetylcholine were significantly lower than the fasting glucose levels. In STZ-adrenalectomized rats, EA did not induce a hypoglycemic response. EA stimulated the expression of IRS1 and AKT2 and atropine treatment blocked the EA-induced expression of those insulin signaling proteins. Taken together, EA at the ST-36 acupoint reduces plasma glucose concentrations by stimulating the cholinergic nerves. PMID:21799686

  16. Nanoparticle Delivered Human Biliverdin Reductase-Based Peptide Increases Glucose Uptake by Activating IRK/Akt/GSK3 Axis: The Peptide Is Effective in the Cell and Wild-Type and Diabetic Ob/Ob Mice

    PubMed Central

    Gibbs, Peter E. M.; Miralem, Tihomir; Lerner-Marmarosh, Nicole; Maines, Mahin D.

    2016-01-01

    Insulin's stimulation of glucose uptake by binding to the IRK extracellular domain is compromised in diabetes. We have recently described an unprecedented approach to stimulating glucose uptake. KYCCSRK (P2) peptide, corresponding to the C-terminal segment of hBVR, was effective in binding to and inducing conformational change in the IRK intracellular kinase domain. Although myristoylated P2, made of L-amino acids, was effective in cell culture, its use for animal studies was unsuitable. We developed a peptidase-resistant formulation of the peptide that was efficient in both mice and cell culture systems. The peptide was constructed of D-amino acids, in reverse order, and blocked at both termini. Delivery of the encapsulated peptide to HepG2 and HSKM cells was confirmed by its prolonged effect on stimulation of glucose uptake (>6 h). The peptide improved glucose clearance in both wild-type and Ob/Ob mice; it lowered blood glucose levels and suppressed glucose-stimulated insulin secretion. IRK activity was stimulated in the liver of treated mice and in cultured cells. The peptide potentiated function of IRK's downstream effector, Akt-GSK3-(α, β) axis. Thus, P2-based approach can be used for improving glucose uptake by cells. Also, it allows for screening peptides in vitro and in animal models for treatment of diabetes. PMID:27294151

  17. Cloning and functional expression of a human pancreatic islet glucose-transporter cDNA

    SciTech Connect

    Permutt, M.A.; Koranyi, L.; Keller, K.; Lacy, P.E.; Scharp, D.W.; Mueckler, M. )

    1989-11-01

    Previous studies have suggested that pancreatic islet glucose transport is mediated by a high-K{sub m}, low-affinity facilitated transporter similar to that expressed in liver. To determine the relationship between islet and liver glucose transporters, liver-type glucose-transporter cDNA clones were isolated from a human liver cDNA library. The liver-type glucose-transporter cDNA clone hybridized to mRNA transcripts of the same size in human liver and pancreatic islet RNA. A cDNA library was prepared from purified human pancreatic islet tissue and screened with human liver-type glucose-transporter cDNA. The authors isolated two overlapping cDNA clones encompassing 2600 base pairs, which encode a pancreatic islet protein identical in sequence to that of the putative liver-type glucose-transporter protein. Xenopus oocytes injected with synthetic mRNA transcribed from a full-length cDNA construct exhibited increased uptake of 2-deoxyglucose, confirming the functional identity of the clone. These cDNA clones can now be used to study regulation of expression of the gene and to assess the role of inherited defects in this gene as a candidate for inherited susceptibility to non-insulin-dependent diabetes mellitus.

  18. Glycaemic responses to cereal-based Indian food preparations in patients with non-insulin-dependent diabetes mellitus and normal subjects.

    PubMed

    Urooj, A; Puttaraj, S

    2000-05-01

    The in vivo glycaemic responses to six cereal-based foods traditionally consumed in South India were evaluated in patients with non-insulin-dependent diabetes mellitus (NIDDM) and healthy volunteers. All foods contained 50 g carbohydrate and were compared with a 50 g glucose load. Also studied were the in vitro starch digestibility and nutrient composition of the foods. The postprandial responses to the foods at 30, 60 and 120 min were significantly (P < 0.05) lower than those to the reference glucose, in both groups. The peak glucose responses for three foods, i.e. chapatti, idli and poori, occurred 60 min postprandially in both groups. The glycaemic index (GI) values ranged from 67 to 90 in NIDDM and from 44 to 69 in healthy subjects with no significant differences within the groups. Significant relationships were observed between peak responses and area under the curve for foods in patients with NIDDM and in vitro rate of starch hydrolysis (r 0.83, r 0.85, P < 0.05). The GI values predicted using in vitro data were found to be similar to the GI values observed in patients with NIDDM. The GI concept is useful for identifying foods in the habitual Indian diet with attributes of the desired glycaemic effect such as delayed peak rise and low area under the curve. PMID:10953672

  19. Poor glycaemic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus.

    PubMed

    Maxwell, S R; Thomason, H; Sandler, D; LeGuen, C; Baxter, M A; Thorpe, G H; Jones, A F; Barnett, A H

    1997-11-01

    The diabetic patient is at significantly increased risk of developing vascular disease. Its aetiology may involve oxidative damage by free radicals and protection against such damage can be offered by radical-scavenging antioxidants. We investigated whether there was a relationship between glycaemic control as assessed by measurement of glycated haemoglobin (HbA1c) and serum antioxidant status in a population of 118 diabetic outpatients with either insulin-dependent or non-insulin-dependent diabetes. Amongst patients with non-insulin-dependent diabetes mellitus there was a significant inverse correlation between levels of glycated haemoglobin and total free radical scavenging activity (r = -0.456, P < 0.0001). This association resulted primarily because of a similar correlation with uric acid (r = -0.421, P = 0.0003). There was also a weak inverse correlation with vitamin A but no significant association with vitamin C or vitamin E levels. There were no significant associations found amongst the patients with insulin-dependent diabetes. These results indicate that poor diabetic control is associated with reduced serum free radical scavenging (antioxidant) activity in non-insulin-dependent diabetes mellitus. By implication improved glycaemic control may preserve serum antioxidant status in diabetes.

  20. Tissue localization of GM-CSF receptor in bovine ovarian follicles and its role on glucose uptake by mural granulosa cells.

    PubMed

    Peralta, O A; Bucher, D; Angulo, C; Castro, M A; Ratto, M H; Concha, Il

    2016-07-01

    The granulocyte-macrophage colony stimulating factor (GM-CSF) is a multifunctional cytokine implicated in proliferation, differentiation, and activation of several cell types including those involved in hematopoiesis and reproduction. In the present study, the expression of the α- and β-subunit genes of GM-CSF receptor during follicular development in cattle was assessed. The spatial association of α- and β-subunits of GM-CSF with follicle stimulating hormone receptor (FSHR) and 3β-hydroxysteroid dehydrogenase (3β-HSD), and the temporal associations with gene expression of hexose transporters (GLUTs) in granulosa cells of cattle were also evaluated. The effect of GM-CSF on the functionality of hexose transporters was also determined in an in vitro primary culture of granulosa cells. The spatial association of subunits of the GM-CSF receptor with 3β-HSD and FSHR suggests a potential steroidogenic regulation of GM-CSF in granulosa cells. Immunodetection of GLUTs and uptake kinetic assays confirmed expression and functionality of these genes for hexose transporters in granulosa cells of cattle. Treatment of granulosa cells with GM-CSF, FSH or insulin- like growth factor-I (IGF-I) alone increased 2-deoxyglucose (DOG) or 3-0-methylglucose (OMG) uptake; however, when cells were treated with various combination of these factors there were no additive effect. Unexpectedly, the combination of GM-CSF and FSH decreased DOG uptake compared to FSH treatment alone. Thus, the expression pattern of GM-CSF receptor subunit genes during follicle development in cattle and promotion of DOG and OMG uptake in granulosa cells indicate a role for GM-CSF, FSH and/or IGF-I alone in regulating granulosa cell metabolic activity, specifically by promoting glucose uptake. PMID:27236376

  1. α-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK

    PubMed Central

    Enriori, Pablo J.; Jensen, Thomas Elbenhardt; Garcia-Rudaz, Cecilia; Litwak, Sara A.; Raun, Kirsten; Wojtaszewski, Jørgen; Wulff, Birgitte Schjellerup; Cowley, Michael A.

    2016-01-01

    The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis. In this study, we examined the molecular signaling pathway involved in α-MSH-stimulated glucose uptake in differentiated L6 myotubes and mouse muscle explants. In order to examine the involvement of AMPK, we investigate α-MSH stimulation in both wild type and AMPK deficient mice. We found that α-MSH significantly induces phosphorylation of TBC1 domain (TBC1D) family member 1 (S237 and T596), which is independent of upstream PKA and AMPK. We find no evidence to support that α-MSH-stimulated glucose uptake involves TBC1D4 phosphorylation (T642 and S704) or GLUT4 translocation. PMID:27467141

  2. Internal diameter of the common femoral artery in patients with insulin-dependent diabetes mellitus.

    PubMed

    Christensen, T; Neubauer, B

    1988-01-01

    By means of an ultrasonographic technique the systolic and diastolic diameters of the common femoral artery were investigated in a group of 50 young insulin-dependent diabetics selected as being free from late diabetic complications and atherosclerotic involvement. After correction for normal physiologic variations there was no correlation of arterial diameters to duration of diabetes and no statistical difference in relation to a control group. It is known that there is a progressive increase of the arterial wall thickness in medium-sized arteries in diabetes. Therefore, it is concluded that there is a corresponding dilatation of the arteries. The reasons for this dilatation are discussed from a biophysical point of view. Furthermore, it is concluded that the increased arterial wall stiffness caused by an increasing elastic modulus and thickness reflects the earliest changes in the diabetic macroangiopathy. Occlusions and narrowing seem only to exist in patients with severe late diabetic complications.

  3. Actinobacillus actinomycetemcomitans in Brazilian insulin-dependent individuals with diabetes mellitus.

    PubMed

    Feitosa, A C; de Uzeda, M; Novaes, A B

    1992-01-01

    The prevalence of Actinobacillus actinomycetemcomitans (Aa) in subgingival plaque specimens from 26 insulin-dependent diabetes mellitus patients, 11-25 years of age, was determined between January 1987 and December 1989. One hundred and thirty subgingival plaque samples were collected with sterile periodontal curettes. The specimens were weighted, diluted, inoculated on trypticase-soy-serum-bacitracin-vancomycin agar medium (TSBV) and incubated under microacrophilic conditions. Aa was isolated from 2.3% of healthy periodontal areas in these patients, while the microorganism was found in 12.5% of the sites with gingivitis and in 2.6% of the periodontal pockets examined. Although biochemical tests used for the characterization of Aa strains showed homogeneous results, different biotypes were isolated from one or more periodontal sites in the same patient.

  4. [Efficiency of cerebrolysin in the diabetic polyneuropathy in patients with insulin-dependency diabetes mellitus].

    PubMed

    Bogdanov, E I; Sakovets, T G

    2011-01-01

    78 patients with clinical features of diabetic polyneuropathy have been examined. 39 patients, who took cerebrolysin, compose the basic group, 39 patients, who made up control one, took milgamma. The dynamics of clinical signs of the diabetic polyneuropathy was evaluated by difference of points in the first and the second examination with the use of scales: NSC (Neuropathy Symptoms and Change) and NDS (Neuropathy Dysfunction Score); the visual analog scale (VAS) and changes of the signs of orthostatic test. For the detection of the effectiveness of treatment was estimated dynamics of neuropathic disorders represented in patient with diabetes mellitus types I and II (with secondary insulin-dependency), witch allowed to reveal the considerable therapeutic effectiveness of cerebrolysin in treatment of diabetic polyneuropathic disorders.

  5. Synthesis of diosgenin-ibuprofen derivatives and their activities against insulin-dependent diabetes mellitus.

    PubMed

    Xin, Guang; Wang, Yanyan; Guo, Xiurong; Huang, Baozhan; Du, Dan; He, Shiliang; Zhang, Rui; Xing, Zhihua; Zhao, Hang; Chen, Qianming; Huang, Wen; He, Yang

    2013-01-01

    The synthesis and anti-diabetes activities of diosgenin-ibuprofen derivatives were investigated. Ibuprofen (IBU) was chemically coupled with diosgenin either directly or through amino acid esters linkers. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) generation were assessed. The results showed spirost-5-en-3β-yl (2-(4-isobutyl-phenyl)-propionate) (4) was of better activity to suppress the production of NO in the supernatant of LPS-stimulated RAW264.7 cells. In vivo investigation on nonobese diabetic (NOD) mice indicated that compound 4 decreased the incidence of insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) of NOD mice which suggested a potential activity of compound 4 against type 1 diabetes.

  6. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model.

    PubMed

    Wang, Yan; Li, Guiling; Mao, Fengbiao; Li, Xianfeng; Liu, Qi; Chen, Lin; Lv, Lu; Wang, Xin; Wu, Jinyu; Dai, Wei; Wang, Guan; Zhao, Enfeng; Tang, Kai-Fu; Sun, Zhong Sheng

    2014-05-16

    RRAD (Ras-related associated with diabetes) is a small Ras-related GTPase that is frequently inactivated by DNA methylation of the CpG island in its promoter region in cancer tissues. However, the role of the methylation-induced RRAD inactivation in tumorigenesis remains unclear. In this study, the Ras-regulated transcriptome and epigenome were profiled by comparing T29H (a Ras(V12)-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through reduced representation bisulfite sequencing and digital gene expression. We found that Ras(V12)-mediated oncogenic transformation was accompanied by RRAD promoter hypermethylation and a concomitant loss of RRAD expression. In addition, we found that the RRAD promoter was hypermethylated, and its transcription was reduced in ovarian cancer versus normal ovarian tissues. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in demethylation in the RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNA methytransferase expression and activity in T29H cells. By employing knockdown and overexpression techniques in T29 and T29H, respectively, we found that RRAD inhibited glucose uptake and lactate production by repressing the expression of glucose transporters. Finally, RRAD overexpression in T29H cells inhibited tumor formation in nude mice, suggesting that RRAD is a tumor suppressor gene. Our results indicate that Ras(V12)-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis.

  7. Ras-induced epigenetic inactivation of the RRAD (Ras-related associated with diabetes) gene promotes glucose uptake in a human ovarian cancer model.

    PubMed

    Wang, Yan; Li, Guiling; Mao, Fengbiao; Li, Xianfeng; Liu, Qi; Chen, Lin; Lv, Lu; Wang, Xin; Wu, Jinyu; Dai, Wei; Wang, Guan; Zhao, Enfeng; Tang, Kai-Fu; Sun, Zhong Sheng

    2014-05-16

    RRAD (Ras-related associated with diabetes) is a small Ras-related GTPase that is frequently inactivated by DNA methylation of the CpG island in its promoter region in cancer tissues. However, the role of the methylation-induced RRAD inactivation in tumorigenesis remains unclear. In this study, the Ras-regulated transcriptome and epigenome were profiled by comparing T29H (a Ras(V12)-transformed human ovarian epithelial cell line) with T29 (an immortalized but non-transformed cell line) through reduced representation bisulfite sequencing and digital gene expression. We found that Ras(V12)-mediated oncogenic transformation was accompanied by RRAD promoter hypermethylation and a concomitant loss of RRAD expression. In addition, we found that the RRAD promoter was hypermethylated, and its transcription was reduced in ovarian cancer versus normal ovarian tissues. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in demethylation in the RRAD promoter and restored RRAD expression in T29H cells. Additionally, treatment with farnesyltransferase inhibitor FTI277 resulted in restored RRAD expression and inhibited DNA methytransferase expression and activity in T29H cells. By employing knockdown and overexpression techniques in T29 and T29H, respectively, we found that RRAD inhibited glucose uptake and lactate production by repressing the expression of glucose transporters. Finally, RRAD overexpression in T29H cells inhibited tumor formation in nude mice, suggesting that RRAD is a tumor suppressor gene. Our results indicate that Ras(V12)-mediated oncogenic transformation induces RRAD epigenetic inactivation, which in turn promotes glucose uptake and may contribute to ovarian cancer tumorigenesis. PMID:24648519

  8. Muscle-specific glucose and free fatty acid uptake after sprint interval and moderate-intensity training in healthy middle-aged men.

    PubMed

    Eskelinen, Jari-Joonas; Heinonen, Ilkka; Löyttyniemi, Eliisa; Saunavaara, Virva; Kirjavainen, Anna; Virtanen, Kirsi A; Hannukainen, Jarna C; Kalliokoski, Kari K

    2015-05-01

    We tested the hypothesis that sprint interval training (SIT) causes larger improvements in glucose and free fatty acid uptake (FFAU) in lower and upper body muscles than moderate-intensity training (MIT). Twenty-eight healthy, untrained, middle-aged men were randomized into SIT (n = 14, 4-6 × 30 s of all-out cycling/4 min recovery) and MIT groups [n = 14, 40-60 min cycling at 60% of peak O2 uptake (V̇o2 peak)] and completed six training sessions within 2 wk. Pre- and postmeasurements included V̇o2 peak, whole body (M-value), muscle-specific insulin-stimulated glucose uptake (GU), and fasting FFAU measured with positron emission tomography in thigh [quadriceps femoris (QF) and hamstrings] and upper body (deltoids, biceps, and triceps brachii) muscles. V̇o2 peak and M-value improved significantly by 6 and 12% in SIT, and 3 and 8% in MIT, respectively,. GU increased significantly only in the QF, and there was no statistically significant difference between the training modes. GU increased in all four heads of QF in response to SIT, but only in the vasti muscles in response to MIT, whereas in rectus femoris the response was completely lacking. Training response in FFAU in QF was smaller and nonsignificant, but it also differed between the training modes in the rectus femoris. In conclusion, SIT and MIT increased insulin-stimulated GU only in the main working muscle QF and not in the upper body muscles. In addition, the biarticular rectus femoris did not respond to moderate-intensity training, reflecting most probably poor activation of it during moderate-intensity cycling. PMID:25767035

  9. Serum sex hormone concentrations in insulin dependent diabetic women with and without amenorrhoea.

    PubMed

    Djursing, H; Hagen, C; Nyboe Andersen, A; Svenstrup, B; Bennett, P; Mølsted Pedersen, L

    1985-08-01

    Abnormal steroid secretion may contribute to anovulation in insulin dependent diabetic patients with amenorrhoea. We have measured serum sex hormone-binding globulin (SHBG) and free and bound oestrogen and androgen levels in 17 such patients. As controls we included 17 patients with insulin dependent diabetes mellitus and normal menstrual cycles, 21 regularly menstruating normal women (both sampled during early follicular phase), and 23 non-diabetic patients with amenorrhoea. The diabetic patients with normal cycles had significantly higher serum concentrations of delta 4-androstenedione and testosterone than the normal women (P less than 0.01). The amenorrhoeic diabetics in contrast had significantly lower serum concentrations of SHBG, 5 alpha-dihydrotestosterone and free and total oestradiol-17 beta than either group of menstruating women (P less than 0.05), and significantly lower concentrations of delta 4-androstenedione (P less than 0.01), dehydroepiandrosterone sulphate (P less than 0.01), testosterone (P less than 0.01), and oestrone (P less than 0.05), than the cycling diabetics. The two amenorrhoeic groups had similar free and bound sex hormone concentrations except that delta 4-androstenedione levels were significantly lower in the diabetics (P less than 0.01). We conclude that the low sex hormone levels in diabetic women with amenorrhea may be due to suppression of the hypothalamic-pituitary axis in view of the impaired LH secretion found in these patients and that excess androgen secretion seems not to be of aetiological importance in amenorrhea related to diabetes mellitus. The decreased steroid levels in amenorrheic diabetics is due to their suppressed ovarian function while the increased androgen levels in diabetics with regular cycles are probably of ovarian origin.

  10. Eating disorders in young adults with insulin dependent diabetes mellitus: a controlled study.

    PubMed Central

    Fairburn, C G; Peveler, R C; Davies, B; Mann, J I; Mayou, R A

    1991-01-01

    OBJECTIVE--To determine the prevalence of clinical eating disorders and lesser degrees of disturbed eating in young adults with insulin dependent diabetes and a matched sample of non-diabetic female controls. DESIGN--Cross sectional survey of eating habits and attitudes in diabetic and non-diabetic subjects. SETTING--Outpatient clinic catering for young adults with diabetes; community sample of non-diabetic women drawn from the lists of two general practices. SUBJECTS--100 patients with insulin dependent diabetes (54 women and 46 men) aged 17-25 and 67 non-diabetic women of the same age. MAIN OUTCOME MEASURES--Eating habits and eating disorder psychopathology were assessed by standardised research interview adapted for the assessment of patients with diabetes (eating disorder examination). Glycaemic control was assessed by glycated haemoglobin assay. RESULTS--In both non-diabetic and diabetic women disturbed eating was common, and in diabetic women the degree of disturbance was related to control of glycaemia. Twenty of the diabetic women (37%) had omitted or underused insulin to influence their weight. This behaviour was not restricted to those with a clinical eating disorder. None of the men showed any features of eating disorders, and none had misused insulin to influence their weight. CONCLUSIONS--There was no evidence that clinical eating disorders are more prevalent in young women with diabetes than in non-diabetic women. Nevertheless, disturbed eating is common and is associated with poor control of glycaemia, and the misuse of insulin to influence body weight is also common in young women with diabetes. PMID:1781827

  11. Aggregation ability of erythrocytes of patients with coronary heart disease depending on different glucose concentration

    NASA Astrophysics Data System (ADS)

    Malinova, Lidia I.; Simonenko, Georgy V.; Kirichuk, Vyacheslav F.; Denisova, Tatyana P.; Tuchin, Valery V.

    2002-07-01

    The aggregation ability of erythrocytes of patients with coronary heart disease comparing to practically healthy persons and patients with coronary heart disease combined with non insulin dependent diabetes mellitus depending on different glucose concentration in unguentums of blood incubates with the help of computer microphotometer - visual analyzer was studied. Two-phase behavior of erythrocytes size changing of practically healthy persons depending on glucose concentration in an incubation medium and instability erythrocyte systems of a whole blood to the influence of high glucose concentration were revealed. Influence of high glucose concentration on aggregation ability of erythrocytes of patients with coronary heart disease and its combination with non insulin dependent diabetes mellitus was revealed.

  12. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock★

    PubMed Central

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.; Biensø, Rasmus S.; Tagliazucchi, Guidantonio M.; Patel, Vishal R.; Forcato, Mattia; Paz, Marcia I.P.; Gudiksen, Anders; Solagna, Francesca; Albiero, Mattia; Moretti, Irene; Eckel-Mahan, Kristin L.; Baldi, Pierre; Sassone-Corsi, Paolo; Rizzuto, Rosario; Bicciato, Silvio; Pilegaard, Henriette; Blaauw, Bert; Schiaffino, Stefano

    2013-01-01

    Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock is to prepare for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle. PMID:24567902

  13. Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: A population-based study

    SciTech Connect

    `t Hart, L.M.; Maassen, J.A.; Does, F.E.E. van der

    1996-11-01

    One of the characteristics of non-insulin-dependent diabetes mellitus (NIDDM) is the presence of insulin. Most NIDDM patients have a normal sequence of the insulin receptor, indicating that, if insulin-receptor mutations contribute to the development of NIDDM, they will be present only in a minor fraction of the NIDDM population. The goal of the present study was to examine whether insulin-receptor mutations contribute to the development of NIDDM. We examined 161 individuals with NIDDM and 538 healthy controls from the population-based Rotterdam study for the presence of mutations in the insulin-receptor gene by SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, this revealed a relative risk for diabetes of 4.49 (95% confidence interval 1.59-12.25) for Met-985 carriers. When the total study group was analyzed, the prevalence of the mutation increased with increasing serum glucose levels (test for trend P < .005). We conclude that the Met-985 insulin-receptor variant associates with hyperglycemia and represents a risk factor for NIDDM. 30 refs., 3 figs., 1 tab.

  14. Impaired activation of skeletal muscle glycogen synthase in non-insulin-dependent diabetes mellitus is unrelated to the degree of obesity.

    PubMed

    Johnson, A B; Argyraki, M; Thow, J C; Jones, I R; Broughton, D; Miller, M; Taylor, R

    1991-03-01

    Twenty-five newly presenting, untreated, white, non-insulin-dependent diabetic (NIDDM) subjects were studied within 72 hours of diagnosis. They were allocated to three groups according to their body mass index [BMI] (lean BMI less than 25.0, n = 9; overweight BMI 25.0 to 30.0, n = 6; obese BMI greater than .30.0 kg/m2, n = 10). All three groups exhibited equivalent hyperglycemia. Eleven normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, before and during a 240-minute insulin infusion (100 mU/kg/h). Fractional GS activity did not increase in the lean (change, -0.9 +/- 3.3%), the overweight (-1.9 +/- 2.7%), or the obese (+2.2 +/- 1.6%) NIDDM subjects during the insulin infusion and was markedly decreased compared with the control subjects (change, +14.6 +/- 2.4%, all P less than .001). Glucose requirement was also significantly decreased in all three NIDDM groups (103 +/- 23 v 81 +/- 14 v 53 +/- 14 mg/m2/min, respectively) compared with the control subjects (319 +/- 18 mg/m2/min, all P less than .001). There was a significant negative correlation with BMI (r = -.51, P less than .01), but the difference in glucose requirement between the lean and obese NIDDM groups was not significant. Muscle GS activity at the end of the euglycemic clamp correlated with glucose requirement (r = .53, P less than .001), and a similar correlation was observed between the insulin-induced change in muscle GS activity from basal and glucose requirement (r = .47, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)

  15. A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient.

    PubMed

    Sanyoura, May; Woudstra, Cédric; Halaby, George; Baz, Patrick; Senée, Valérie; Guillausseau, Pierre-Jean; Zalloua, Pierre; Julier, Cécile

    2014-01-01

    Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alström syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alström syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.

  16. The Effects of Physical Training on Blood Lipid Profiles in Adolescents with Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Campaigne, B. N.; And Others

    1985-01-01

    Fourteen adolescents with insulin-dependent diabetes mellitus (IDDM) participated in a 12-week exercise program to determine whether such training would bring about changes in blood lipid and lipoprotein profiles. The findings support the beneficial effects of regular exercise for individuals with IDDM. (MT)

  17. Shifts in Doctor-Patient Communication during a Series of Outpatient Consultations in Non-Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    van Dulmen, Alexandra M.; Verhaak, Peter F. M.; Bilo, Henk J. G.

    1997-01-01

    The first three consultations between 18 new patients with poorly controlled non-insulin-dependent diabetes mellitus and their medical specialist were videotaped. Changes in doctors' and patients' verbal and nonverbal communication behaviors were analyzed, and those most strongly related to patient satisfaction were distinguished. Discussion…

  18. Deuterohemin-AlaHisLys mitigates the symptoms of rats with non-insulin dependent diabetes mellitus by scavenging reactive oxygen species and activating the PI3-K/AKT signal transduction pathway.

    PubMed

    Lei, Liyan; Zhang, Guangji; Li, Pengfei; Zhang, Yuan; Guo, Youming; Zhang, Wenqi; Zhang, Wenbo; Hu, Bing; Wang, Liping

    2014-09-01

    Damage to pancreatic β-cells plays an important role in the development of type 2 diabetes, and oxidative stress is a likely contributor. In the present study, we investigated the effect of deuterohemin-AlaHisLys (DhHP-3), a microperoxidase-11 mimic, on rats with non-insulin dependent diabetes mellitus and examined the action mechanisms of DhHP-3. The induced hyperglycemia, glucose intolerance, and insulin resistance in diabetic rats were associated with increased oxidative stress and damage to pancreatic islets. DhHP-3 (3 mg/kg) ameliorated hyperglycemia and insulin resistance, protected pancreas islet, decreased the content of malondialdehyde, and increased the activity of superoxide dismutase in plasma and pancreatic tissue by reducing ROS levels. Furthermore, DhHP-3 stimulated the proliferation of INS-1 cells and inhibited apoptosis by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3-K/AKT) signaling pathway. Our results demonstrated for the first time that DhHP-3 decreased blood glucose level in rats with non-insulin dependent diabetes mellitus, scavenged reactive oxygen species, activated the PI3-K/AKT signaling pathway, and protected pancreatic β-cells against apoptosis.

  19. Suppressing the activity of ERRalpha in 3T3-L1 adipocytes reduces mitochondrial biogenesis but enhances glycolysis and basal glucose uptake.

    PubMed

    Nie, Yaohui; Wong, Chiwai

    2009-09-01

    Estrogen-related receptor alpha (ERRalpha) is thought to primarily regulate lipid oxidation and control the transcription of genes in the oxidative phosphorylation pathway in skeletal and cardiac muscles. However, its role in white adipose tissue is not well studied. In this study, we aimed to establish a role for ERRalpha in adipocytes by down-regulating its activity through its inverse agonist XCT-790 in differentiated 3T3-L1 adipocytes. We found that XCT-790 differentially reduced the expression of ERRalpha target genes. Specifically, XCT-790 reduced the expressions of peroxisome proliferator-activated receptor gamma co-activator-1beta (PGC-1beta), resulting in reductions of mitochondrial biogenesis, adiogenesis and lipogeneis. Through suppressing the expression of another ERRalpha target gene pyruvate dehydrogenase kinase 2 (PDK2), we found that XCT-790 not only enhanced the conversion of pyruvate to acetyl-CoA and hyper-activated the tricarboxylic acid (TCA) cycle, but also led to higher levels of mitochondrial membrane potential and reactive oxidant species (ROS) production. Additionally, XCT-790 treatment also resulted in enhanced rates of glycolysis and basal glucose uptake. Therefore, ERRalpha stands at the crossroad of glucose and fatty acid utilization and acts as a homeostatic switch to regulate the flux of TCA cycle, mitochondrial membrane potential and glycolysis to maintain a steady level of ATP production, particularly, when mitochondrial biogenesis is reduced. PMID:18544047

  20. Bioactive components from flowers of Sambucus nigra L. increase glucose uptake in primary porcine myotube cultures and reduce fat accumulation in Caenorhabditis elegans.

    PubMed

    Bhattacharya, Sumangala; Christensen, Kathrine B; Olsen, Louise C B; Christensen, Lars P; Grevsen, Kai; Færgeman, Nils J; Kristiansen, Karsten; Young, Jette F; Oksbjerg, Niels

    2013-11-20

    Obesity and insulin resistance in skeletal muscles are major features of type 2 diabetes. In the present study, we examined the potential of Sambucus nigra flower (elderflowers) extracts to stimulate glucose uptake (GU) in primary porcine myotubes and reduce fat accumulation (FAc) in Caenorhabditis elegans. Bioassay guided chromatographic fractionations of extracts and fractions resulted in the identification of naringenin and 5-O- caffeoylquinic acid exhibiting a significant increase in GU. In addition, phenolic compounds related to those found in elderflowers were also tested, and among these, kaempferol, ferulic acid, p-coumaric acid, and caffeic acid increased GU significantly. FAc was significantly reduced in C. elegans, when treated with elderflower extracts, their fractions and the metabolites naringenin, quercetin-3-O-rutinoside, quercetin-3-O-glucoside, quercetin-3-O-5″-acetylglycoside, kaempferol-3-O-rutinoside, isorhamnetin-3-O-rutinoside, and isorhamnetin-3-O-glucoside and the related phenolic compounds kaempferol and ferulic acid. The study indicates that elderflower extracts contain bioactive compounds capable of modulating glucose and lipid metabolism, suitable for nutraceutical and pharmaceutical applications. PMID:24156563

  1. Thermography of gingival condition in children and adolescents with insulin-dependent diabetes mellitus (IDDM)

    NASA Astrophysics Data System (ADS)

    Burchardt, Dorota; Borysewicz-Lewicka, Maria

    2001-03-01

    Patients diagnosed with periodonthopathies were subjected to thermographic study in order to analyze blood circulation in the periodontal region and pattern of temperature changes in the gingival crevice. The aim of the study was to assess the influence of insulin-dependent diabetes mellitus (IDDM) on the status of blood vessels in the periodontal region in children and adolescents. Clinical status of the periodontal region was assessed with CPITN (Community Periodontal Index of Treatment Needs). Thermographic patterns were taken in the vicinity of teeth 11 and 21 at some distance from the gingival margin and frenulum of the upper lip, which permitted elimination of a possible influence of other factors on the parameters studied. The thermographic measurements were a few times repeated for each patient and made before and 1, 2, 3, and 4 minutes after cooling of a selected surface of gingival mucosa. Interpretation of the thermographic patterns was performed taking into account the minimum and maximum temperatures: T min and T max, and Tx - the weighted mean for the left and right sides. Preliminary observations revealed a difference between the data obtained in the group with IDDM and the control group. The results suggest the suitability of the thermographic study for assessment of vascular changes in IDDM patients.

  2. Effect of diabetes associated increases in lens optical density on colour discrimination in insulin dependent diabetes.

    PubMed Central

    Hardy, K J; Scarpello, J H; Foster, D H; Moreland, J D

    1994-01-01

    Optical density (OD) of the crystalline lens has been shown in non-diabetics to increase linearly with age over the first five decades and at an increased rate thereafter; in insulin dependent diabetic (IDDM) patients, lens OD increases with age and with duration of diabetes at a rate similar to that in non-diabetics over the age of 60 years. Recently, it has been established that colour discrimination is abnormal in a majority of young patients with uncomplicated IDDM and angiographically normal retinas. Colour discrimination loss was attributed to functional abnormalities in the retina or neural pathways; yet the possibility exists that increases in lens OD may account for part or all of the colour discrimination loss in IDDM. In the present study, colour discrimination was compared in aretinopathic IDDM patients and age-matched controls, and then in a group of aretinopathic IDDM patients individually matched to controls with respect to lens OD. Colour discrimination was significantly worse in diabetic patients than in age-matched controls, and was significantly worse when diabetic patients were compared with controls matched for OD. The magnitude of the difference in 100 hue error score between diabetic patients and OD matched controls was, however, considerably less than the difference between diabetic patients and age-matched controls. These data suggest that colour discrimination loss in aretinopathic IDDM patients cannot be explained solely on the basis of diabetes induced increases in lens OD, but must involve abnormalities of the retina or its neural connections. PMID:7803350

  3. [Spontaneous animal models for insulin-dependent diabetes (type 1 diabetes)].

    PubMed

    Saï, P; Gouin, E

    1997-01-01

    Insulin dependent (type 1) diabetes in humans is a polygenic, auto-immune disease that is characterized, among other things, by the infiltration of the islets of Langerhans by immune cells (insulite) as well as many serum auto-antibodies (including islet cell antibodies: ICA). The medical goal is to diagnose the condition at a sub-clinical stage and then to prevent the disease from developing. Spontaneous diabetic rodent models, in particular the NOD mouse and BB rat are invaluable to the continuing progress of the work aimed at better understanding the human disease. In addition to these models, the study of type 1 diabetes in larger animals, having a longer life-span would also be helpful. In dogs and cats, certain minor kinds of diabetes appear to be of type 1. The classification of diabetes types in carnivores remains poorly defined, however, epidemiological, genetic and metabolic studies are required before these diabetes can be used as operational models for the human pathology. Even if the classification of these diseases is clarified, the ethical and social considerations involved with the use of companion animals, will limit the use of these animals as models for spontaneous diabetes. The selection of a specific line of diabetic dogs should perhaps be considered. PMID:9273084

  4. Are the nutritional recommendations for insulin-dependent diabetic patients being achieved?

    PubMed

    Humphreys, M; Cronin, C C; Barry, D G; Ferriss, J B

    1994-01-01

    Dietary intake was assessed, using a 3-day recorded food diary, in 122 patients with insulin-dependent diabetes. Subjects were selected randomly from patients attending a diabetic clinic and stratified for age, sex, and duration of diabetes. The findings were compared to the dietary recommendations of the European Association for the Study of Diabetes (EASD) and to the findings in a recent Irish National Nutrition Survey. The average daily protein intake among diabetic patients was 18% of the total calories, significantly higher than recommended by EASD and significantly higher than in the age-matched general population. Dietary fat intake was on average 37% of total calorie intake, again significantly higher than recommended and greater than in the general population among older patients. Saturated fat intake was higher than recommended and polyunsaturated fat intake was low. The average carbohydrate intake was 42% of total calories, significantly lower than recommended and similar to that in the general population. Sugar intake was lower and starch intake was higher among patients than in the general population, however. Fibre intake was also lower than recommended, but was higher than in the general population. We conclude that the present dietary targets for diabetic patients are not being fully achieved. PMID:8181258

  5. Reactive oxygen species are involved in insulin-dependent regulation of autophagy in primary rat podocytes.

    PubMed

    Audzeyenka, Irena; Rogacka, Dorota; Piwkowska, Agnieszka; Rychlowski, Michal; Bierla, Joanna Beata; Czarnowska, Elżbieta; Angielski, Stefan; Jankowski, Maciej

    2016-06-01

    Autophagy is an intracellular defense mechanism responsible for the turnover of damaged or non-functional cellular constituents. This process provides cells with energy and essential compounds under unfavorable environmental conditions-such as oxidative stress and hyperglycemia, which are both observed in diabetes. The most common diabetes complication is diabetic nephropathy (DN), which can lead to renal failure. This condition often includes impaired podocyte function. Here we investigated autophagic activity in rat podocytes cultured with a high insulin concentration (300nM). Autophagy was activated after 60min of insulin stimulation. Moreover, this effect was abolished following pharmacological (apocynin) or genetic (siRNA) inhibition of NAD(P)H oxidase activity, indicating that insulin-dependent autophagy stimulation involved reactive oxygen species (ROS). We also observed a continuous and time-dependent increase of podocyte albumin permeability in response to insulin, and this process was slightly improved by autophagy inhibition following short-term insulin exposure. Our results suggest that insulin may be a factor affecting the development of diabetic nephropathy. PMID:27026581

  6. Altered action of glucagon on human liver in type 2 (non-insulin-dependent) diabetes mellitus.

    PubMed

    Arner, P; Einarsson, K; Ewerth, S; Livingston, J N

    1987-05-01

    Glucagon may play a role in the metabolic derangements of overt Type 2 (non-insulin-dependent) diabetes mellitus. We therefore have evaluated the early steps in glucagon action by investigating the hormone-sensitive adenylyl cyclase system in liver membranes from seven Type 2 diabetic patients with fasting hyperglycaemia and two-fold elevations in plasma glucagon. The comparison was made with seven control subjects matched for age, sex and body weight. Glucagon receptor binding was almost identical in the two groups. There were, however, marked alterations in the adenylyl cyclase activity in membranes from the diabetic patients. This activity was reduced by 35-50% when compared to control activity. Basal cyclase activity, as well as the activity after stimulation with glucagon or with agents (i.e., sodium fluoride and forskolin) that act beyond the glucagon receptor, was significantly decreased (p less than 0.05, p less than 0.001 respectively). In conclusion, uncontrolled Type 2 diabetes in associated with an over-all loss of responsiveness of the hormone-sensitive adenylyl cyclase in human liver, which apparently results from post-receptor alterations. This change may provide a mechanism for reducing the effect of hyperglycagonaemia in Type 2 diabetes mellitus. PMID:3038642

  7. HLA-DR and -DQ gene polymorphism in Latvian patients with insulin-dependent diabetes mellitus.

    PubMed

    Shtauvere, A; Rumba, I; Dzivite, I; Sanjeevi, C B

    1998-10-01

    Latvian insulin-dependent diabetes mellitus (IDDM) patients (n=101) and healthy controls (n=111) were analyzed for HLA-DR and DQ polymorphism. DR3-DQ2 and DR4-DQ8 were positively associated and DR15-DQ6, DR13-DQ6, DR1-DQ5 and DQ7 negatively associated with the disease. The incidence of IDDM in Latvia is very low (6.5 per 100,000) compared to Sweden (24.4 per 100,000), even though Latvia is close to Sweden. The reasons for the decreased incidence are not clear. When the negatively associated DQ were taken together in the healthy controls, more than 75% of the healthy controls were positive for one of the four negatively associated DQ molecules. The excess frequency of the negatively associated DQ molecules in the general population could explain the lower incidence of IDDM in Latvia. Association of HLA-DR and DQ genes with autoantibody markers shows DR3, but not DQ2, to be increased in GAD65 antibody-positive compared to antibody-negative patients. This association was not observed with ICA512 antibodies.

  8. A solution to the genetic and environmental puzzles of insulin-dependent diabetes mellitus.

    PubMed

    Adams, D D; Adams, Y J; Knight, J G; McCall, J; White, P; Horrocks, R; van Loghem, E

    1984-02-25

    Studies of the segregation of heterozygous immunoglobulin allotypes in families with several cases of insulin-dependent diabetes mellitus (IDDM) show that germline heavy-chain V (variable region) genes are not major genetic determinants for IDDM, but data for IDDM and Graves' disease together suggest involvement of kappa light-chain V genes. Absence of IDDM at birth, the semi-random age of onset, and the 50% discordance of identical twins suggest that somatic mutation of germline V genes is involved in the development of the pathogenetic anti-beta-cell clones. The effect of histocompatibility and other alloantigens on the prevalence of IDDM is readily accounted for by the effect of the "holes" they induce, by natural tolerance, in the immune response repertoire; these alterations apparently affect the chance of emergence of anti-beta-cell clones by the somatic mutations and network of interclonal deletions that constantly change the fringes of the repertoire. Histocompatibility antigens can also influence repertoire development by changing the specificity of conjoint presentation of foreign antigens by macrophages. Antigenic stimulation by particular environmental microorganisms is probably essential to the repertoire development necessary for the occurrence of IDDM. Additionally, beta-cell damage by local infection may play a part by facilitating autoantigen presentation to the immune system.

  9. Background, quality of life and metabolic control in patients with insulin-dependent diabetes mellitus.

    PubMed

    Wikby, A; Hörnquist, J O; Andersson, P O

    1991-08-01

    The interference of background characteristics with quality of life and metabolic control in patients with insulin-dependent diabetes mellitus (IDDM) were examined. Seventy-three consecutive outpatients who switched from syringe injections to multiple pen-injection treatment comprised the study group. Perceived status as well as retrospective changes in quality of life, attributed to the new treatment modality, were assessed at follow-up after 9-13 months. Data on metabolic control (HbA1C) were collected at base-line and follow-up. Sub-group comparisons in life quality and metabolic control were performed with regard to differences in sex, age, cohabitation, onset and duration of IDDM. Most of the background characteristics had no or just minor significance for status and change in the life quality and metabolic control of the patients. Cohabitation, however, was linked to a better life quality status pertaining to different domains and a tendency to better metabolic control. In addition, females reported a slightly better health status and a more healthy life style (i.e. eating, drinking and smoking habits) than did males. Extra treatment attention may therefore be justified for non-cohabiting males.

  10. Community-based approaches for the primary prevention of non-insulin-dependent diabetes mellitus.

    PubMed

    Simmons, D; Voyle, J; Swinburn, B; O'Dea, K

    1997-07-01

    The prevalence of non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) is increasing worldwide. Although recent studies suggest that primary prevention of NIDDM is possible, strategies for controlling the NIDDM pandemic remain under development. Successful interventions to date have mainly relied upon the control of obesity and increased exercise, although pharmacological agents are being studied. While a mixture of both high risk and population-based approaches is likely to be required, the former will not prevent new high risk cases developing. Unfortunately, the success in the primary prevention of cardiovascular disease through risk factor reduction has not controlled obesity, the most important risk factor for NIDDM. New strategies are currently being developed and focus upon changes in the food supply of whole populations and a community development approach to altering attitudes to food and exercise. As these interventions are in the early stages of their development, formative, process, and quantitative evaluation remain essential components of any community-based programme aimed at the primary prevention of NIDDM.

  11. Prolonged inorganic arsenite exposure suppresses insulin-stimulated AKT S473 phosphorylation and glucose uptake in 3T3-L1 adipocytes: Involvement of the adaptive antioxidant response

    SciTech Connect

    Xue, Peng; Hou, Yongyong; Zhang, Qiang; Woods, Courtney G.; Yarborough, Kathy; Liu, Huiyu; Sun, Guifan; Andersen, Melvin E.; Pi, Jingbo

    2011-04-08

    Highlights: {yields} In 3T3-L1 adipocytes iAs{sup 3+} decreases insulin-stimulated glucose uptake. {yields} iAs{sup 3+} attenuates insulin-induced phosphorylation of AKT S473. {yields} iAs{sup 3+} activates the cellular adaptive oxidative stress response. {yields} iAs{sup 3+} impairs insulin-stimulated ROS signaling. {yields} iAs{sup 3+} decreases expression of adipogenic genes and GLUT4. -- Abstract: There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of type 2 diabetes (T2D). One critical feature of T2D is insulin resistance in peripheral tissues, especially in mature adipocytes, the hallmark of which is decreased insulin-stimulated glucose uptake (ISGU). Despite the deleterious effects of reactive oxygen species (ROS), they have been recognized as a second messenger serving an intracellular signaling role for insulin action. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcription factor regulating cellular adaptive response to oxidative stress. This study proposes that in response to arsenic exposure, the NRF2-mediated adaptive induction of endogenous antioxidant enzymes blunts insulin-stimulated ROS signaling and thus impairs ISGU. Exposure of differentiated 3T3-L1 cells to low-level (up to 2 {mu}M) inorganic arsenite (iAs{sup 3+}) led to decreased ISGU in a dose- and time-dependent manner. Concomitant to the impairment of ISGU, iAs{sup 3+} exposure significantly attenuated insulin-stimulated intracellular ROS accumulation and AKT S473 phosphorylation, which could be attributed to the activation of NRF2 and induction of a battery of endogenous antioxidant enzymes. In addition, prolonged iAs{sup 3+} exposure of 3T3-L1 adipocytes resulted in significant induction of inflammatory response genes and decreased expression of adipogenic genes and glucose transporter type 4 (GLUT4), suggesting chronic inflammation and reduction in GLUT4

  12. Effect of Oral Sebacic Acid on Postprandial Glycemia, Insulinemia, and Glucose Rate of Appearance in Type 2 Diabetes

    PubMed Central

    Iaconelli, Amerigo; Gastaldelli, Amalia; Chiellini, Chiara; Gniuli, Donatella; Favuzzi, Angela; Binnert, Christophe; Macé, Katherine; Mingrone, Geltrude

    2010-01-01

    OBJECTIVE Dicarboxylic acids are natural products with the potential of being an alternate dietary source of energy. We aimed to evaluate the effect of sebacic acid (a 10-carbon dicarboxylic acid; C10) ingestion on postprandial glycemia and glucose rate of appearance (Ra) in healthy and type 2 diabetic subjects. Furthermore, the effect of C10 on insulin-mediated glucose uptake and on GLUT4 expression was assessed in L6 muscle cells in vitro. RESEARCH DESIGN AND METHODS Subjects ingested a mixed meal (50% carbohydrates, 15% proteins, and 35% lipids) containing 0 g (control) or 10 g C10 in addition to the meal or 23 g C10 as a substitute of fats. RESULTS In type 2 diabetic subjects, the incremental glucose area under the curve (AUC) decreased by 42% (P < 0.05) and 70% (P < 0.05) in the 10 g C10 and 23 g C10 groups, respectively. At the largest amounts used, C10 reduced the glucose AUC in healthy volunteers also. When fats were substituted with 23 g C10, AUC of Ra was significantly reduced on the order of 18% (P < 0.05) in both healthy and diabetic subjects. The insulin-dependent glucose uptake by L6 cells was increased in the presence of C10 (38.7 ± 10.3 vs. 11.4 ± 5.4%; P = 0.026). This increase was associated with a 1.7-fold raise of GLUT4. CONCLUSIONS Sebacic acid significantly reduced hyperglycemia after a meal in type 2 diabetic subjects. This beneficial effect was associated with a reduction in glucose Ra, probably due to lowered hepatic glucose output and increased peripheral glucose disposal. PMID:20724647

  13. Lowering of triglycerides by gemfibrozil affects neither the glucoregulatory nor antilipolytic effect of insulin in type 2 (non-insulin-dependent) diabetic patients.

    PubMed

    Vuorinen-Markkola, H; Yki-Järvinen, H; Taskinen, M R

    1993-02-01

    Hypertriglyceridaemia and insulin resistance are closely associated but it is unknown whether hypertriglyceridaemia per se contributes to insulin resistance. In the present study we examined whether gemfibrozil, by lowering triglyceride levels, improves the glucoregulatory and antilipolytic action of insulin in Type 2 (non-insulin-dependent) diabetes mellitus. Twenty patients were randomly allocated to receive either placebo or gemfibrozil 1200 mg daily for 12 weeks in a double-blind study. Very low density lipoprotein triglyceride levels decreased in the gemfibrozil group by 42 +/- 12% (p < 0.01). Gemfibrozil had no effect on the diurnal concentration of non-esterified fatty acids (NEFA). At the randomization HbA1c levels were comparable (7.6 +/- 0.3 vs 7.8 +/- 0.2%, NS) and increased slightly both in the gemfibrozil (8.2 +/- 0.4%, p < 0.05) and placebo groups (8.0 +/- 0.3%, NS). Pre- and post-treatment diurnal glucose and insulin concentrations remained unchanged. Basal pre- and post-treatment hepatic glucose production rates were comparable in both groups and similarly suppressed by insulin. Rate of whole body glucose disposal during a low-dose insulin infusion (serum insulin -90 pmol/l) (pre- vs post-gemfibrozil 11.9 +/- 1.1 vs 11.1 +/- 0.7, pre- vs post-placebo 9.9 +/- 1.1 vs 10.8 +/- 0.8 mumol.kg-1.min-1, NS for both) and a high-dose insulin infusion (serum insulin approximately 500 pmol/l) (16.2 +/- 1.7 vs 17.7 +/- 2.7, 17.1 +/- 4.2 vs 17.4 +/- 2.9 mumol.kg-1 x min-1, respectively, NS for both) remained unchanged. Basal pre- and post-treatment NEFA turnover rates were comparable in both groups and similarly suppressed by insulin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8458531

  14. Development of diagnotors based on time-average values of plasma glucose and immunoreactive insulin levels during intravenous glucose tolerance testing

    NASA Astrophysics Data System (ADS)

    Denisova, Tatyana P.; Malinov, Igor A.; Malinova, Lidia I.; Brook, Sergey B.

    2000-04-01

    The diagnostic algorithm of glucose-insulinic violations for the patients with a clinically obvious atherosclerosis of coronary arteries, non-insulin dependent diabetes mellitus and persons with the heritable predisposition to these forms of pathology was designed. The realization of intravenous glucose tolerance test in specially fitted groups of patients served as basis of the algorithm.

  15. Association of blindness to intensification of glycemic control in insulin-dependent diabetes mellitus.

    PubMed

    Moskalets, E; Galstyan, G; Starostina, E; Antsiferov, M; Chantelau, E

    1994-01-01

    Intensive glycemic control (IGC) in previously hyperglycemic insulin-dependent diabetes mellitus (IDDM) patients is associated with a decreased long-term risk of progression of diabetic retinopathy (DR); up to 12 months after institution of IGC, however, the risk of progression of DR transiently increases. In an observational study, a cohort of 122 patients with IDDM was followed prospectively for changes in glycosylated hemoglobin (HbA1, normal < 8%) and in DR 0-12 months after institution of IGC. In six of these patients (women, mean age 24 years, duration of diabetes 14.3 years, with incipient nephropathy and retinopathy) a total of seven eyes went blind after 6-12 months of IGC, despite laser coagulation treatment. From the whole sample, a control groups of eight patients (six women) was set up, matched for age, duration of IDDM, degree of retinopathy, visual acuity, blood pressure, and microalbuminuria, with preserved vision after 12 months of IGC. In the case patients, the mean (95% confidence interval) initial HbA1 was 14.9% (13.8%-16.1%), versus 13.4% (12.4%-14.4%) in the control patients (p < 0.05). The mean HbA1 decrements after 4 months of IGC, were 3.0% (1.9%-4.1%) in the cases, and 2.1% (1.2%-3.0%) in the controls (NS); and after 12 months, the respective decrements were 4.9% (2.4%-7.4%) in the cases versus 2.0% (0.5%-3.5%) in the controls (p = 0.04). In conclusion, IGC with a decrement of > 2% per year is associated with a high risk of progression of antecedent diabetic retinopathy to blindness in IDDM patients with an extremely high initial HbA1.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Proximal glomerulo-tubular balance in patients with type 1 (insulin-dependent) diabetes mellitus.

    PubMed

    Brøchner-Mortensen, J; Støckel, M; Sørensen, P J; Nielsen, A H; Ditzel, J

    1984-08-01

    To evaluate the glomerulo-tubular balance of sodium and water in the proximal tubules of diabetic patients with elevated glomerular filtration rate, the renal plasma clearance of lithium and the glomerular filtration rate (51Cr-EDTA plasma clearance) were determined simultaneously in 11 ambulatory Type 1 (insulin-dependent) diabetic patients (aged 25-35 years) with no evidence of diabetic nephropathy and in 10 age-matched healthy subjects. The renal plasma clearance of lithium, which is a measure of flow from the proximal tubule into the thin descending limb of the loop of Henle, did not differ between diabetic and control subjects (28.9 +/- 4.0 versus 28.3 +/- 5.1 ml/min per 1.73 m2 surface area, mean +/- SD), whereas the glomerular filtration rate in the diabetic patients was significantly higher than in the control subjects (136 +/- 10.2 versus 108 +/- 13.6 ml/min per 1.73 m2, p less than 0.001). The same held true for the fractional reabsorption rate in the proximal tubules (78.7 +/- 3.2 versus 73.6 +/- 4.9%, p less than 0.02). The results indicate that the elevation of the glomerular filtration rate in diabetic patients is associated with a parallel increase in the proximal reabsorption rate. This type of glomerulo-tubular balance implies that the flow of water and flux of sodium to the segments distal to the proximal tubule are kept constant during variations in the glomerular filtration rate.

  17. Lipogenic potential of liver from morbidly obese patients with and without non-insulin-dependent diabetes

    SciTech Connect

    Barakat, H.A.; McLendon, V.D.; Carpenter, J.W.; Marks, R.H.; Legett, N.; O'Brien, K.; Caro, J.F. )

    1991-03-01

    Intra-abdominal liver biopsies were obtained during surgery from fasted obese patients with non-insulin-dependent diabetes mellitus (NIDDM), obese normoglycemic controls, and lean controls. Lipid synthesis was studied in freshly isolated hepatocytes and liver homogenates from the three groups of subjects. Incorporation of 3H2O into the lipids of hepatocytes was determined in the absence and presence of insulin (0.1 mumol/L). The activities of five enzymes involved in fatty acid synthesis, and the incorporation of 14C-glycerol-3-phosphate into lipids were determined in liver homogenates. Basal lipid synthesis by hepatocytes was not different in the three groups of patients. Insulin stimulated lipogenesis by 8% +/- 30% in the lean controls, 33% +/- 8% in the obese controls and 17% +/- 6% in the NIDDM patients. No significant differences in the activities of the five enzymes that are involved in de novo fatty acid synthesis among the three groups of patients were observed. Similarly, incorporation of 14C-glycerol-3-phosphate by liver homogenates, in the presence of saturating or submaximal concentrations of fatty acids, did not differ among the three groups. These results show that under the experimental conditions of this study, including the fasted state of the patients, the basal capacity of liver of NIDDM patients to synthesize fatty acids or glycerides is the same as that of liver from obese and lean controls. Thus, it is likely that an increase in fatty acid flux into a liver with normal lipogenic potential may contribute to the increased synthesis of triglycerides by the liver of these patients in vivo.

  18. Transmission test for linkage disequilibrium: The insulin gene region and insulin-dependent diabetes mellitus (IDDM)

    SciTech Connect

    Spielman, R.S.; McGinnis, R.E. ); Ewens, W.J. )

    1993-03-01

    A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the class 1 alleles of the region of tandem-repeat DNA (5[prime] flanking polymorphism [5[prime]FP])adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. The authors consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, they evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper they describe the statistical basis for this transmission test for linkage disequilibrium (transmission/disequilibrium test [TDT]). They then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5[prime]FP and susceptibility to IDDM. 27 refs., 6 tabs.

  19. Calculation of the intake of three intense sweeteners in young insulin-dependent diabetics.

    PubMed

    Garnier-Sagne, I; Leblanc, J C; Verger, P

    2001-07-01

    In 1994, European Directive 94/35/CE authorised the use as food additives of five intense sweeteners for which Acceptable Daily Intakes (ADI) were established. The same directive stipulated that member states should organise a monitoring system to determine the consumption of these substances. Diabetic children are normally considered to constitute a group with a high consumption of sweeteners (European Commission, 1998. Report on Methodology for the Monitoring of Food Additives Intake across the European Union. Report of the Scientific Cooperation, Task 4.2 SCOOP/INT/REPORT/2. European Commission Directorate General III, Brussels.). A stepwise approach to the food additive intake in the general population had shown that three of the five authorised intense sweeteners (aspartame, saccharin and acesulfame K) are used at particularly high levels in sugar-free foods and are also very commonly utilised as table-top sweeteners. This paper presents the results of a food intake survey conducted in a group of French, insulin-dependent children in 1997, aimed at estimating the Theoretical Maximum Daily Intake (TMDI) for these three sweeteners and comparing this with the relevant ADI values. A 5-day diary questionnaire was used to estimate the intake of sugar-free, artificially sweetened foods and table-top sweeteners. When assessing the intake of each additive, all sugar-free products were assumed to be sweetened using a single sweetener at its maximum authorised level. This study was performed in five age groups, and based on the mean and 97.5th percentile of the distribution of consumption, demonstrated that it was unlikely that total exposure could rise above the ADI.

  20. Simulated Microgravity Reduces TNF-Alpha Activity, Suppresses Glucose Uptake and Enhances Arginine Flux in Pancreatic Islets of Langerhans

    NASA Technical Reports Server (NTRS)

    Tobin, Brian W.; Leeper-Woodford, Sandra K.; Hashemi, Brian B.; Smith, Scott M.; Sams, Clarence F.; Paloski, W. H. (Technical Monitor)

    2000-01-01

    The present studies were designed to determine effects of microgravity upon lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha (TNF - alpha) activity and indices of insulin and fuel homeostasis of pancreatic islets of Langerhans. Islets (1726+/-117,150 u IEU) from Wistar Furth rats were treated as: 1) HARV (High Aspect Ratio Vessel cell culture) , 2) HARV plus LPS 3) static culture, 4) static culture plus LPS TNF-alpha (L929 cytotoxicity assay) was significantly increased in LPS-induced HARV and static cultures, yet the increase was more pronounced in the static culture group (p<0.05). A decrease in insulin concentration was demonstrated in the LPS stimulated HARV culture (p<0.05). We observed a greater glucose concentration and increased disappearance of arginine in islets cultured in HARVs. While nitrogenous compound analysis indicated a ubiquitous reliance upon glutamine in all experimental groups, arginine was converted to ornithine at a two-fold greater rate in the islets cultured in the HARV microgravity paradigm (p<0.05). These studies demonstrate alterations in LPS induced TNF-alpha production of pancreatic islets of Langerhans, favoring a lesser TNF activity in the HARV paradigm. These alterations in fuel homeostasis may be promulgated by gravity averaged cell culture methods or by three dimensional cell assembly.

  1. Manipulation under anaesthesia for frozen shoulder in patients with and without non-insulin dependent diabetes mellitus.

    PubMed

    Wang, Jung-Pan; Huang, Tung-Fu; Ma, Hsiao-Li; Hung, Shih-Chieh; Chen, Tain-Hsiung; Liu, Chien-Lin

    2010-12-01

    Manipulation under anaesthesia (MUA) has been used to speed up recovery. However, the outcome of frozen shoulder after MUA in patients with diabetes has not been well documented in the past. A higher prevalence of frozen shoulder has been reported in diabetes mellitus (DM) patients. In this study, we revealed the short- and long-term outcomes for treatment of frozen shoulders by MUA and compared these results in patients with and without non-insulin dependent DM by adjusted Constant score. The scores showed no significant differences between the two groups at both early and late follow-ups. Our results revealed that MUA for frozen shoulders is a simple and noninvasive procedure to improve symptoms and shoulder function within a short period of time. Even though DM is a predisposing factor to frozen shoulder, non-insulin dependent DM alone does not influence both the short- and long-term outcomes of frozen shoulder.

  2. Implications of the diabetes control and complications trial for persons with non-insulin-dependent diabetes mellitus.

    PubMed

    Vinik, A I; Richardson, D W

    1997-03-01

    The Diabetes Control and Complications Trial has conclusively established that intensive control of insulin-dependent diabetes mellitus in persons aged 19 to 26 years (almost exclusively white, normotensive, nondyslipidemic, of normal weight, and insulin sensitive) reduces by +/- 50% the likelihood of retinopathy, nephropathy, and neuropathy. In contrast, persons with non-insulin-dependent diabetes mellitus (NIDDM) are older, overweight, hypertensive, dyslipidemic, and insulin resistant. Glycemia is only one of their risk factors, and they die of macrovascular disease. Review of studies supporting glycemic control versus risk factor reduction as management of NIDDM suggests a clear need to address risk factors besides glycemic control for successful prevention of complications of NIDDM. A new schematic proposal for intervention based upon risk factor reduction is presented. PMID:9076296

  3. Cocoa, glucose tolerance, and insulin signaling: cardiometabolic protection.

    PubMed

    Grassi, Davide; Desideri, Giovambattista; Mai, Francesca; Martella, Letizia; De Feo, Martina; Soddu, Daniele; Fellini, Emanuela; Veneri, Mariangela; Stamerra, Cosimo A; Ferri, Claudio

    2015-11-18

    Experimental and clinical evidence reported that some polyphenol-rich natural products may offer opportunities for the prevention and treatment of type 2 diabetes, due to their biological properties. Natural products have been suggested to modulate carbohydrate metabolism by various mechanisms, such as restoring β-cell integrity and physiology and enhancing insulin-releasing activity and glucose uptake. Endothelium is fundamental in regulating arterial function, whereas insulin resistance plays a pivotal role in pathophysiological mechanisms of prediabetic and diabetic states. Glucose and insulin actions in the skeletal muscle are improved by insulin-dependent production of nitric oxide, favoring capillary recruitment, vasodilatation, and increased blood flow. Endothelial dysfunction, with decreased nitric oxide bioavailability, is a critical step in the development of atherosclerosis. Furthermore, insulin resistance has been described, at least in part, to negatively affect endothelial function. Consistent with this, conditions of insulin resistance are usually linked to endothelial dysfunction, and the exposure of the endothelial cells to cardiovascular risk factors such as hypertension, dyslipidemia, and hyperglycemia is associated with reduced nitric oxide bioavailability, resulting in impaired endothelial-dependent vasodilatation. Moreover, endothelial dysfunction has been described as an independent predictor of cardiovascular risk and events. Cocoa and cocoa flavonoids may positively affect the pathophysiological mechanisms involved in insulin resistance and endothelial dysfunction with possible benefits in the prevention of cardiometabolic diseases. PMID:26126077

  4. Cocoa, glucose tolerance, and insulin signaling: cardiometabolic protection.

    PubMed

    Grassi, Davide; Desideri, Giovambattista; Mai, Francesca; Martella, Letizia; De Feo, Martina; Soddu, Daniele; Fellini, Emanuela; Veneri, Mariangela; Stamerra, Cosimo A; Ferri, Claudio

    2015-11-18

    Experimental and clinical evidence reported that some polyphenol-rich natural products may offer opportunities for the prevention and treatment of type 2 diabetes, due to their biological properties. Natural products have been suggested to modulate carbohydrate metabolism by various mechanisms, such as restoring β-cell integrity and physiology and enhancing insulin-releasing activity and glucose uptake. Endothelium is fundamental in regulating arterial function, whereas insulin resistance plays a pivotal role in pathophysiological mechanisms of prediabetic and diabetic states. Glucose and insulin actions in the skeletal muscle are improved by insulin-dependent production of nitric oxide, favoring capillary recruitment, vasodilatation, and increased blood flow. Endothelial dysfunction, with decreased nitric oxide bioavailability, is a critical step in the development of atherosclerosis. Furthermore, insulin resistance has been described, at least in part, to negatively affect endothelial function. Consistent with this, conditions of insulin resistance are usually linked to endothelial dysfunction, and the exposure of the endothelial cells to cardiovascular risk factors such as hypertension, dyslipidemia, and hyperglycemia is associated with reduced nitric oxide bioavailability, resulting in impaired endothelial-dependent vasodilatation. Moreover, endothelial dysfunction has been described as an independent predictor of cardiovascular risk and events. Cocoa and cocoa flavonoids may positively affect the pathophysiological mechanisms involved in insulin resistance and endothelial dysfunction with possible benefits in the prevention of cardiometabolic diseases.

  5. [Difficulties and concerns identified by Puerto Rican youth with insulin-dependent diabetes mellitus (IDDM): their relationship with metabolic control, hopelessness, social support, and depressive symptoms].

    PubMed

    Rosselló, Jeannette; Maysonet Guzmán, Marielisa

    2006-12-01

    Insulin-dependent diabetes mellitus (IDDM) is a chronic health condition that affects 18 of every 100,000 Puerto Rican youth. Few research studies have been performed on the problems that youth with diabetes encounter and how they are related to adherence to treatment and adequate metabolic control. Adequate metabolic control is associated with fewer short and long-term medical complications, as well as better quality of life. Adapting to the demands and stressors associated with IDDM and its treatment is a task that can prove to be difficult for youth with diabetes due to having to make adjustments, alterations, and following a prescribed regimen in their daily activities. The main purpose of this investigation was to explore difficulties and worries identified by Puerto Rican youth with IDDM. This study examined whether there is a relationship between difficulties and worries, and adequate metabolic control, hopelessness, social support and depressive symptomatology. One hundred and one youth with IDDM between the ages of 8 and 17 (45 male, 56 female) were evaluated. Analysis of frequencies, correlations, and comparison tests were performed by group (gender, age, diabetes duration, and metabolic control. Results reveal that some of the difficulties identified by Puerto Rican youth with IDDM were: not eating candy and/or cake, self-monitoring blood glucose at school, doing things on time, and waking up early. Among the worries they reported were: insulin reactions and thinking that they might have to go to the hospital. PMID:17550100

  6. Effect of multiple risk factors on differences between blacks and whites in the prevalence of non-insulin-dependent diabetes mellitus in the United States.

    PubMed

    Cowie, C C; Harris, M I; Silverman, R E; Johnson, E W; Rust, K F

    1993-04-01

    The higher prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in US blacks as compared with whites may be due to a higher frequency of NIDDM risk factors in blacks, a higher inherent susceptibility to NIDDM among blacks, or the risk factors' having a greater effect in blacks. The authors evaluated 4,379 subjects from the Second National Health and Nutrition Examination Survey (1976-1980) for whom NIDDM was ascertained by medical history and oral glucose tolerance test, and for whom data on a number of risk factors were available. The prevalence of NIDDM was 60% higher in blacks than in whites (p < 0.001) and was highest in black women. Although most risk factors for NIDDM were more common in blacks, this higher frequency did not completely explain the racial disparity in the prevalence of NIDDM. After adjustment for all risk factors by logistic regression, an elevated risk of NIDDM was particularly evident at higher obesity levels in blacks as compared with whites; the odds were 70% higher for blacks at a percentage of desirable weight of 150 (95% confidence interval 1.1-2.8). The risk of NIDDM associated with obesity was greatest in black women: The odds in this group were sevenfold higher at a percentage of desirable weight of 150 versus 100 (95% confidence interval 2.6-18.8). The possibility of racial differences in metabolic adaptation to obesity highlights the importance of preventing this condition in blacks, particularly in black women. PMID:8484363

  7. Recent development of single preparations and fixed-dose combination tablets for the treatment of non-insulin-dependent diabetes mellitus : A comprehensive summary for antidiabetic drugs.

    PubMed

    Li, Jianwen; Lian, He

    2016-06-01

    As a complex endocrine and metabolic disorder, type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM) has become a major threat to human health. Because of the heterogeneous and progressive disorders induced by insulin resistance and pancreatic b-cell dysfunction, the treatment of NIDDM is still challenging. Although antidiabetic drugs with different pharmacological mechanisms of action have been used clinically, different degrees of undesirable glucose control and the incidences of a variety of side effects, including hypoglycemia, cardiovascular complications and weight gain require the better treatment options. This article has overviewed the current literature about commercially available antidiabetic drugs with different pharmacological mechanisms of action in the treatment of NIDDM, and summarized the published data regarding the efficacy, tolerability, and safety of currently available single preparations and fixed-dose combinations, aiming to provide important information for the development and application of antidiabetic drugs in the future. The literature search from 1989 to 2015 was conducted by PubMed, ScienceDirect, Springer, American Diabetes Association, and U.S. FDA Drugs databases. PMID:27230777

  8. Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q

    SciTech Connect

    Bell, G.I.; Xiang, Kunsan; Newman, M.V.; Wu, Songhua; Cox, N.J. ); Wright, L.G.; Spielman, R.S. ); Fajans, S.S. )

    1991-02-15

    Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterized by an early age of onset, usually before 25 years of age, and an autosomal dominant mode of inheritance. The largest and best-studies MODY pedigree is the TW family. The majority of the diabetic subjects in this pedigree has a reduced and delayed insulin-secretory response to glucose, and it has been proposed that this abnormal response is the manifestation of the basic genetic defect that leads to diabetes. Using DNA from members of the TW family, the authors tested more than 75 DNA markers for linkage with MODY. A DNA polymorphism in the adenosine deaminase gene (ADA) on the long arm of chromosome 20 was found to cosegregate with MODY. The maximum logarithm of adds (lod score) for linkage between MODY and ADA was 5.25 at a recombination fraction of 0.00. These results indicate that the odds are {gt}178,000:1 that the gene responsible for MODY is this family is tightly linked to the ADA gene on chromosome 20q.

  9. Recent development of single preparations and fixed-dose combination tablets for the treatment of non-insulin-dependent diabetes mellitus : A comprehensive summary for antidiabetic drugs.

    PubMed

    Li, Jianwen; Lian, He

    2016-06-01

    As a complex endocrine and metabolic disorder, type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus, NIDDM) has become a major threat to human health. Because of the heterogeneous and progressive disorders induced by insulin resistance and pancreatic b-cell dysfunction, the treatment of NIDDM is still challenging. Although antidiabetic drugs with different pharmacological mechanisms of action have been used clinically, different degrees of undesirable glucose control and the incidences of a variety of side effects, including hypoglycemia, cardiovascular complications and weight gain require the better treatment options. This article has overviewed the current literature about commercially available antidiabetic drugs with different pharmacological mechanisms of action in the treatment of NIDDM, and summarized the published data regarding the efficacy, tolerability, and safety of currently available single preparations and fixed-dose combinations, aiming to provide important information for the development and application of antidiabetic drugs in the future. The literature search from 1989 to 2015 was conducted by PubMed, ScienceDirect, Springer, American Diabetes Association, and U.S. FDA Drugs databases.

  10. [Difficulties and concerns identified by Puerto Rican youth with insulin-dependent diabetes mellitus (IDDM): their relationship with metabolic control, hopelessness, social support, and depressive symptoms].

    PubMed

    Rosselló, Jeannette; Maysonet Guzmán, Marielisa

    2006-12-01

    Insulin-dependent diabetes mellitus (IDDM) is a chronic health condition that affects 18 of every 100,000 Puerto Rican youth. Few research studies have been performed on the problems that youth with diabetes encounter and how they are related to adherence to treatment and adequate metabolic control. Adequate metabolic control is associated with fewer short and long-term medical complications, as well as better quality of life. Adapting to the demands and stressors associated with IDDM and its treatment is a task that can prove to be difficult for youth with diabetes due to having to make adjustments, alterations, and following a prescribed regimen in their daily activities. The main purpose of this investigation was to explore difficulties and worries identified by Puerto Rican youth with IDDM. This study examined whether there is a relationship between difficulties and worries, and adequate metabolic control, hopelessness, social support and depressive symptomatology. One hundred and one youth with IDDM between the ages of 8 and 17 (45 male, 56 female) were evaluated. Analysis of frequencies, correlations, and comparison tests were performed by group (gender, age, diabetes duration, and metabolic control. Results reveal that some of the difficulties identified by Puerto Rican youth with IDDM were: not eating candy and/or cake, self-monitoring blood glucose at school, doing things on time, and waking up early. Among the worries they reported were: insulin reactions and thinking that they might have to go to the hospital.

  11. Increased glycated Cu,Zn-superoxide dismutase levels in erythrocytes of patients with insulin-dependent diabetis mellitus.

    PubMed

    Kawamura, N; Ookawara, T; Suzuki, K; Konishi, K; Mino, M; Taniguchi, N

    1992-06-01

    Our previous study indicated that erythrocyte Cu,Zn-superoxide dismutase (Cu,Zn-SOD) undergoes glycation and inactivation in vivo (1) and in vitro (2). The aim of the present study was to assess glycated Cu,Zn-SOD in patients with insulin-dependent diabetes mellitus. Glycated Cu,Zn-SOD, which binds to a boronic acid affinity column, was measured by the enzyme-linked immunosorbent assay. The percentage of the glycated form in 25 insulin-dependent diabetic children was 40.2 +/- 8.2%; this was significantly higher than that in the normal controls (P less than 0.01). The specific activity of the glycated form in the diabetic children was 163,000 +/- 33,000 IU/mg Cu,Zn-SOD protein, significantly lower than that in controls (P less than 0.01). These data indicate that glycated and less active Cu,Zn-SOD is increased in erythrocytes of patients with insulin-dependent diabetes mellitus.

  12. Green tea polyphenol extract regulates the expression of genes involved in glucose uptake and insulin signaling in rats fed a high fructose diet.

    PubMed

    Cao, Heping; Hininger-Favier, Isabelle; Kelly, Meghan A; Benaraba, Rachida; Dawson, Harry D; Coves, Sara; Roussel, Anne M; Anderson, Richard A

    2007-07-25

    Green tea has antidiabetic, antiobesity, and anti-inflammatory activities in animal models, but the molecular mechanisms of these effects have not been fully understood. Quantitative real-time polymerase chain reaction (PCR) was used to investigate the relative expression levels and the effects of green tea (1 and 2 g solid extract/kg diet) on the expression of glucose transporter family genes (Glut1/Slc2a1, Glut2/Slc2a2, Glut3/Slc2a3, and Glut4/Slc2a4) and insulin signaling pathway genes (Ins1, Ins2, Insr, Irs1, Irs2, Akt1, Grb2, Igf1, Igf2, Igf1r, Igf2r, Gsk3b, Gys1, Pik3cb, Pik3r1, Shc1, and Sos1) in liver and muscle of rats fed a high-fructose diet known to induce insulin resistance and oxidative stress. Glut2 and Glut4 were the major Glut mRNAs in rat liver and muscle, respectively. Green tea extract (1 g) increased Glut1, Glut4, Gsk3b, and Irs2 mRNA levels by 110, 160, 30, and 60% in the liver, respectively, and increased Irs1 by 80% in the muscle. Green tea extract (2 g) increased Glut4, Gsk3b, and Pik3cb mRNA levels by 90, 30, and 30% but decreased Shc1 by 60% in the liver and increased Glut2, Glut4, Shc1, and Sos1 by 80, 40, 60, and 50% in the muscle. This study shows that green tea extract at 1 or 2 g/kg diet regulates gene expression in the glucose uptake and insulin signaling pathway in rats fed a fructose-rich diet.

  13. A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle

    PubMed Central

    Mackenzie, R. W. A.; Watt, P.

    2016-01-01

    Although the mechanisms are largely unidentified, the chronic or intermittent hypoxic patterns occurring with respiratory diseases, such as chronic pulmonary disease or obstructive sleep apnea (OSA) and obesity, are commonly associated with glucose intolerance. Indeed, hypoxia has been widely implicated in the development of insulin resistance either via the direct action on insulin receptor substrate (IRS) and protein kinase B (PKB/Akt) or indirectly through adipose tissue expansion and systemic inflammation. Yet hypoxia is also known to encourage glucose transport using insulin-dependent mechanisms, largely reliant on the metabolic master switch, 5′ AMP-activated protein kinase (AMPK). In addition, hypoxic exposure has been shown to improve glucose control in type 2 diabetics. The literature surrounding hypoxia-induced changes to glycemic control appears to be confusing and conflicting. How is it that the same stress can seemingly cause insulin resistance while increasing glucose uptake? There is little doubt that acute hypoxia increases glucose metabolism in skeletal muscle and does so using the same pathway as muscle contraction. The purpose of this review paper is to provide an insight into the mechanisms underpinning the observed effects and to open up discussions around the conflicting data surrounding hypoxia and glucose control. PMID:27274997

  14. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice.

    PubMed

    Tomimoto, Daisuke; Okuma, Chihiro; Ishii, Yukihito; Kobayashi, Akio; Ohta, Takeshi; Kakutani, Makoto; Imanaka, Tsuneo; Ogawa, Nobuya

    2015-09-01

    Type 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice. JTT-553 was repeatedly administered to DIO and KK-A(y) mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-A(y) mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.

  15. Effect of insulin on the distribution and disposition of glucose in man.

    PubMed Central

    Ferrannini, E; Smith, J D; Cobelli, C; Toffolo, G; Pilo, A; DeFronzo, R A

    1985-01-01

    -independent glucose uptake was estimated (from published data) at 75% of basal glucose uptake, and was constrained not to change with euglycemic hyperinsulinemia. When the kinetic data obtained during insulin administration were fitted to this model, neither the size nor the exchange rates of the plasma or the rapid pool were appreciably changed. In contrast, the slow pool was markedly expanded (from 96 +/- 9 to 190 +/- 30 mg/kg, P less than 0.02) at the same time as total glucose disposal rose fourfold above basal (to 7.96 +/- 0.85 mg/min kg, P less than 0.001). Furthermore, a significant direct correlation was found to exist between the change in size of the slow pool and the insulin-stimulated rate of total glucose turnover (r=0.92, P<0.01). We conclude that hyperinsulinemia, independent of hyperglycemia, markedly increases the exchangeable mass of glucose in the body, presumably reflecting the accumulation of free, intracellular glucose in insulin-dependent tissues. PMID:3894421

  16. Trophic effects of vanadium on beta-cells of STZ-induced insulin dependent diabetic rats & evidence for long-term relief of diabetes mellitus.

    PubMed

    Dehghani, G A; Sotoodeh, M; Omrani, G R

    1999-08-01

    The effects of one year combined vanadium and insulin treatment (VIT) on blood glucose levels of insulin dependent diabetic (IDD) rats were studied. Rats made diabetic by an i.v. injection of 55-60 mg/kg streptozotocin (STZ), divided into two groups and treated with a low dose of NPH insulin (2-4 U/rat) for two months to survive from hyperglycaemic shock. In group A, hyperglycaemia ameliorated during one year by increasing the daily dose of insulin to 8.2 +/- 0.4 U/100 g (IT) and in group B by switching over to hydrated vanadium solution (1 mg/ml vanadyl oxide sulphate pentahydrate in drinking water; VIT). The results of the study indicated that one year VIT regenerated new beta-cells, and relieved diabetes both during treatment and after withdrawal. However, one year IT showed no trophic effects on the destroyed beta-cells, hence no improvement in the glycaemic status of the animal was seen after withdrawal. The action of VIT was such that in group B normoglycaemeia persisted in 90 per cent of diabetic rats two weeks after insulin withdrawal. But in the same group, 45 days after combined vanadium and insulin withdrawal blood glucose was normal in 60 per cent of the rats, it was between 250-300 mg/dl in 18 per cent and between 350-400 mg/dl in 24 per cent of the rats. In conclusion it appears that long term VIT regenerates pancreatic beta-cells of IDD rats and possibly by improving their secretory functions it relieves diabetes mellitus.

  17. Systematic search for markers linked to insulin-dependent diabetes on chromosome 17

    SciTech Connect

    Williams, S.R.; Shephard, J.M.; Berger, J.S.

    1994-09-01

    We tested 19 microsatellite markers on chromosome 17 for linkage with insulin-dependent diabetes mellitus (IDDM). Nuclear families (N = 235) with at least two affected offspring were provided by the British Diabetic Association, Human Biological Data Interchange, and our own lab. The mean interval ({plus_minus}sd) between markers was 8 {plus_minus} 3 cM. For each parent heterozygous at the marker locus being studied, we determined whether the same or different alleles were transmitted to the two affected sibs. The {open_quotes}degree of sharing{close_quotes} for each marker is the frequency with which the same parental allele is transmitted to both affected sibs. Linkage with IDDM susceptibility leads to values higher than 0.50 for degree of sharing. Unlike lods, this approach makes no assumption about mode of inheritance. Mean sharing for the 19 markers was 0.51 (range 0.460 to 0.557; sd = .03). Three markers on 17q (all mutually unlinked) showed sharing of {approximately}0.55. The degree of sharing was 228/414 = 0.551 for D17A807 ({chi}{sup 2} = 4.26, p = .04), 172/309 = 0.557 for D17S784 ({chi}{sup 2} = 3.96, p = .04), and 218/398 = 0.548 for D17S798 ({chi}{sup 2} = 3.63, p =.06). We also looked for evidence of linkage disequilibrium between IDDM and alleles of each of these markers, by means of the transmission/disequilibrium test of Spielman. No significant linkage disequilibrium was found for D17S784 or D17S798. However, allele 6 of D17S807 was transmitted from heterozygous parents to IDDM offspring with frequency 131/230 = 0.57 ({chi}{sup 2} = 4.45, p = .035), supporting linkage with IDDM. We are currently investigating other markers and candidate genes in the region of D17S807.

  18. Novel benzothiazinones (BTOs) as allosteric modulator or substrate competitive inhibitor of glycogen synthase kinase 3β (GSK-3β) with cellular activity of promoting glucose uptake.

    PubMed

    Zhang, Peng; Li, Shufen; Gao, Yang; Lu, Wenbo; Huang, Ke; Ye, Deyong; Li, Xi; Chu, Yong

    2014-12-15

    Glycogen synthase kinase 3β (GSK-3β) plays a key role in insulin metabolizing pathway and therefore inhibition of the enzyme might provide an important therapeutic approach for treatment of insulin resistance and type 2 diabetes. Recently, discovery of ATP noncompetitive inhibitors is gaining importance not only due to their generally increased selectivity but also for the potentially subtle modulation of the target. These kinds of compounds include allosteric modulators and substrate competitive inhibitors. Here we reported two benzothiazinone compounds (BTO), named BTO-5h (IC50=8 μM) and BTO-5s (IC50=10 μM) as novel allosteric modulator and substrate competitive inhibitor of GSK-3β, respectively. Their different action modes were proved by kinetic experiments. Furthermore, BTO-5s was selected to check the kinases profile and showed little or even no activity to a panel of ten protein kinases at 100 μM, indicating it has good selectivity. Docking studies were performed to give suggesting binding modes which can well explain their impacts on the enzyme. Moreover, cell experiments displayed both compounds reduced the phosphorylation level of glycogen synthase in an intact cell, and greatly enhanced the glucose uptake in both HpG2 and 3T3-L1 cells. All of these results suggested BTO-5s and BTO-5h maybe have potentially therapeutic value for anti-diabetes. The results also offer a new scaffold for designing and developing selective inhibitors with novel mechanisms of action.

  19. Liv.52 up-regulates cellular antioxidants and increase glucose uptake to circumvent oleic acid induced hepatic steatosis in HepG2 cells.

    PubMed

    Vidyashankar, Satyakumar; Sharath Kumar, L M; Barooah, Vandana; Sandeep Varma, R; Nandakumar, Krishna S; Patki, Pralhad Sadashiv

    2012-10-15

    HepG2 cells were rendered steatotic by supplementing 2.0mM oleic acid (OA) in the culture media for 24h. OA induced hepatic steatosis in HepG2 cells was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. It was also marked by increased inflammatory cytokines TNF-α and IL-8 with decreased enzymic and non-enzymic antioxidant molecules and decreased cell proliferation associated with insulin resistance and DNA fragmentation. Addition of Liv.52 hydro-alcoholic extract (LHAE) 50μg/mL to the steatotic cells was effective in increasing the insulin mediated glucose uptake by 3.13 folds and increased cell proliferation by 3.81 folds with decreased TAG content (55%) and cytokines. The intracellular glutathione content was increased by 8.9 folds without substantial increase in GSSG content. LHAE decreased TNF-α and IL-8 by 51% and 6.5% folds respectively, lipid peroxidation by 65% and inhibited DNA fragmentation by 69%. The superoxide dismutase, catalase and glutathione peroxidase activities were increased by 88%, 128% and 64% respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by LHAE. Hence, LHAE effectively attenuate molecular perturbations associated with non-alcoholic fatty liver disease (NAFLD) indications in HepG2 cells. PMID:22940028

  20. Liv.52 up-regulates cellular antioxidants and increase glucose uptake to circumvent oleic acid induced hepatic steatosis in HepG2 cells.

    PubMed

    Vidyashankar, Satyakumar; Sharath Kumar, L M; Barooah, Vandana; Sandeep Varma, R; Nandakumar, Krishna S; Patki, Pralhad Sadashiv

    2012-10-15

    HepG2 cells were rendered steatotic by supplementing 2.0mM oleic acid (OA) in the culture media for 24h. OA induced hepatic steatosis in HepG2 cells was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. It was also marked by increased inflammatory cytokines TNF-α and IL-8 with decreased enzymic and non-enzymic antioxidant molecules and decreased cell proliferation associated with insulin resistance and DNA fragmentation. Addition of Liv.52 hydro-alcoholic extract (LHAE) 50μg/mL to the steatotic cells was effective in increasing the insulin mediated glucose uptake by 3.13 folds and increased cell proliferation by 3.81 folds with decreased TAG content (55%) and cytokines. The intracellular glutathione content was increased by 8.9 folds without substantial increase in GSSG content. LHAE decreased TNF-α and IL-8 by 51% and 6.5% folds respectively, lipid peroxidation by 65% and inhibited DNA fragmentation by 69%. The superoxide dismutase, catalase and glutathione peroxidase activities were increased by 88%, 128% and 64% respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by LHAE. Hence, LHAE effectively attenuate molecular perturbations associated with non-alcoholic fatty liver disease (NAFLD) indications in HepG2 cells.

  1. Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes.

    PubMed

    Schnuck, Jamie K; Sunderland, Kyle L; Gannon, Nicholas P; Kuennen, Matthew R; Vaughan, Roger A

    2016-01-01

    Leucine stimulates anabolic and catabolic processes in skeletal muscle, however little is known about the effects of leucine on peroxisome proliferator-activated receptor (PPAR) activity. This work characterized the effects of 24-h leucine treatment on metabolic parameters and protein expression in cultured myotubes. Leucine significantly increased PPARβ/δ expression as well as markers of mitochondrial biogenesis, leading to significantly increased mitochondrial content and oxidative metabolism in a PPARβ/δ-dependent manner. However, leucine-treated cells did not display significant alterations in uncoupling protein expression or oxygen consumed per relative mitochondrial content suggesting leucine-mediated increases in oxidative metabolism are a function of increased mitochondrial content and not altered mitochondrial efficiency. Leucine treatment also increased GLUT4 content and glucose uptake as well as PPARγ and FAS expression leading to increased total lipid content. Leucine appears to activate PPAR activity leading to increased mitochondrial biogenesis and elevated substrate oxidation, while simultaneously promoting substrate/lipid storage and protein synthesis. PMID:27345255

  2. Acute Glycemic Effects of Exercise in Adolescents with Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Stratton, Ron; And Others

    1988-01-01

    A study of eight diabetic adolescents with moderately well-controlled diabetes concludes that recreational activities are as effective in lowering blood glucose levels as structured exercise. This might allow diabetic adolescents to participate in a wider variety of sports activities. Research, methodology, and results are discussed. (Author/JL)

  3. Berberine treatment attenuates the palmitate-mediated inhibition of glucose uptake and consumption through increased 1,2,3-triacyl-sn-glycerol synthesis and accumulation in H9c2 cardiomyocytes.

    PubMed

    Chang, Wenguang; Chen, Li; Hatch, Grant M

    2016-04-01

    Dysfunction of lipid metabolism and accumulation of 1,2-diacyl-sn-glycerol (DAG) may be a key factor in the development of insulin resistance in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid extract that has shown promise as a hypoglycemic agent in the management of diabetes in animal and human studies. However, its mechanism of action is not well understood. To determine the effect of BBR on lipid synthesis and its relationship to insulin resistance in H9c2 cardiomyocytes, we measured neutral lipid and phospholipid synthesis and their relationship to glucose uptake. Compared with controls, BBR treatment stimulated 2-[1,2-(3)H(N)]deoxy-D-glucose uptake and consumption in palmitate-mediated insulin resistant H9c2 cells. The mechanism was though an increase in protein kinase B (AKT) activity and GLUT-4 glucose transporter expression. DAG accumulated in palmitate-mediated insulin resistant H9c2 cells and treatment with BBR reduced this DAG accumulation and increased accumulation of 1,2,3-triacyl-sn-glycerol (TAG) compared to controls. Treatment of palmitate-mediated insulin resistant H9c2 cells with BBR increased [1,3-(3)H]glycerol and [1-(14)C]glucose incorporation into TAG and reduced their incorporation into DAG compared to control. In addition, BBR treatment of these cells increased [1-(14)C]palmitic acid incorporation into TAG and decreased its incorporation into DAG compared to controls. BBR treatment did not alter phosphatidylcholine or phosphatidylethanolamine synthesis. The mechanism for the BBR-mediated decreased precursor incorporation into DAG and increased incorporation into TAG in palmitate-incubated cells was an increase in DAG acyltransferase-2 activity and its expression and a decrease in TAG hydrolysis. Thus, BBR treatment attenuates palmitate-induced reduction in glucose uptake and consumption, in part, through reduction in cellular DAG levels and accumulation of TAG in H9c2 cells. PMID:26774040

  4. Berberine treatment attenuates the palmitate-mediated inhibition of glucose uptake and consumption through increased 1,2,3-triacyl-sn-glycerol synthesis and accumulation in H9c2 cardiomyocytes.

    PubMed

    Chang, Wenguang; Chen, Li; Hatch, Grant M

    2016-04-01

    Dysfunction of lipid metabolism and accumulation of 1,2-diacyl-sn-glycerol (DAG) may be a key factor in the development of insulin resistance in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid extract that has shown promise as a hypoglycemic agent in the management of diabetes in animal and human studies. However, its mechanism of action is not well understood. To determine the effect of BBR on lipid synthesis and its relationship to insulin resistance in H9c2 cardiomyocytes, we measured neutral lipid and phospholipid synthesis and their relationship to glucose uptake. Compared with controls, BBR treatment stimulated 2-[1,2-(3)H(N)]deoxy-D-glucose uptake and consumption in palmitate-mediated insulin resistant H9c2 cells. The mechanism was though an increase in protein kinase B (AKT) activity and GLUT-4 glucose transporter expression. DAG accumulated in palmitate-mediated insulin resistant H9c2 cells and treatment with BBR reduced this DAG accumulation and increased accumulation of 1,2,3-triacyl-sn-glycerol (TAG) compared to controls. Treatment of palmitate-mediated insulin resistant H9c2 cells with BBR increased [1,3-(3)H]glycerol and [1-(14)C]glucose incorporation into TAG and reduced their incorporation into DAG compared to control. In addition, BBR treatment of these cells increased [1-(14)C]palmitic acid incorporation into TAG and decreased its incorporation into DAG compared to controls. BBR treatment did not alter phosphatidylcholine or phosphatidylethanolamine synthesis. The mechanism for the BBR-mediated decreased precursor incorporation into DAG and increased incorporation into TAG in palmitate-incubated cells was an increase in DAG acyltransferase-2 activity and its expression and a decrease in TAG hydrolysis. Thus, BBR treatment attenuates palmitate-induced reduction in glucose uptake and consumption, in part, through reduction in cellular DAG levels and accumulation of TAG in H9c2 cells.

  5. Hypoglycemic effect of triphala on selected non insulin dependent Diabetes mellitus subjects

    PubMed Central

    Rajan, Sowmya S.; Antony, Seema

    2008-01-01

    Modern life style is characterized by high stress, increased automation, junk food consumption and sedentary life style which have lead to the incidence of Diabetes. The study involved selection of NIDDM subjects who were supplemented with Triphala powder called, The Three Myrobalans (Terminalia bellirica- Belliric myrobalan, Terminalia chebula-Inknut, Embilica officinalis - Indian gooseberry) for a period of 45 days. Statistical evaluation of the blood profile showed significant reduction in the blood glucose level of the subjects. PMID:22557278

  6. Evaluation of exogenous insulin homoeostasis by the artificial pancreas in insulin-dependent diabetes.

    PubMed

    Mirouze, J; Selam, J L; Pham, T C; Cavadore, D

    1977-05-01

    With the artificial pancreas used by the authors, insulin was delivered through a venous infusion and the rate of delivery was adjusted according to data provided by a continuous blood glucose monitor. After different trials we selected control algorithms integrating two parameters: instantaneous blood glucose concentration and increasing or decreasing patterns of blood glucose. A constant basal insulin infusion rate was added and improved the control of glycaemic excursions. Different parameters concerning exogenous insulin homoeostasis were determined. The delay to reach an insulin effect was 18+/-2 min and was shortened by a priming-dose at the beginning of the infusion. The insulin effect remained for 28+/-2 min after the infusion had been stopped, but differences were noted in the morning (21+/-2 min), in the afternoon (32+/-2 min) and during the night (25+/-3 min). Insulin needs were evaluated during meals. Related to the amount of carbohydrates, the doses fell from 0.53 units/hr/g of carbohydrate for breakfast to 0.15 for dinner. From these data, it appears that the efficiency of exogenous insulin exhibits a circadian rhythm.

  7. Mild hypoglycemia associated with deterioration of mental efficiency in children with insulin-dependent diabetes mellitus.

    PubMed

    Ryan, C M; Atchison, J; Puczynski, S; Puczynski, M; Arslanian, S; Becker, D

    1990-07-01

    To assess the effects of mild hypoglycemia on cognitive functioning in diabetic children, we used an insulin glucose clamp technique to induce and maintain a hypoglycemic state. Eleven patients, 11 to 18 years of age, completed a series of cognitive tests during a baseline euglycemic state (100 mg/dl (5.5 mmol/L] and repeated those measures at the beginning and end of a hypoglycemic plateau (55 to 65 mg/dl (3.1 to 3.6 mmol/L], and again at restoration of euglycemia. At plasma glucose levels of 60 to 65 mg/dl (3.3 to 3.6 mmol/L), a significant decline in mental efficiency was found. This was most apparent on measures of mental "flexibility" (Trial Making Test) and on measures that required planning and decision making, attention to detail, and rapid responding. Moreover, complete recovery of cognitive function was not contemporaneous with restoration of euglycemia, particularly on those tests requiring rapid responding and decision making (choice reaction time). Not all subjects showed evidence of cognitive impairment during hypoglycemia. The very high degree of intersubject variability suggests that, in addition to plasma glucose values, unknown physiologic variables are responsible for triggering cognitive impairments in school-aged youngsters with diabetes during an episode of mild hypoglycemia. PMID:2196358

  8. Four-year follow-up of retinal status and glycosylated haemoglobin in patients with insulin-dependent diabetes mellitus.

    PubMed

    Chantelau, E; Weiss, H; Weber, U; Sonnenberg, G E; Berger, M

    1988-01-01

    Retinal status and glycosylated hemoglobin (GHb) was followed in 32 patients with insulin-dependent diabetes mellitus (18 females; age upon entering the study 26 +/- 8 years; duration of diabetes 10 +/- 6 years; means +/- SD) during a total of 136 patient-years, i.e. during 4.3 +/- 0.6 years per patient. Annual mean GHb (given in percent of the mean normal GHb) was calculated from 7 +/- 3 determinations of GHb per patient-year. Fluorescein angiographs were performed at least once per patient-year, and retinal status was assessed by counting microaneurysms. Upon entering the study, early diabetic (background) retinopathy was present in 14 patients; at the end of the follow-up period, it was present in 20 patients. Retinal status deteriorated in 4/42 patient-years with excellent metabolic control (annual mean GHb less than or equal to 125%), in 13/70 patient-years with good control (annual mean GHb 126-150%) and in 8/24 patient-years with poor control (annual mean GHb greater than 150%). The incidence rate of retinal deterioration differed significantly between years with excellent control and years with poor control (X2 5.7, df = 1, p less than 0.05). It is concluded that excellent metabolic control within 14 +/- 6 years after onset of insulin-dependent diabetes mellitus appears to be a protective factor against the development or progression of early diabetic retinopathy.

  9. Non-insulin-dependent diabetes mellitus among First Nations children. New entity among First Nations people of north western Ontario.

    PubMed Central

    Harris, S. B.; Perkins, B. A.; Whalen-Brough, E.

    1996-01-01

    OBJECTIVE: To describe the emergence of a new clinical form of non-insulin-dependent diabetes mellitus (NIDDM) among First Nations children. DESIGN: Case series developed through retrospective review of a computerized diabetes registry and of records from a hospital and clinic. SETTING: Sioux Lookout Zone Hospital, a secondary care referral hospital for 28 remote First Nations communities in northwestern Ontario, affiliated with the University of Toronto's Sioux Lookout Program. PARTICIPANTS: Eighteen First Nations youths younger than 16 years identified via the Sioux Lookout Diabetes Program registry and via hospital discharge records from 1978 to 1994. Three of the 18 subjects were excluded because data essential to the study were missing from their records. MAIN OUTCOME MEASURES: Prevalence of NIDDM in this population, clinical presentation at diagnosis, and associated risk factors (including family history, obesity, and clinical management). RESULTS: Age-adjusted prevalence was 2.5/1000 in this population, the highest yet reported for NIDDM in this age group. Ratio of female to male subjects was 6:1. Typical patients were asymptomatic, obese adolescents who were not prone to ketosis and whose families had a strong history of NIDDM. CONCLUSIONS: Non-insulin-dependent diabetes mellitus can occur during childhood, particularly among First Nations people. PMID:8688690

  10. The role of mouse Akt2 in insulin-dependent suppression of adipocyte lipolysis in vivo

    PubMed Central

    Koren, Shlomit; DiPilato, Lisa M.; Emmett, Matthew J.; Shearin, Abigail L.; Chu, Qingwei; Monks, Bob; Birnbaum, Morris J.

    2015-01-01

    Aim/hypothesis The release of fatty acids from adipocytes, i.e. lipolysis, is maintained under tight control, primarily by the opposing actions of catecholamines and insulin. A widely accepted model is that insulin antagonises catecholamine-dependent lipolysis through phosphorylation and activation of cAMP phosphodiesterase 3B (PDE3B) by the serine-threonine protein kinase Akt (protein kinase B). Recently, this hypothesis has been challenged, as in cultured adipocytes insulin appears, under some conditions, to suppress lipolysis independently of Akt. Methods To address the requirement for Akt2, the predominant isoform expressed in classic insulin target tissues, in the suppression of fatty acid release in vivo, we assessed lipolysis in mice lacking Akt2. Results In the fed state and following an oral glucose challenge, Akt2 null mice were glucose intolerant and hyperinsulinaemic, but nonetheless exhibited normal serum NEFA and glycerol levels, suggestive of normal suppression of lipolysis. Furthermore, insulin partially inhibited lipolysis in Akt2 null mice during an insulin tolerance test (ITT) and hyperinsulinaemic–euglycaemic clamp, respectively. In support of these in vivo observations, insulin antagonised catecholamine-induced lipolysis in primary brown fat adipocytes from Akt2-deficient nice. Conclusion These data suggest that suppression of lipolysis by insulin in hyperinsulinaemic states can take place in the absence of Akt2. PMID:25740694

  11. Suppression of Very Early Stage Of Adipogenesis by Baicalein, a Plant-Derived Flavonoid through Reduced Akt-C/EBPα-GLUT4 Signaling-Mediated Glucose Uptake in 3T3-L1 Adipocytes

    PubMed Central

    2016-01-01

    Baicalein has been used as a Chinese medicine, and is an abundant plant flavonoid present in fruits and vegetables. Here, we examined the effects of baicalein in adipogenesis and investigated its molecular mechanism in adipocytes. Baicalein lowered the intracellular lipid accumulation and decreased the transcription levels of the adipocyte-specific genes in mouse 3T3-L1 adipocytes. Glucose uptake mediated by glucose transporter 4 (GLUT4) was reduced, causing down-regulation of the intracellular lipid accumulation. These reductions were also observed even when baicalein was added in only early stage of adipogenesis (0–2 days) of 6-day-adipogenesis. Chromatin immunoprecipitation assay showed that baicalein decreased the binding level of C/EBPα protein to the promoter region of the GLUT4 gene. Phosphorylation of Akt at 1 h after the initiation of adipogenesis was inhibited by the treatment with baicalein. Inhibition during only the first 1.5 h after the initiation of adipogenesis by baicalein or an Akt inhibitor was enough to decrease the lipid contents in the cells undergoing adipocyte differentiation for 6 days. These results indicate that baicalein decreased the intracellular lipid accumulation by down-regulation of glucose uptake via repression of Akt-C/EBPα-GLUT4 signaling in the very early stage of adipogenesis of 3T3-L1 adipocytes. PMID:27669565

  12. The effect of sulphonylurea therapy on skeletal muscle glycogen synthase activity and insulin secretion in newly presenting type 2 (non-insulin-dependent) diabetic patients.

    PubMed

    Johnson, A B; Argyraki, M; Thow, J C; Jones, I R; Broughton, D; Miller, M; Taylor, R

    1991-04-01

    Ten newly presenting, Type 2 (non-insulin-dependent), Caucasian diabetic patients were studied before and after 8 weeks treatment with the sulphonylurea gliclazide, and in parallel 13 similar patients were studied before and after 8 weeks treatment with diet alone. Eight non-diabetic subjects were also studied. Insulin action was assessed by measuring activation of skeletal muscle glycogen synthase (GS) prior to and during a 4-h hyperinsulinaemic euglycaemic clamp (100 mU kg-1 h-1). Fasting plasma glucose (+/- SE) and glycosylated haemoglobin decreased to a greater extent in the gliclazide treated patients (fall of 6.2 +/- 0.7 vs 2.1 +/- 0.5 mmol l-1, p less than 0.005 and 4.7 +/- 0.5 vs 2.1 +/- 0.5%, p less than 0.005). This was accompanied by an increase in fasting serum insulin concentrations in the gliclazide treated patients (7.0 +/- 1.3 to 10.1 +/- 1.1 mU l-1, p less than 0.005), but no change in the diet treated patients. Fractional GS activity did not increase during the clamp at presentation in either treatment group (change +2.9 +/- 1.8 and -1.5 +/- 1.9%, respectively) whereas it increased markedly in the control subjects (+16.4 +/- 3.4%, both p less than 0.001). After 8-week treatment there was a significant increase in GS activity during the clamp in the patients receiving gliclazide (+6.9 +/- 2.7%, p less than 0.05), but no change in GS activity in the patients on diet alone (+0.5 +/- 1.4%). The difference in post-treatment muscle insulin action was significant (p less than 0.05). There was no correlation between the degree of improvement in metabolic control and the improvement in response of GS to insulin in the gliclazide treated patients (r = -0.06), suggesting a possible direct drug effect on skeletal muscle. Glucose requirement during the clamp at presentation was markedly lower in both treatment groups than in the non-diabetic subjects (gliclazide 2.1 +/- 0.3, diet 2.0 +/- 0.6 vs 7.8 +/- 0.4 mg kg-1 min-1, both p less than 0.001), and despite a

  13. Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

    PubMed

    Blanco, Cynthia L; McGill-Vargas, Lisa L; Gastaldelli, Amalia; Seidner, Steven R; McCurnin, Donald C; Leland, Michelle M; Anzueto, Diana G; Johnson, Marney C; Liang, Hanyu; DeFronzo, Ralph A; Musi, Nicolas

    2015-03-01

    Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

  14. Increased arterial wall stiffness and thickness in medium-sized arteries in patients with insulin-dependent diabetes mellitus.

    PubMed

    Christensen, T; Neubauer, B

    1988-01-01

    By means of ultrasonography, arterial wall stiffness, arterial wall thickness, and the elastic modulus of the common femoral artery were estimated in a group of 19 young insulin-dependent diabetics. The ultrasound technique for determination of these parameters is described as well as the echo-anatomy of the arterial wall. In accordance with a previous investigation a significant rise in arterial wall stiffness was found. Furthermore, there was a highly significant correlation between the stiffness and the thickness of the arterial wall. The elastic modulus also correlated to the stiffness. It is concluded that the diabetic macroangiopathy is characterized by an increased stiffness of the arterial wall caused by increased thickness as well as by progressive alterations of the elastic characteristics of the wall tissue. Possible pathogenetic reasons are discussed.

  15. Insulin algorithms in the self-management of insulin-dependent diabetes: the interactive 'Apple Juice' program.

    PubMed

    Williams, A G

    1996-01-01

    The 'Apple Juice' program is an interactive diabetes self-management program which runs on a lap-top Macintosh Powerbook 100 computer. The dose-by-dose insulin advisory program was initially designed for children with insulin-dependent (type 1) diabetes mellitus. It utilizes several different insulin algorithms, measurement formulae, and compensation factors for meals, activity, medication and the dawn phenomenon. It was developed to assist the individual with diabetes and/or care providers, in determining specific insulin dosage recommendations throughout a 24 h period. Information technology functions include, but are not limited to automated record keeping, data recall, event reminders, data trend/pattern analyses and education. This paper highlights issues, observations and recommendations surrounding the use of the current version of the software, along with a detailed description of the insulin algorithms and measurement formulae applied successfully with the author's daughter over a six year period.

  16. Assessing adolescents with insulin-dependent diabetes mellitus: a multiple perspective pilot study using visual illness narratives and interviews.

    PubMed

    Buchbinder, Mara H; Detzer, Mark J; Welsch, Robert L; Christiano, Ann S; Patashnick, Jennifer L; Rich, Michael

    2005-01-01

    This study explored the illness experiences of adolescents with insulin-dependent diabetes mellitus (IDDM) using Video Intervention/Prevention Assessment (VIA). Five adolescents with IDDM were asked to videotape 8 hours of their lives over a 1-month period. At the conclusion of the study, the primary investigator interviewed each adolescent and their diabetes clinician. VIA visual illness narratives and follow-up interviews provided clinically important, previously unknown information about how adolescents live with diabetes, including the negative and positive influences of diabetes on the family unit and the individual, that parental involvement was associated with adolescents' diabetes control, and that gender may be a significant mediating factor in control. PMID:15661602

  17. Hypoglycaemia and non-cognitive aspects of psychological function in insulin-dependent (type 1) diabetes mellitus (IDDM).

    PubMed

    Gold, A E; Deary, I J; Frier, B M

    1997-02-01

    Hypoglycaemia provokes unpleasant symptoms and sensations in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). There is much interest in, and information on, the cognitive effects of acute insulin-induced hypoglycaemia. However, the effects of hypoglycaemia on brain function extend to important, non-cognitive aspects of psychological functioning, which are reviewed here. Acute hypoglycaemia induces changes in mood which result in a transient state of 'tense tiredness', a decrease in happiness, an increase in tense arousal, and decreased energetic arousal. Appraisals of life problems are affected adversely. Frequent exposure to hypoglycaemia is associated with heightened fear of hypoglycaemia, which can be quantitated in individuals. Personality may also influence behavioural responses to hypoglycaemia and the ability of an individual to cope with diabetes. The adverse effects of hypoglycaemia on mood, behaviour, personality, social function and management of diabetes in individual patients may be profound and need to be identified and addressed appropriately. PMID:9047087

  18. Is there a role for TENS application in the control of diabetes mellitus in insulin-dependent patients?

    PubMed

    Khan, Mueen Ullah

    2012-11-01

    An 80-year-old man with insulin-dependent diabetes mellitus presented to the hospital with low back pain. He was initially managed with non-steroidal anti-inflammatory drugs, tramadol and epidural steroid injection. Transcutaneous electrical nerve stimulation (TENS), applied on the back and buttocks, was subsequently advised. Initially, TENS was applied once every 24 hours. On improvement of pain symptoms, it was increased to thrice every 24 hours. The patient then complained of symptoms of hypoglycaemia (blood sugar level < 4 mmol/L). Discontinuation of TENS resulted in raised blood sugar level. When TENS was restarted, the same hypoglycaemic response was noted. The insulin dosage was adjusted to half of the patient's routine daily requirement with continued application of TENS. This incidental finding has alerted us to hypoglycaemic episodes following TENS application, which may be due to effective pain control, decreased sympathetic stimulation, enhanced insulin sensitivity or altered muscle metabolism due to electrical stimulation.

  19. Psychological reactions at the onset of insulin-dependent diabetes mellitus in children and later adjustment and metabolic control.

    PubMed

    Thernlund, G; Dahlquist, G; Hägglöf, B; Ivarsson, S A; Lernmark, B; Ludvigsson, J; Sjöblad, S

    1996-08-01

    The initial psychological reactions at the onset of insulin-dependent diabetes mellitus (IDDM) in a population-based sample of 76 children were studied with staff observations and a self-report questionnaire for children 12 years of age and more. Younger children reacted with more anger and less distress than the older children. High initial self-reported distress was associated with poorer subjective psychological IDDM adjustment at a follow-up 10 months later for the older children. The children's initial reactions as well as later adjustment were intimately associated with maternal initial reactions in the total group. The metabolic control, estimated as the mean level of the major fraction of glycosylated haemoglobin (Hb AIc) during the first 2 years, was poorer in the adolescent group. Initial anxiety over injections and protest but low general distress in mothers and children were associated with better metabolic control. PMID:8863877

  20. Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene.

    PubMed Central

    Kwok, W W; Lotshaw, C; Milner, E C; Knitter-Jack, N; Nepom, G T

    1989-01-01

    The human major histocompatibility complex includes approximately 14 class II HLA genes within the HLA-D region, most of which exist in multiple allelic forms. One of these genes, the DQ3.2 beta gene, accounts for the well-documented association of HLA-DR4 with insulin-dependent diabetes mellitus and is the single allele most highly correlated with this disease. We analyzed the amino acid substitutions that lead to the structural differences distinguishing DQ3.2 beta from its nondiabetogenic, but closely related allele, DQ3.1 beta. Site-directed mutagenesis of the DQ3.2 beta gene was used to convert key nucleotides into DQ3.1 beta codons. Subsequent expression studies of these mutated DQ3.2 beta clones using retroviral vectors defined amino acid 45 as critical for generating serologic epitopes characterizing the DQw3.1 beta and DQw3.2 beta molecules. Images PMID:2783780

  1. Allelic sequence variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility.

    PubMed Central

    Horn, G T; Bugawan, T L; Long, C M; Erlich, H A

    1988-01-01

    Analysis of sequence variation in the polymorphic second exon of the major histocompatibility complex genes HLA-DQ alpha and -DQ beta has revealed 8 allelic variants at the alpha locus and 13 variants at the beta locus. Correlation of sequence variation with serologic typing suggests that the DQw2, DQw3, and DQ(blank) types are determined by the DQ beta subunit, while the DQw1 specificity is determined by DQ alpha. The nature of the amino acid at position 57 in the DQ beta subunit is correlated with susceptibility to insulin-dependent diabetes mellitus. This region of the DQ beta chain contains shared peptides with Epstein-Barr virus and rubella virus. PMID:2842756

  2. Neuropsychological function in older subjects with non-insulin-dependent diabetes mellitus.

    PubMed

    Atiea, J A; Moses, J L; Sinclair, A J

    1995-08-01

    Neuropsychological function was compared in three well-matched groups of subjects: Group 1, 20 diabetic patients with hypertension, mean age 69.1 +/- 4.8 years, 14 males and 6 females; Group 2, 20 normotensive diabetic patients, mean age 69.0 +/- 6.2 years, 14 males and 6 females; Group 3, 20 healthy community controls, mean age 68.1 +/- 4.5 years, 13 males and 7 females. There were no significant differences between the groups in education or estimated IQ using the NART (National Adult Reading Test). Groups 1 and 2 did not differ significantly in duration of diabetes (mean 10.6 and 9.5 years, respectively), or mean glycosylated haemoglobin, HbA1 (mean 9.8 and 10.6%, respectively), or mean blood glucose before and after testing. On a battery neuropsychological tests, sensitive to cognitive impairment in older subjects, analysis of covariance using estimated IQ as the covariate showed no significant differences between the groups on tests of recall, with (Brown-Peterson Test) and without (Kendrick Object Learning Test) interference, forward and backward digit span, concentration (serial subtraction), verbal fluency, immediate and delayed prose recall, digit symbol substitution or psychomotor speed (Kendrick Digit Copying Test). These results provide no support for an association between cognitive deficits and Type 2 diabetes mellitus in older subjects or for the view that such deficits may also be mediated by hypertension.

  3. Formation of an adduct between insulin and the toxic lipoperoxidation product acrolein decreases both the hypoglycemic effect of the hormone in rat and glucose uptake in 3T3 adipocytes.

    PubMed

    Medina-Navarro, Rafael; Guzmán-Grenfell, Alberto M; Díaz-Flores, Margarita; Duran-Reyes, Genoveva; Ortega-Camarillo, Clara; Olivares-Corichi, Ivonne M; Hicks, Juan José

    2007-10-01

    Lipid peroxidation induced by reactive oxygen species might modify circulating biomolecules because of the formation of alpha,beta-unsaturated or dicarbonylic aldehydes. In order to investigate the interaction between a lipoperoxidation product, acrolein, and a circulating protein, insulin, the acrolein-insulin adduct was obtained. To characterize the adduct, gel filtration chromatography, sodium dodecylsulfate-polyacrylamide gel electrophoresis and carbonyl determination were performed. Induction of hypoglycemia in the rat and stimulation of glucose uptake by 3T3 adipocytes were used to evaluate the biological efficiency of the adduct compared with that of native insulin (Mackness, B., Quarck, R., Verte, W., Mackness, M., and Holvoet, P. (2006) Arterioscler., Thromb. Vasc. Biol. 26, 1545-1550). Formation of the acrolein-insulin complex in vitro increased the carbonyl group concentration from 2.5 to 22.5 nmol/mg of protein, and it formed without intermolecular aggregates (Halliwell, B., and Whiteman, M. (2004) Br. J. Pharmacol. 142, 231-255. The hypoglycaemic effect 18 min after administration to the rat is decreased by 25% (Robertson, R. P. (2004) J. Biol. Chem. 279, 42351-42354. An adduct concentration of 94 nM, compared to 10 nM for native insulin, was required to obtain the A 50% (concentration needed to obtain 50% of maximum transport of glucose uptake by 3T3 adipocytes). In conclusion, formation of the acrolein-insulin adduct modifies the structure of insulin and decreases its hypoglycemic effect in rat and glucose uptake by 3T3 adipocytes. These results help explain how a toxic aldehyde prone to be produced in vivo can structurally modify insulin and change its biological action.

  4. Role of Myotonic Dystrophy Protein Kinase (DMPK) in Glucose Homeostasis and Muscle Insulin Action

    PubMed Central

    Marti, Luc; Liesa, Marc; Camps, Marta; Ciaraldi, Theodore P.; Kondo, Richard; Reddy, Sita; Dillmann, Wolfgang H.; Palacin, Manuel; Zorzano, Antonio; Ruiz-Lozano, Pilar; Gomis, Ramon; Kaliman, Perla

    2007-01-01

    Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes. PMID:17987120

  5. Enhanced Response of Human Head and Neck Cancer Xenograft Tumors to Cisplatin Combined With 2-Deoxy-D-Glucose Correlates With Increased {sup 18}F-FDG Uptake as Determined by PET Imaging

    SciTech Connect

    Simons, Andrean L.; Fath, Melissa A.; Mattson, David M.; Smith, Brian J.; Walsh, Susan A.; Graham, Michael M.; Hichwa, Richard D.; Buatti, John M.; Dornfeld, Ken; Spitz, Douglas R.

    2007-11-15

    Purpose: To determine whether the response of human head and neck cancer xenografts to cisplatin (CIS) could be enhanced with 2-deoxy-D-glucose (2DG); whether 2-[{sup 18}F]-fluoro-2-deoxy-D-glucose (FDG) uptake correlated with responses to this drug combination; and whether 2DG would enhance CIS-induced radiosensitization. Methods and Materials: Clonogenic survival responses to CIS + 2DG were determined in FaDu and Cal-27 cells and reduced/oxidized glutathione levels were monitored as parameters indicative of oxidative stress. The efficacy of CIS + 2DG was determined in FaDu and Cal-27 xenografts, and FDG uptake was determined by using positron emission tomography. Results: Use of CIS + 2DG enhanced cell killing of FaDu and Cal-27 cells compared with either drug alone while increasing the percentage of oxidized glutathione in vitro. Use of CIS + 2DG inhibited FaDu and Cal-27 tumor growth and increased disease-free survival compared with either drug alone. The Cal-27 tumors showed greater pretreatment FDG uptake and increased disease-free survival when treated with 2DG + CIS relative to FaDu tumors. Treatment with 2DG enhanced CIS-induced radiosensitization in FaDu tumor cells grown in vitro and in vivo and resulted in apparent cures in 50% of tumors. Conclusions: These results show the enhanced therapeutic efficacy of CIS + 2DG in human head and neck cancer cells in vitro and in vivo compared with either drug alone, as well as the potential for FDG uptake to predict tumor sensitivity to 2DG + CIS. These findings provide a strong rationale for evaluating 2DG + CIS in combined-modality head and neck cancer therapy with radiation in a clinical setting.

  6. In vivo cardiac glucose metabolism in the high-fat fed mouse: Comparison of euglycemic–hyperinsulinemic clamp derived measures of glucose uptake with a dynamic metabolomic flux profiling approach

    SciTech Connect

    Kowalski, Greg M.; De Souza, David P.; Risis, Steve; Burch, Micah L.; Hamley, Steven; Kloehn, Joachim; Selathurai, Ahrathy; Lee-Young, Robert S.; Tull, Dedreia; O'Callaghan, Sean; McConville, Malcolm J.; Bruce, Clinton R.

    2015-08-07

    Rationale: Cardiac metabolism is thought to be altered in insulin resistance and type 2 diabetes (T2D). Our understanding of the regulation of cardiac substrate metabolism and insulin sensitivity has largely been derived from ex vivo preparations which are not subject to the same metabolic regulation as in the intact heart in vivo. Studies are therefore required to examine in vivo cardiac glucose metabolism under physiologically relevant conditions. Objective: To determine the temporal pattern of the development of cardiac insulin resistance and to compare with dynamic approaches to interrogate cardiac glucose and intermediary metabolism in vivo. Methods and results: Studies were conducted to determine the evolution of cardiac insulin resistance in C57Bl/6 mice fed a high-fat diet (HFD) for between 1 and 16 weeks. Dynamic in vivo cardiac glucose metabolism was determined following oral administration of [U-{sup 13}C] glucose. Hearts were collected after 15 and 60 min and flux profiling was determined by measuring {sup 13}C mass isotopomers in glycolytic and tricarboxylic acid (TCA) cycle intermediates. Cardiac insulin resistance, determined by euglycemic–hyperinsulinemic clamp, was evident after 3 weeks of HFD. Despite the presence of insulin resistance, in vivo cardiac glucose metabolism following oral glucose administration was not compromised in HFD mice. This contrasts our recent findings in skeletal muscle, where TCA cycle activity was reduced in mice fed a HFD. Similar to our report in muscle, glucose derived pyruvate entry into the TCA cycle in the heart was almost exclusively via pyruvate dehydrogenase, with pyruvate carboxylase mediated anaplerosis being negligible after oral glucose administration. Conclusions: Under experimental conditions which closely mimic the postprandial state, the insulin resistant mouse heart retains the ability to stimulate glucose metabolism. - Highlights: • Insulin clamp was used to determine the evolution of cardiac

  7. Inulin increases glucose transport in C2C12 myotubes and HepG2 cells via activation of AMP-activated protein kinase and phosphatidylinositol 3-kinase pathways.

    PubMed

    Yun, Hee; Lee, Jong Hwa; Park, Chang Eun; Kim, Min-Jung; Min, Byung-Il; Bae, Hyunsu; Choe, Wonchae; Kang, Insug; Kim, Sung-Soo; Ha, Joohun

    2009-10-01

    Inulin, a naturally occurring, functional food ingredient found in various edible plants, has been reported to exert potential health benefits, including decreased risk of colonic diseases, non-insulin-dependent diabetes, obesity, osteoporosis, and cancer. However, the mechanism of the antidiabetic activity of inulin has not yet been elucidated. In this study, we showed that inulin increased the uptake of glucose in C2C12 myotubes, which was associated with both AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways, but both of these pathways appeared to transmit their signals in an independent manner. Moreover, we found that inulin was able to increase the uptake of glucose in C2C12 myotubes in which insulin resistance was induced by exposing cells to high glucose concentrations. The identical effects of inulin were also observed in HepG2 hepatoma cells. Collectively, we report the antidiabetic activity of inulin and further demonstrate for the first time that such activity is associated with AMPK and PI3-K activation.

  8. Ablation of the ID2 gene results in altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue.

    PubMed

    Mathew, Deepa; Zhou, Peng; Pywell, Cameron M; van der Veen, Daan R; Shao, Jinping; Xi, Yang; Bonar, Nicolle A; Hummel, Alyssa D; Chapman, Sarah; Leevy, W Matthew; Duffield, Giles E

    2013-01-01

    Inhibitor of DNA binding 2 (ID2) is a helix-loop-helix transcriptional repressor rhythmically expressed in many adult tissues. Our earlier studies have demonstrated a role for ID2 in the input pathway, core clock function and output pathways of the mouse circadian system. We have also reported that Id2 null (Id2-/-) mice are lean with low gonadal white adipose tissue deposits and lower lipid content in the liver. These results coincided with altered or disrupted circadian expression profiles of liver genes including those involved in lipid metabolism. In the present phenotypic study we intended to decipher, on a sex-specific basis, the role of ID2 in glucose metabolism and in the circadian regulation of activity, important components of energy balance. We find that Id2-/- mice exhibited altered daily and circadian rhythms of feeding and locomotor activity; activity profiles extended further into the late night/dark phase of the 24-hr cycle, despite mice showing reduced total locomotor activity. Also, male Id2-/- mice consumed a greater amount of food relative to body mass, and displayed less weight gain. Id2-/- females had smaller adipocytes, suggesting sexual-dimorphic programing of adipogenesis. We observed increased glucose tolerance and insulin sensitivity in male Id2-/- mice, which was exacerbated in older animals. FDG-PET analysis revealed increased glucose uptake by skeletal muscle and brown adipose tissue of male Id2-/- mice, suggesting increased glucose metabolism and thermogenesis in these tissues. Reductions in intramuscular triacylglycerol and diacylglycerol were detected in male Id2-/- mice, highlighting its possible mechanistic role in enhanced insulin sensitivity in these mice. Our findings indicate a role for ID2 as a regulator of glucose and lipid metabolism, and in the circadian control of feeding/locomotor behavior; and contribute to the understanding of the development of obesity and diabetes, particularly in shift work personnel among whom

  9. Spectral analysis of time functions of plasma glucose and immunoreactive insulin during intravenous glucose tolerance testing on atherosclerosis and noninsulin-dependent diabetes mellitus

    NASA Astrophysics Data System (ADS)

    Malinov, Igor A.; Denisova, Tatyana P.; Malinova, Lidia I.; Brook, Sergey B.

    2000-04-01

    The time functions of plasma glucose and insulin obtained during intravenous glucose tolerance test were approximated by sections of Fourier series. The convincing quantitative and quality distinctions of amplitudes both phases of the first and second harmonics of decomposition of the indicated time functions are obtained. These distinctions were used as a basis of diagnostic algorithm of metabolic violations appropriate for atherosclerosis and non-insulin dependent diabetes mellitus in clinically obvious and preclinical stages.

  10. Prognostic value of high sensitivity C-reaction protein in non-insulin dependent diabetes mellitus patients with non-alcoholic fatty liver disease

    PubMed Central

    Bi, Yiliang; Min, Min; Shen, Wei; Deng, Pei; Du, Qiupeng; Dong, Mingjie; Liu, Yan

    2015-01-01

    Background and purpose: High sensitivity C-reaction protein (hsCRP) has been used as a significant predictive factor of cardiovascular events in patients with non-insulin dependent diabetes mellitus (NIDDM). However, existing reports in regards to the significance of hsCRP in predicting the progression of hepatic complications in NIDDM patients are too sparse to deliver clear results. This study is aimed at investigating the prognostic value of hsCRP in NIDDM patients with non-alcoholic fatty liver disease (NAFLD). Methods: 1128 NIDDM patients with a definite diagnosis of NAFLD were enrolled and followed for one year. The baseline body mass index (BMI), waist-hip circumference ratio (WHR), serum aspartate aminotransferase (AST), presence of hypertension, alanine aminotransferase (ALT), serum hsCRP, total cholesterol (Tch), fasting blood glucose (FBG), triglycerine (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and hepatitis B surface antigen (HBsAg) were recorded to analyze the significance of hsCRP in predicting the short-term progression from NAFLD to non-alcoholic steatohepatitis (NASH). Results: One year after baseline, 32% of the NAFLD patients suffered progression to NASH and the percentages of NASH were respectively 8.2%, 12.5%, 33.8% and 72.6% in 4 groups with quartered baseline serum level of hsCRP; there was significant difference among the 4 groups in percentage of NASH (P<0.001). With sex, age, WHR, BMI, hypertension, TG, TCH, HDL-C, LDL-C, FBG and HBsAg included, the calibrated regression model gave the OR values of 1.000, 1.669, 6.635 and 32.131 in in 4 quartered baseline serum levels of hsCRP. Conclusion: High serum level of hsCRP is an independent risk factor of short-term progression to NASH in patients with NIDDM and NAFLD. Those NIDDM patients with NAFLD that present with high serum level of hsCRP should be subjected to regular monitoring, lifestyle intervention and medication. PMID:26339423

  11. Applying the Transactional Stress and Coping Model to Sickle Cell Disorder and Insulin-Dependent Diabetes Mellitus: Identifying Psychosocial Variables Related to Adjustment and Intervention

    ERIC Educational Resources Information Center

    Hocking, Matthew C.; Lochman, John E.

    2005-01-01

    This review paper examines the literature on psychosocial factors associated with adjustment to sickle cell disease and insulin-dependent diabetes mellitus in children through the framework of the transactional stress and coping (TSC) model. The transactional stress and coping model views adaptation to a childhood chronic illness as mediated by…

  12. Evaluation of Jump into Action: A Program to Reduce the Risk of Non-Insulin Dependent Diabetes Mellitus in School Children on the Texas-Mexico Border.

    ERIC Educational Resources Information Center

    Holcomb, J. David; Lira, Juanita; Kingery, Paul M.; Smith, D. W.; Lane, Dorothy; Goodway, Jackie

    1998-01-01

    Evaluated Jump into Action, a non-insulin dependent diabetes mellitus (NIDDM)-prevention program that encouraged students to eat well and exercise regularly to reduce NIDDM risks. Surveys of predominantly Hispanic fifth graders and their teachers at Texas-Mexico border schools indicated that the program increased NIDDM-prevention knowledge and…

  13. Social Competence and Parental Support as Mediators of the Link between Stress and Metabolic Control in Adolescents with Insulin-Dependent Diabetes Mellitus.

    ERIC Educational Resources Information Center

    Hanson, Cindy L.; And Others

    1987-01-01

    Measured metabolic control, adherence, life stress, social competence, and parental support in adolescents (N=104) with insulin-dependent diabetes mellitus. Found that stress was directly associated with metabolic control, independent of the link between adherence and metabolic control. Social competence buffered negative association between…

  14. Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling.

    PubMed

    Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane; Faure, Robert; Marceau, Normand

    2013-02-15

    As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

  15. Keratin 8/18 regulation of glucose metabolism in normal versus cancerous hepatic cells through differential modulation of hexokinase status and insulin signaling

    SciTech Connect

    Mathew, Jasmin; Loranger, Anne; Gilbert, Stéphane; Faure, Robert; Marceau, Normand

    2013-02-15

    As differentiated cells, hepatocytes primarily metabolize glucose for ATP production through oxidative phosphorylation of glycolytic pyruvate, whereas proliferative hepatocellular carcinoma (HCC) cells undergo a metabolic shift to aerobic glycolysis despite oxygen availability. Keratins, the intermediate filament (IF) proteins of epithelial cells, are expressed as pairs in a lineage/differentiation manner. Hepatocyte and HCC (hepatoma) cell IFs are made solely of keratins 8/18 (K8/K18), thus providing models of choice to address K8/K18 IF functions in normal and cancerous epithelial cells. Here, we demonstrate distinctive increases in glucose uptake, glucose-6-phosphate formation, lactate release, and glycogen formation in K8/K18 IF-lacking hepatocytes and/or hepatoma cells versus their respective IF-containing counterparts. We also show that the K8/K18-dependent glucose uptake/G6P formation is linked to alterations in hexokinase I/II/IV content and localization at mitochondria, with little effect on GLUT1 status. In addition, we find that the insulin-stimulated glycogen formation in normal hepatocytes involves the main PI-3 kinase-dependent signaling pathway and that the K8/K18 IF loss makes them more efficient glycogen producers. In comparison, the higher insulin-dependent glycogen formation in K8/K18 IF-lacking hepatoma cells is associated with a signaling occurring through a mTOR-dependent pathway, along with an augmentation in cell proliferative activity. Together, the results uncover a key K8/K18 regulation of glucose metabolism in normal and cancerous hepatic cells through differential modulations of mitochondrial HK status and insulin-mediated signaling.

  16. Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling.

    PubMed

    Watanabe, Marina; Hisatake, Mitsuhiro; Fujimori, Ko

    2015-05-27

    3,7,3',4'-Tetrahydroxyflavone (fisetin) is a flavonoid found in vegetables and fruits having broad biological activities. Here the effects of fisetin on adipogenesis and its regulatory mechanism in mouse adipocytic 3T3-L1 cells are studied. Fisetin inhibited the accumulation of intracellular lipids and lowered the expression of adipogenic genes such as peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein (C/EBP) α and fatty acid-binding protein 4 (aP2) during adipogenesis. Moreover, the mRNA levels of genes such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase involved in the fatty acid biosynthesis (lipogenesis) were reduced by the treatment with fisetin. The expression level of the glucose transporter 4 (GLUT4) gene was also decreased by fisetin, resulting in down-regulation of glucose uptake. Furthermore, fisetin inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) and that of p70 ribosomal S6 kinase, a target of the mTOR complex, the inhibition of which was followed by a decreased mRNA level of the C/EBPα gene. The results obtained from a chromatin immunoprecipitation assay demonstrated that the ability of C/EBPα to bind to the GLUT4 gene promoter was reduced by the treatment with fisetin, which agreed well with those obtained when 3T3-L1 cells were allowed to differentiate into adipocytes in medium in the presence of rapamycin, an inhibitor for mTOR. These results indicate that fisetin suppressed the accumulation of intracellular lipids by inhibiting GLUT4-mediated glucose uptake through inhibition of the mTOR-C/EBPα signaling in 3T3-L1 cells.

  17. Major decrements in glycated hemoglobin levels between 1978 and 1989 in patients with insulin-dependent diabetes mellitus.

    PubMed

    Arfken, C L; Schmidt, L E; McGill, J B; White, N H; Santiago, J V

    1996-01-01

    The Diabetes Control and Complications Trial has shown that intensive treatment can deter the development and progression of diabetic complications. Integral to intensive treatment is improved glycemic control. To describe the trend in glycemic control for subjects with insulin-dependent diabetes mellitus, we examined the medical records of 662 subjects seen between 1978 and 1989 at the Model Demonstration Unit of the Diabetes Research and Training Center (Washington University School of Medicine). Mean value of glycated hemoglobin showed steady decline from a peak of 11.5% in 1979 to 9.0% in 1989. This decline was observed both in subjects evaluated only once (annual rate of decline estimated from linear regression, -0.17 +/1 0.03; p = 0.0001) and in subjects evaluated more than once (annual rate of decline estimated from growth curves, -0.18 +/- 0.06; p = 0.0001). These results suggest that substantial lowering of glycated hemoglobin has occurred during the last decade. This reduction should result in a lowered risk of diabetic complications.

  18. Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes.

    PubMed

    Mansfield, M W; Stickland, M H; Grant, P J

    1995-10-01

    Elevated levels of PAI-1 are found in coronary artery disease (CAD) and non-insulin-dependent diabetes (NIDDM). PAI-1 may be involved in the pathogenesis of CAD through suppression of fibrinolysis, alternatively the high levels may result from vascular damage. There is evidence that PAI-1 levels are related to genotype at a PAI-1 promoter polymorphism. Genotype at this 4G/5G polymorphism was determined in 160 NIDDM (90 males and 70 females) patients with (n = 38) or without (n = 122) clinical evidence of CAD. Levels of cholesterol were higher (6.5 vs 5.9 mM, p < 0.01) and PAI-1 tended to be higher (PAI-1 activity 23.0 vs 20.4 U/ml) with CAD. The frequency of the 4G/4G genotype was increased and the 5G/5G genotype decreased, in the group CAD compared to those without (p < 0.05). These results suggest that possession of the 4G/4G PAI-1 promoter genotype is a risk factor for the development of CAD in subjects with NIDDM.

  19. TAP1 alleles in insulin-dependent diabetes mellitus: a newly defined centromeric boundary of disease susceptibility.

    PubMed Central

    Jackson, D G; Capra, J D

    1993-01-01

    It has been previously demonstrated that individuals with certain DR alleles have an increased relative risk of developing insulin-dependent diabetes mellitus (IDDM). The disease association is even stronger with certain DQ alleles but there is little association with DP providing a boundary of disease association to the 430 kb between DQ and DP. The recently described TAP (transporter associated with antigen processing) genes have been mapped approximately midway between DP and DQ. Therefore, it was of interest to determine if any TAP alleles were associated with IDDM. In addition to the alleles of TAP1 that have been described, others were identified during this study. Diabetics and normal controls were screened for TAP1 using single-stranded conformational polymorphism and relative risk was determined. In the same population group we have studied extensively in the past, we found a higher association of a TAP1 allele with IDDM than with any single HLA-DP allele but the risk was lower than with HLA-DQB1*0302. These data provide new limits for IDDM susceptibility to the 190-kb interval between TAP1 and HLA-DQB1. PMID:8248212

  20. Hypoglycemia associated hospitalizations in a population with a high prevalence of non-insulin-dependent diabetes mellitus.

    PubMed

    Sugarman, J R

    1991-11-01

    In order to evaluate the rates, causes, and clinical features of hospitalizations associated with hypoglycemia in a population with a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM), a retrospective analysis of medical records was conducted in a multi-hospital primary care system on the Navajo Indian Reservation. During an estimated 26,125 person-years of observation among diabetic patients, there were 126 hypoglycemia-associated admissions related to diabetes among 109 diabetic patients, yielding a hospitalization rate of 4.7 per 1000 person-years (95% CI 4.1-5.7). Using estimates of drug utilization based on a defined daily dose, hospitalization rates were 5.8 per 1000 PY (95% CI 4.4-7.6) for chlorpropamide, 16.0 per 1000 PY (95% CI 9.5-26.9) for glyburide, and 9.1 per 1000 PY (95% CI 6.9-11.9) for insulin. After stratification by age, the relative risk for hypoglycemia-associated hospitalization among patients prescribed glyburide compared to those prescribed chlorpropamide was 2.8 (95% CI 1.6-4.9). Hypoglycemia-associated hospitalizations were relatively common among patients with NIDDM, particularly among those treated with glyburide. PMID:1756685

  1. Vaccination of non-obese diabetic mice with a fragment of peptide P277 attenuates insulin-dependent diabetes mellitus.

    PubMed

    Ma, Yan-Jun; Lu, Yong; Hou, Jing; Dong, Yuan-Kai; Du, Ming-Zhu; Xing, Yun; Ge, Chi-Yu; Xu, Mao-Lei; Jin, Liang; Cao, Rong-Yue; Li, Tai-Ming; Wu, Jie; Liu, Jing-Jing

    2011-09-01

    P277 is a peptide derived from the HSP60 regions, have potent immunological effect on insulin-dependent diabetes mellitus (IDDM) and its phase III clinical trials are currently under investigation. However, we recently discovered a positive correlation between anti-P277 autoantibodies and the presence of endothelial cells damage in inducing vascular leak syndrome. Therefore, the aim of our study was to demonstrate the critical peptide epitope of P277 to IDDM and to highlight the effects of this peptide therapy on inflammation of the islets. Groups of 4-week old female non-obese diabetic (NOD) mice were immunized one time every three weeks for three times with a residue of P277, showing a significant effect of down-regulating immunity to P277 protein and preventing the development of IDDM. Immunologic results including the suppression of T-cell proliferation, the increase of interleukin-10 (IL-10) production and reduction of interferon-γ (IFN-γ) production caused immune tolerance to P277. Hence, a functional role of the key epitope in P277 peptide capable of preventing IDDM is suggested, which could be modified to develop a novel safe and effective peptide vaccine against IDDM by reconstructing P277 in the further studies.

  2. Determination of insulin in humans with insulin-dependent diabetes mellitus patients by HPLC with diode array detection.

    PubMed

    Yilmaz, Bilal; Kadioglu, Yucel; Capoglu, Ilyas

    2012-08-01

    A simple and reliable high-performance liquid chromatographic method with diode array detection has been developed and validated for the determination of insulin in human plasma. A good chromatographic separation was achieved on a C18 column with a mobile phase consisting of acetonitrile and 0.2M sodium sulfate (pH 2.4), 25:75 (v/v). Its flow rate was 1.2 mL/min. Calibration curve was linear within the concentration range of 0.15-25 µg/mL. Intra-day and inter-day relative standard deviations for insulin in human plasma were less than 6.3 and 8.5%, respectively. The limits of detection and quantification of insulin were 0.10 and 0.15 µg/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of insulin in eight insulin-dependent diabetes mellitus patients after subcutaneous injection of 25 IU of Actrapid HM.

  3. Tumor necrosis factor-alpha allele 2 shows an association with insulin-dependent diabetes mellitus in Latvians.

    PubMed

    Shtauvere-Brameus, A; Dabadghao, P; Rumba, I; Sanjeevi, C B

    2002-04-01

    Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA-DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF-alpha) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF-alpha production and susceptibility to autoimmune and infectious diseases. Ninety-two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age- and sex-matched healthy controls were analyzed for the frequency of TNF-alpha alleles to test the hypothesis that TNF-alpha is associated with IDDM. We found that TNF-alpha microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF-alpha allele 2 with IDDM showed that both are independently associated with the disease.

  4. A pilot study of support and education groups for college students with insulin-dependent diabetes mellitus.

    PubMed

    Shalom, R

    1991-05-01

    College students with insulin-dependent diabetes mellitus often ignore the care of their illness. Faced with managing this illness independently for the first time, they lack the knowledge and experience to do so effectively. Their need to establish autonomy often prevents them from seeking the advice of health professionals. In view of this, the author undertook a pilot study to investigate the role of a peer support group on a college campus as a means of improving the diabetic students' management of their illness. Three closed-membership groups met for 10 weekly sessions. Hemoglobin A1c (the measure of average blood sugar over the preceding 3-month interval) determinations prior to participation in the group ranged from 4.0 to 11.7, with a mean of 8.16; after participation in the group, the mean hemoglobin A1c levels of group members dropped to 6.10 (p less than .001). (Hemoglobin A1c measures lower than 6.2 reflect physiologic blood sugar measures of someone without diabetes.) These results suggest that the peer-group approach may be a viable way to improve the metabolic control of young adults with diabetes at the time in their lives when they are learning to manage their illness independently. PMID:2033172

  5. Will older sedentary people with non-insulin-dependent diabetes mellitus start exercising? A health promotion model.

    PubMed

    Samaras, K; Ashwell, S; Mackintosh, A M; Fleury, A C; Campbell, L V; Chisholm, D J

    1997-08-01

    Exercise and diet are the cornerstones of management of non-insulin-dependent diabetes mellitus (NIDDM). Many older people have difficulty in exercising, missing benefits on glycaemic control, weight, cardiac disease and mood. We report the outcomes of a 6 month structured exercise and support programme based on a health promotion model, on physical activity, glycaemic control and parameters of cardiovascular risk in non-exercisers, compared with standard outpatient clinic education. A total of 26 non-exercising patients were randomised to an intervention or control group (ten men, 16 women; mean age (+/- S.D.) 60 +/- 8 years). Programme participation was not associated with any significant increase in activity. Glycated hemoglobin (HbAtc) levels tended to stabilise in the intervention group during the 6 month programme and to deteriorate in the control group (P = 0.03); by 12 months HbA1C levels deteriorated to a similar level in both. Programme participation did not cause significant change in anthropometric or metabolic parameters. Examining the cohort as a whole, increased activity over 6 months was associated with improvements in weight, body mass index (BMI), body fat and fasting insulin. Activity increases over 12 months were associated with improvements in weight and BMI. These changes could not be attributed to changes in energy intake or dietary composition. We conclude that while exercise can benefit older people with NIDDM, a programme based on a model of health promotion was not effective in increasing physical activity.

  6. Mechanisms underlying the protective effects of myricetin and quercetin following oxygen/glucose deprivation-induced cell swelling and the reduction in glutamate uptake in glial cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    C6 glial cells were exposed to oxygen-glucose deprivation (OGD) in cell culture for 5 hr and cell swelling was determined 90 min after the end of OGD. The OGD-induced increase in swelling was significantly blocked by the two flavonoids studied, quercetin and myricetin. The OGD-induced increase in ...

  7. Yoga: As an adjunct therapy to trim down the Ayurvedic drug requirement in non insulin-dependent diabetes mellitus

    PubMed Central

    Sharma, Rohit; Amin, Hetal; Prajapati, P.K.

    2014-01-01

    Introduction: In spite of a large number of drugs showing anti-hyperglycemic activities, none of them have been successful in complete management of diabetes mellitus (DM). Yoga and Ayurveda are the two schools of thought in India, which have a history of curing diseases since thousands of years. Yogic techniques and Ayurvedic herbs have proven their anti-diabetic potential without inducing untoward effects. The present study combines Ayurvedic medication with Yoga techniques as a new approach toward healing DM. Aims and Objectives: To assess the effect of Yoga therapy in the management of non insulin-dependent DM (NIDDM) and to decrease the oral drug dose requirement of guḍūcī ghana Tablet. Materials and Methods: Thirty known NIDDM patients of both genders, who were on guḍūcī ghana (solidified aqueous extract of Tinospora cordifolia (Willd.) Miers.) tablets from past 2 months as Ayurvedic remedy for DM were selected. Along with guḍūcī ghana administration, the subjects were instructed to follow Yogic procedures including Āsanas, prāṇāyāma, and śuddhi kriyās. The study was conducted for 8 weeks, wherein fasting blood sugar (FBS) and postprandial blood sugar (PPBS) levels along with relief in sign and symptoms were assessed at every 2 weeks intervals, and according to relief in sign and symptoms, tapering of drug dosage was carried out. The obtained data were analyzed statistically by applying paired t-test. Results and Conclusion: The results obtained were promising as the relief in diabetic symptomatology was highly significant in terms of P value. 80.83% reduction in dose of guḍūcī ghana tablets and 7.85% and 8.78% fall in FBS and PPBS levels, respectively, after the complete course of treatment. The obtained P value showed highly significant results. PMID:25593403

  8. Human Monoclonal Islet Cell Antibodies From a Patient with Insulin- Dependent Diabetes Mellitus Reveal Glutamate Decarboxylase as the Target Antigen

    NASA Astrophysics Data System (ADS)

    Richter, Wiltrud; Endl, Josef; Eiermann, Thomas H.; Brandt, Michael; Kientsch-Engel, Rosemarie; Thivolet, Charles; Jungfer, Herbert; Scherbaum, Werner A.

    1992-09-01

    The autoimmune phenomena associated with destruction of the β cell in pancreatic islets and development of type 1 (insulin-dependent) diabetes mellitus (IDDM) include circulating islet cell antibodies. We have immortalized peripheral blood lymphocytes from prediabetic individuals and patients with newly diagnosed IDDM by Epstein-Barr virus transformation. IgG-positive cells were selected by anti-human IgG-coupled magnetic beads and expanded in cell culture. Supernatants were screened for cytoplasmic islet cell antibodies using the conventional indirect immunofluorescence test on cryostat sections of human pancreas. Six islet cell-specific B-cell lines, originating from a patient with newly diagnosed IDDM, could be stabilized on a monoclonal level. All six monoclonal islet cell antibodies (MICA 1-6) were of the IgG class. None of the MICA reacted with human thyroid, adrenal gland, anterior pituitary, liver, lung, stomach, and intestine tissues but all six reacted with pancreatic islets of different mammalian species and, in addition, with neurons of rat cerebellar cortex. MICA 1-6 were shown to recognize four distinct antigenic epitopes in islets. Islet cell antibody-positive diabetic sera but not normal human sera blocked the binding of the monoclonal antibodies to their target epitopes. Immunoprecipitation of 35S-labeled human islet cell extracts revealed that a protein of identical size to the enzyme glutamate decarboxylase (EC 4.1.1.15) was a target of all MICA. Furthermore, antigen immunotrapped by the MICA from brain homogenates showed glutamate decarboxylase enzyme activity. MICA 1-6 therefore reveal glutamate decarboxylase as the predominant target antigen of cytoplasmic islet cell autoantibodies in a patient with newly diagnosed IDDM.

  9. Changing prevalence of retinopathy in newly diagnosed non-insulin dependent diabetes mellitus patients in Hong Kong.

    PubMed

    Wang, W Q; Ip, T P; Lam, K S

    1998-03-01

    In this retrospective study, the prevalence of chronic microangiopathic complications was determined in 474 Chinese patients with non-insulin dependent diabetes mellitus (NIDDM) who presented within 1 year of diagnosis to the diabetes clinic from January 1990 to December 1996. Mean age (+/- S.E.) was 53.6 (+/- 0.6) years. The overall prevalence of retinopathy was 21.9%. A significant increase was observed from 1990 to 1994 (P < 0.005), with the prevalence being 14.8, 13.0, 24.5, 32.3 and 35.4%, respectively, in consecutive years. A decreasing prevalence was seen from 1994 to 1996 (P < 0.001), being 8.2 and 7.4% in 1995 and 1996, respectively. A total of 95% of patients had nonproliferative retinopathy--proliferative retinopathy was found in 5% only. The overall prevalence of clinical nephropathy (proteinuria > 0.5 g/day) was 3.7%. Clinical neuropathy (increased vibration perception threshold) was found in 12.8% of patients. Patients with retinopathy and neuropathy were older (P < 0.0001 and P < 0.005, respectively) than those without the complications and systolic hypertension was more prevalent in patients with retinopathy (P < 0.05). In conclusion, a high prevalence of diabetic microangiopathic complications, especially of retinopathy, is present in newly diagnosed NIDDM patients in our population. It remains to be determined whether the changing prevalence of retinopathy at diagnosis bears any relationship to the increasing public awareness of diabetes and its complications in Hong Kong in recent years. Examination for chronic microangiopathic complications should be carried out in all newly diagnosed NIDDM patients.

  10. Association between a polymorphism of the 65K-glutamate decarboxylase gene and insulin-dependent diabetes mellitus

    SciTech Connect

    Kure, S.; Aoki, Y.; Narisawa, K.

    1994-09-01

    Autoimmunity against 65K-glutamate decarboxylase (GAD65), one of two forms of the {gamma}-aminobutyric acid-synthesizing enzyme, is commonly associated with insulin-dependent diabetes mellitus (IDDM). To study the predisposing effect of the GAD65 genotype on IDDM, we performed a case-control study screening an association between a newly-identified GAD65 polymorphism and IDDM in the Japanese population. The identified polymorphism was a microsatellite that was located in an intron near the 3{prime} end of the GAD65 gene consisting of variable numbers of a (CA)-dinucleotide repeat. We amplified the polymorphic region by polymerase chain reaction, and, for each individual in the control group (n=254) and the IDDM group (n=108), determined a pair of (CA)-repeat numbers, each number derived from one or the other of their alleles. In both groups we found 13 allelic variants with different repeat numbers, ranging from 19 to 31 repeats of the (CA) dinucleotide. The most frequent allelic variant in the IDDM group was 20 repeats; (CA){sub 20}. A higher frequency of a genotype containing two (CA){sub 20} alleles (p=0.005) was observed in the IDDM group (41.7%) compared with the control group (26.8%). Odds ratio (a 95% confidence interval) for a heterozygote or a homozygote of (CA){sub 20} versus a subject without (CA){sub 20} was 1.2 (0.66-2.25) and 2.23 (1.18-4.21), respectively. No significant association was observed between the (CA)-repeat genotype and the appearance of anti-GAD antibodies in the patients whose duration of the diabetes was less than 4 years (n=35). Therefore, genetic variations in GAD65 appears to be associated with IDDM susceptibility.

  11. Novel therapy for insulin-dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells.

    PubMed

    Dave, S D; Vanikar, A V; Trivedi, H L; Thakkar, U G; Gopal, S C; Chandra, T

    2015-02-01

    Insulin-dependent diabetes mellitus (IDDM) is a metabolic disease usually resulting from autoimmune-mediated β-cell destruction requiring lifetime exogenous insulin replacement. Mesenchymal stem cells (MSC) hold promising therapy. We present our experience of treating IDDM with co-infusion of in vitro autologous adipose tissue-derived MSC-differentiated insulin-secreting cells (ISC) with hematopoietic stem cells (HSC). This was an Institutional Review Board approved prospective non-randomized open-labeled clinical trial after informed consent from ten patients. ISC were differentiated from autologous adipose tissue-derived MSC and were infused with bone marrow-derived HSC in portal, thymic circulation by mini-laparotomy and in subcutaneous circulation. Patients were monitored for blood sugar levels, serum C-peptide levels, glycosylated hemoglobin (Hb1Ac) and glutamic acid decarboxylase (GAD) antibodies. Insulin administration was made on sliding scale with an objective of maintaining FBS < 150 mg/dL and PPBS around 200 mg/dL. Mean 3.34 mL cell inoculums with 5.25 × 10(4) cells/μL were infused. No untoward effects were observed. Over a mean follow-up of 31.71 months, mean serum C-peptide of 0.22 ng/mL before infusion had sustained rise of 0.92 ng/mL with decreased exogenous insulin requirement from 63.9 international units (IU)/day to 38.6 IU/day. Improvement in mean Hb1Ac was observed from 10.99 to 6.72%. Mean GAD antibodies were positive in all patients with mean of 331.10 IU/mL, which decreased to mean of 123 IU/mL. Co-infusion of autologous ISC with HSC represents a viable novel therapeutic option for IDDM.

  12. Detection of autoantibodies to the pancreatic islet heat shock protein 60 in insulin-dependent diabetes mellitus.

    PubMed

    Ozawa, Y; Kasuga, A; Nomaguchi, H; Maruyama, T; Kasatani, T; Shimada, A; Takei, I; Miyazaki, J; Saruta, T

    1996-08-01

    Autoantibodies against heat shock protein (hsp) 60 have been reported to be detected in sera of non-obese diabetic mice, in an experimental model of IDDM. However, there are only a few studies which have examined IDDM patients for antibodies against mammalian hsp60. We produced murine hsp60 derived from pancreatic beta cells which has high homology to human hsp60 and examined antibodies against the hsp60 in IDDM patients using an enzyme-linked immunosorbent assay. We extended the analysis to patients with other immune-mediated diseases and non-insulin-dependent diabetes mellitus (NIDDM). Positive sera for hsp60 antibody were more frequently detected in 13 out of 84 IDDM (15.5%) and 5 out of 25 rheumatoid