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Sample records for increases glucose metabolism

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

    PubMed

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

    2004-01-01

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

  2. MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity

    PubMed Central

    Vaitheesvaran, B.; LeRoith, D.

    2014-01-01

    Aims/hypothesis Recent work has shown that there can be significant differences when glucose disposal is assessed for high-fat induced insulin resistance by static clamp methods vs dynamic assessment during a stable isotope i.p. glucose tolerance test. MKR mice, though lean, have severe insulin resistance and decreased muscle fatty acid oxidation. Our goal was to assess dynamic vs static glucose disposal in MKR mice, and to correlate glucose disposal and muscle–adipose–liver flux interactions with metabolic flexibility (indirect calorimetry) and muscle characteristics. Methods Stable isotope flux phenotyping was performed using [6,6-2H2]glucose, [U-13C6]glucose and [2-13C]glycerol. Muscle triacylglycerol (TAG) and diacylglycerol (DAG) content was assessed by thin layer chromatography, and histological determination of fibre type and cytochrome c activity performed. Metabolic flexibility was assessed by indirect calorimetry. Results Indirect calorimetry showed that MKR mice used more glucose than FVB/N mice during fasting (respiratory exchange ratio [RER] 0.88 vs 0.77, respectively). Compared with FVB/N mice, MKR mice had faster dynamic glucose disposal, despite increased whole-muscle DAG and TAG, and similar hepatic glucose production with higher fasting insulin and unchanged basal glucose. Fed MKR muscle had more glycogen, and increased levels of GLUT1 and GLUT4 than FVB/N muscle. Histology indicated that MKR soleus had mildly decreased cytochrome c activity overall and more type II (glycolytic) fibres compared with that in FVB/N mice. Conclusions/interpretation MKR muscle adapts to using glucose, with more type II fibres present in red muscle. Fasting RER is elevated and glucose disposal during an i.p. glucose tolerance test is accelerated despite increased muscle DAG and TAG. Metabolic inflexibility may result from the compensatory use of fuel that can be best utilised for energy requirements; static vs dynamic glucose disposal assessments may measure

  3. DMH1 increases glucose metabolism through activating Akt in L6 rat skeletal muscle cells.

    PubMed

    Xie, Xin; Xu, Xiao-Ming; Li, Na; Zhang, Yong-Hui; Zhao, Yu; Ma, Chun-Yan; Dong, De-Li

    2014-01-01

    DMH1(4-[6-(4-Isopropoxyphenyl)pyrazolo [1,5-a]pyrimidin-3-yl] quinoline) is a compound C analogue with the structural modifications at the 3- and 6-positions in pyrazolo[1,5-a]pyrimidine backbone. Compound C was reported to inhibit both AMPK and Akt. Our preliminary work found that DMH1 activated Akt. Since Akt was involved in glucose metabolism, we aimed to identify the effects of DMH1 on glucose metabolism in L6 rat muscle cells and the potential mechanism. Results showed that DMH1 increased lactic acid release and glucose consumption in L6 rat muscle cells in a dose-dependent manner. DMH1 activated Akt in L6 cells. Akt inhibitor inhibited DMH1-induced Akt activation and DMH1-induced increases of glucose uptake and consumption. DMH1 had no cytotoxicity in L6 cells, but inhibited mitochondrial function and reduced ATP production. DMH1 showed no effect on AMPK, but in the presence of Akt inhibitor, DMH1 significantly activated AMPK. Compound C inhibited DMH1-induced Akt activation in L6 cells. Compound C inhibited DMH1-induced increase of glucose uptake, consumption and lactic acid release in L6 cells. DMH1 inhibited PP2A activity, and PP2A activator forskolin reversed DMH1-induced Akt activation. We concluded that DMH1 increased glucose metabolism through activating Akt and DMH1 activated Akt through inhibiting PP2A activity in L6 rat muscle cells. In view of the analogue structure of DMH1 and compound C and the contrasting effects of DMH1 and compound C on Akt, the present study provides a novel leading chemical structure targeting Akt with potential use for regulating glucose metabolism.

  4. Metabolic alterations in the human erythrocyte produced by increases in glucose concentration

    PubMed Central

    Travis, Susan F.; Morrison, Anthony D.; Clements, Rex S.; Winegrad, Albert I.; Oski, Frank A.

    1971-01-01

    Human erythrocytes incubated in medium containing 50 mM glucose have increased intracellular sorbitol and fructose concentrations as compared with samples incubated with 5 mM glucose. Increased medium glucose concentration did not significantly alter total glucose consumption or lactate production. However, the intracellular lactate:pyruvate ratio rose, the concentrations of fructose diphosphate, and triose phosphates increased, and the 2,3-diphosphoglycerate concentration fell. [14C]O2 production from glucose-1-14C also increased with increased medium glucose concentration. These changes are believed to reflect changes in the redox states of the diphosphopyridine nucleotide/reduced form of diphosphopyridine nucleotide (NAD/NADH) and nicotinamide—adenine dinucleotide phosphate/reduced form of nicotinamide—adenine dinucleotide phosphate (NADP/NADPH) couples resulting from increased activity of the polyol pathway. Addition of pyruvate to the incubation media prevented these changes. These studies illustrate that an increase in the red cell's normal substrate, glucose, can produce changes in red cell metabolism. PMID:4398937

  5. Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle

    NASA Technical Reports Server (NTRS)

    Henriksen, Erik J.; Tischler, Marc E.; Johnson, David G.

    1986-01-01

    Hind leg muscles of female rats were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D(U-C-14) glucose, release of lactate and pyruvate, incorporation of D-(U-C-14) glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-(1,2-H-3) glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased, by 50 percent the concentration of insuling receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.

  6. Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle

    NASA Technical Reports Server (NTRS)

    Henriksen, Erik J.; Tischler, Marc E.; Johnson, David G.

    1986-01-01

    Hind leg muscles of female rats were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D(U-C-14) glucose, release of lactate and pyruvate, incorporation of D-(U-C-14) glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-(1,2-H-3) glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased, by 50 percent the concentration of insuling receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.

  7. 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

  8. Methylglyoxal alters glucose metabolism and increases AGEs content in C6 glioma cells.

    PubMed

    Hansen, Fernanda; de Souza, Daniela Fraga; Silveira, Simone da Luz; Hoefel, Ana Lúcia; Fontoura, Júlia Bijoldo; Tramontina, Ana Carolina; Bobermin, Larissa Daniele; Leite, Marina Concli; Perry, Marcos Luiz Santos; Gonçalves, Carlos Alberto

    2012-12-01

    Methylglyoxal is a dicarbonyl compound that is physiologically produced by enzymatic and non-enzymatic reactions. It can lead to cytotoxicity, which is mainly related to Advanced Glycation End Products (AGEs) formation. Methylglyoxal and AGEs are involved in the pathogenesis of Neurodegenerative Diseases (ND) and, in these situations, can cause the impairment of energetic metabolism. Astroglial cells play critical roles in brain metabolism and the appropriate functioning of astrocytes is essential for the survival and function of neurons. However, there are only a few studies evaluating the effect of methylglyoxal on astroglial cells. The aim of this study was to evaluate the effect of methylglyoxal exposure, over short (1 and 3 h) and long term (24 h) periods, on glucose, glycine and lactate metabolism in C6 glioma cells, as well as investigate the glyoxalase system and AGEs formation. Glucose uptake and glucose oxidation to CO(2) increased in 1 h and the conversion of glucose to lipids increased at 3 h. In addition, glycine oxidation to CO(2) and conversion of glycine to lipids increased at 1 h, whereas the incorporation of glycine in proteins decreased at 1 and 3 h. Methylglyoxal decreased glyoxalase I and II activities and increased AGEs content within 24 h. Lactate oxidation and lactate levels were not modified by methylglyoxal exposure. These data provide evidence that methylglyoxal may impair glucose metabolism and can affect glyoxalase activity. In periods of increased methylglyoxal exposure, such alterations could be exacerbated, leading to further increases in intracellular methylglyoxal and AGEs, and therefore triggering and/or worsening ND.

  9. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster

    PubMed Central

    Wagner, Anika E.; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-01-01

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies. PMID:26375250

  10. Epigallocatechin gallate affects glucose metabolism and increases fitness and lifespan in Drosophila melanogaster.

    PubMed

    Wagner, Anika E; Piegholdt, Stefanie; Rabe, Doerte; Baenas, Nieves; Schloesser, Anke; Eggersdorfer, Manfred; Stocker, Achim; Rimbach, Gerald

    2015-10-13

    In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies.

  11. Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle

    PubMed Central

    2014-01-01

    Background Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. Methods C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Results Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. Conclusions Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders. PMID:25114710

  12. Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle.

    PubMed

    Tsutsumi, Rie; Yoshida, Tomomi; Nii, Yoshitaka; Okahisa, Naoki; Iwata, Shinya; Tsukayama, Masao; Hashimoto, Rei; Taniguchi, Yasuko; Sakaue, Hiroshi; Hosaka, Toshio; Shuto, Emi; Sakai, Tohru

    2014-01-01

    Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.

  13. Increased adipose tissue heme levels and exportation are associated with altered systemic glucose metabolism.

    PubMed

    Moreno-Navarrete, José María; Rodríguez, Amaia; Ortega, Francisco; Becerril, Sara; Sabater-Masdeu, Mònica; Latorre, Jessica; Ricart, Wifredo; Frühbeck, Gema; Fernández-Real, José Manuel

    2017-07-13

    Iron status is known to be associated with the physiology of adipose tissue (AT). We aimed to investigate AT heme and expression of heme exporter (FLVCR1) in association with obesity and type 2 diabetes (T2D). Substantial amounts of FLVCR1 mRNA and protein levels were detected in AT, being significantly increased in subjects with T2D, and positively correlated with fasting glucose, fasting triglycerides and with circulating markers of iron stores (serum ferritin, blood hemoglobin and hematocrit). In both visceral (VAT) and subcutaneous AT (SAT), increased heme levels were found in subjects with T2D. Reinforcing these associations, FLVCR1 mRNA levels were positively linked to fasting glucose in an independent cohort. Longitudianlly, the percent change of FLVCR1 positively correlated with the percent change in fasting glucose (r = 0.52, p = 0.03) after bariatric surgery-induced weight loss. High-fat diet-induced weight gain in rats did not result in significant changes in AT Flvcr1 mRNA but, remarkably, the expression of this gene positively correlated with fasting glucose and negatively with insulin sensitivity (QUICKI). Altogether, these findings showed a direct association between FLVCR1 mRNA levels and hyperglycemia, suggesting that increased adipose tissue heme exportation might disrupt, or is the consequence of, impaired systemic glucose metabolism during the progression to T2D.

  14. The role of α1-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation.

    PubMed

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

    2017-04-01

    The role of α1-adrenergic receptors (α1-ARs) and their subtypes in metabolism is not well known. Most previous studies were performed before the advent of transgenic mouse models and utilized transformed cell lines and poorly selective antagonists. We have now studied the metabolic regulation of the α1A- and α1B-AR subtypes in vivo using knock-out (KO) and transgenic mice that express a constitutively active mutant (CAM) form of the receptor, assessing subtype-selective functions. CAM mice increased glucose tolerance while KO mice display impaired glucose tolerance. CAM mice increased while KO decreased glucose uptake into white fat tissue and skeletal muscle with the CAM α1A-AR showing selective glucose uptake into the heart. Using indirect calorimetry, both CAM mice demonstrated increased whole body fatty acid oxidation, while KO mice preferentially oxidized carbohydrate. CAM α1A-AR mice displayed significantly decreased fasting plasma triglycerides and glucose levels while α1A-AR KO displayed increased levels of triglycerides and glucose. Both CAM mice displayed increased plasma levels of leptin while KO mice decreased leptin levels. Most metabolic effects were more efficacious with the α1A-AR subtype. Our results suggest that stimulation of α1-ARs results in a favorable metabolic profile of increased glucose tolerance, cardiac glucose uptake, leptin secretion and increased whole body lipid metabolism that may contribute to its previously recognized cardioprotective and neuroprotective benefits.

  15. Glucose metabolism and hyperglycemia.

    PubMed

    Giugliano, Dario; Ceriello, Antonio; Esposito, Katherine

    2008-01-01

    Islet dysfunction and peripheral insulin resistance are both present in type 2 diabetes and are both necessary for the development of hyperglycemia. In both type 1 and type 2 diabetes, large, prospective clinical studies have shown a strong relation between time-averaged mean values of glycemia, measured as glycated hemoglobin (HbA1c), and vascular diabetic complications. These studies are the basis for the American Diabetes Association's current recommended treatment goal that HbA1c should be <7%. The measurement of the HbA1c concentration is considered the gold standard for assessing long-term glycemia; however, it does not reveal any information on the extent or frequency of blood glucose excursions, but provides an overall mean value only. Postprandial hyperglycemia occurs frequently in patients with diabetes receiving active treatment and can occur even when metabolic control is apparently good. Interventional studies indicate that reducing postmeal glucose excursions is as important as controlling fasting plasma glucose in persons with diabetes and impaired glucose tolerance. Evidence exists for a causal relation between postmeal glucose increases and microvascular and macrovascular outcomes; therefore, it is not surprising that treatment with different compounds that have specific effects on postprandial glucose regulation is accompanied by a significant improvement of many pathways supposed to be involved in diabetic complications, including oxidative stress, endothelial dysfunction, inflammation, and nuclear factor-kappaB activation. The goal of therapy should be to achieve glycemic status as near to normal as safely possible in all 3 components of glycemic control: HbA1c, fasting glucose, and postmeal glucose peak.

  16. Reduced cerebral glucose metabolism and increased brain capillary permeability following high-dose methotrexate chemotherapy: a positron emission tomographic study

    SciTech Connect

    Phillips, P.C.; Dhawan, V.; Strother, S.C.; Sidtis, J.J.; Evans, A.C.; Allen, J.C.; Rottenberg, D.A.

    1987-01-01

    Regional glucose metabolic rate constants and blood-to-brain transport of rubidium were estimated using positron emission tomography in an adolescent patient with a brain tumor, before and after chemotherapy with intravenous high-dose methotrexate. Widespread depression of cerebral glucose metabolism was apparent 24 hours after drug administration, which may reflect reduced glucose phosphorylation, and the influx rate constant for /sup 82/Rb was increased, indicating a drug-induced alteration in blood-brain barrier function. Associated changes in neuropsychological performance, electroencephalogram, and plasma amino acid concentration were identified in the absence of evidence of systemic methotrexate toxicity, suggesting primary methotrexate neurotoxicity.

  17. Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells

    SciTech Connect

    Bolado-Carrancio, A.; Riancho, J.A.; Sainz, J.; Rodríguez-Rey, J.C.

    2014-04-04

    Highlights: • NR5A2 expression in C2C12 is associated with myotube differentiation. • DLPC induces an increase in GLUT4 levels and glucose uptake in C2C12 myotubes. • In high glucose conditions the activation of NR5A2 inhibits fatty acids oxidation. - Abstract: NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.

  18. Increasing adipocyte lipoprotein lipase improves glucose metabolism in high fat diet-induced obesity.

    PubMed

    Walton, R Grace; Zhu, Beibei; Unal, Resat; Spencer, Michael; Sunkara, Manjula; Morris, Andrew J; Charnigo, Richard; Katz, Wendy S; Daugherty, Alan; Howatt, Deborah A; Kern, Philip A; Finlin, Brian S

    2015-05-01

    Lipid accumulation in liver and skeletal muscle contributes to co-morbidities associated with diabetes and obesity. We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage. These mice (Adipoq-LPL) have improved glucose and insulin tolerance as well as increased energy expenditure when challenged with a high fat diet (HFD). To identify the mechanism(s) involved, we determined whether the Adipoq-LPL mice diverted dietary lipid to adipose tissue to reduce peripheral lipotoxicity, but we found no evidence for this. Instead, characterization of the adipose tissue of the male mice after HFD challenge revealed that the mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ) and a number of PPARγ-regulated genes were higher in the epididymal fat pads of Adipoq-LPL mice than control mice. This included adiponectin, whose mRNA levels were increased, leading to increased adiponectin serum levels in the Adipoq-LPL mice. In many respects, the adipose phenotype of these animals resembles thiazolidinedione treatment except for one important difference, the Adipoq-LPL mice did not gain more fat mass on HFD than control mice and did not have increased expression of genes in adipose such as glycerol kinase, which are induced by high affinity PPAR agonists. Rather, there was selective induction of PPARγ-regulated genes such as adiponectin in the adipose of the Adipoq-LPL mice, suggesting that increasing adipose tissue LPL improves glucose metabolism in diet-induced obesity by improving the adipose tissue phenotype. Adipoq-LPL mice also have increased energy expenditure.

  19. Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

    PubMed

    Chukwuma, Chika Ifeanyi; Mopuri, Ramgopal; Nagiah, Savania; Chuturgoon, Anil Amichund; Islam, Md Shahidul

    2017-08-02

    Studies have reported that erythritol, a low or non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1 g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

  20. Increased glucose metabolism and alpha-glucosidase inhibition in Cordyceps militaris water extract-treated HepG2 cells

    PubMed Central

    Kim, Dae Jung; Kang, Yun Hwan; Kim, Kyoung Kon; Kim, Tae Woo; Park, Jae Bong

    2017-01-01

    BACKGROUND/OBJECTIVES Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism. MATERIALS/METHODS Colorimetric assay kits were used to determine the glucokinase (GK) and pyruvate dehydrogenase (PDH) activities, glucose uptake, and glycogen content. Either RT-PCR or western blot analysis was performed for quantitation of glucose transporter 2 (GLUT2), hepatocyte nuclear factor 1 alpha (HNF-1α), phosphatidylinositol 3-kinase (PI3k), protein kinase B (Akt), phosphorylated AMP-activated protein kinase (pAMPK), phosphoenolpyruvate carboxykinase, GK, PDH, and glycogen synthase kinase 3 beta (GSK-3β) expression levels. The α-glucosidase inhibitory activities of acarbose and CMW were evaluated by absorbance measurement. RESULTS CMW induced glucose uptake in HepG2 cells by increasing GLUT2 through HNF-1α expression stimulation. Glucose in the cells increased the CMW-induced phosphorylation of AMPK. In turn, glycolysis was stimulated, and glyconeogenesis was inhibited. Furthermore, by studying the mechanism of action of PI3k, Akt, and GSK-3β, and measuring glycogen content, the study confirmed that the glucose was stored in the liver as glycogen. Finally, CMW resulted in a higher level of α-glucosidase inhibitory activity than that from acarbose. CONCLUSION CMW induced the uptake of glucose into HepG2 cells, as well, it induced metabolism of the absorbed glucose. It is concluded that CMW is a candidate or potential use in diabetes prevention and treatment. PMID:28584574

  1. Increased glucose metabolism and alpha-glucosidase inhibition in Cordyceps militaris water extract-treated HepG2 cells.

    PubMed

    Kim, Dae Jung; Kang, Yun Hwan; Kim, Kyoung Kon; Kim, Tae Woo; Park, Jae Bong; Choe, Myeon

    2017-06-01

    Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism. Colorimetric assay kits were used to determine the glucokinase (GK) and pyruvate dehydrogenase (PDH) activities, glucose uptake, and glycogen content. Either RT-PCR or western blot analysis was performed for quantitation of glucose transporter 2 (GLUT2), hepatocyte nuclear factor 1 alpha (HNF-1α), phosphatidylinositol 3-kinase (PI3k), protein kinase B (Akt), phosphorylated AMP-activated protein kinase (pAMPK), phosphoenolpyruvate carboxykinase, GK, PDH, and glycogen synthase kinase 3 beta (GSK-3β) expression levels. The α-glucosidase inhibitory activities of acarbose and CMW were evaluated by absorbance measurement. CMW induced glucose uptake in HepG2 cells by increasing GLUT2 through HNF-1α expression stimulation. Glucose in the cells increased the CMW-induced phosphorylation of AMPK. In turn, glycolysis was stimulated, and glyconeogenesis was inhibited. Furthermore, by studying the mechanism of action of PI3k, Akt, and GSK-3β, and measuring glycogen content, the study confirmed that the glucose was stored in the liver as glycogen. Finally, CMW resulted in a higher level of α-glucosidase inhibitory activity than that from acarbose. CMW induced the uptake of glucose into HepG2 cells, as well, it induced metabolism of the absorbed glucose. It is concluded that CMW is a candidate or potential use in diabetes prevention and treatment.

  2. Simultaneous Voltammetric Measurements of Glucose and Dopamine Demonstrate the Coupling of Glucose Availability with Increased Metabolic Demand in the Rat Striatum.

    PubMed

    Smith, Samantha K; Lee, Christie A; Dausch, Matthew E; Horman, Brian M; Patisaul, Heather B; McCarty, Gregory S; Sombers, Leslie A

    2017-02-15

    Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain. This work evaluates several waveforms to enable the first simultaneous detection of endogenous glucose and dopamine at single recording sites. These molecules, one electroactive and one nonelectroactive, were found to fluctuate in the dorsal striatum in response to electrical stimulation of the midbrain and systemic infusion of cocaine/raclopride. The data reveal the second-by-second dynamics of these species in a striatal microenvironment, and directly demonstrate the coupling of glucose availability with increased metabolic demand. This work provides a foundation that will enable detailed investigation of local mechanisms that regulate the coupling of cerebral blood flow with metabolic demand under normal conditions, and in animal studies of drug abuse and addiction.

  3. Cardiac energy dependence on glucose increases metabolites related to glutathione and activates metabolic genes controlled by mechanistic target of rapamycin.

    PubMed

    Schisler, Jonathan C; Grevengoed, Trisha J; Pascual, Florencia; Cooper, Daniel E; Ellis, Jessica M; Paul, David S; Willis, Monte S; Patterson, Cam; Jia, Wei; Coleman, Rosalind A

    2015-02-24

    Long chain acyl-CoA synthetases (ACSL) catalyze long-chain fatty acids (FA) conversion to acyl-CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1(H-/-)) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Metabolomics analysis identified 60 metabolites altered in Acsl1(H-/-) hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1(H-/-) hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1(H-/-) mice increased expression of several Hif1α-responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid-responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. The switch from FA to glucose use causes mTOR-dependent alterations in cardiac metabolism. We identified cardiac mTOR-regulated genes not previously identified in other cellular models, suggesting heart-specific mTOR signaling. Increased glucose use also changed glutathione-related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  4. Cardiac Energy Dependence on Glucose Increases Metabolites Related to Glutathione and Activates Metabolic Genes Controlled by Mechanistic Target of Rapamycin

    PubMed Central

    Schisler, Jonathan C.; Grevengoed, Trisha J.; Pascual, Florencia; Cooper, Daniel E.; Ellis, Jessica M.; Paul, David S.; Willis, Monte S.; Patterson, Cam; Jia, Wei; Coleman, Rosalind A.

    2015-01-01

    Background Long chain acyl‐CoA synthetases (ACSL) catalyze long‐chain fatty acids (FA) conversion to acyl‐CoAs. Temporal ACSL1 inactivation in mouse hearts (Acsl1H−/−) impaired FA oxidation and dramatically increased glucose uptake, glucose oxidation, and mTOR activation, resulting in cardiac hypertrophy. We used unbiased metabolomics and gene expression analyses to elucidate the cardiac cellular response to increased glucose use in a genetic model of inactivated FA oxidation. Methods and Results Metabolomics analysis identified 60 metabolites altered in Acsl1H−/− hearts, including 6 related to glucose metabolism and 11 to cysteine and glutathione pathways. Concurrently, global cardiac transcriptional analysis revealed differential expression of 568 genes in Acsl1H−/− hearts, a subset of which we hypothesized were targets of mTOR; subsequently, we measured the transcriptional response of several genes after chronic mTOR inhibition via rapamycin treatment during the period in which cardiac hypertrophy develops. Hearts from Acsl1H−/− mice increased expression of several Hif1α‐responsive glycolytic genes regulated by mTOR; additionally, expression of Scl7a5, Gsta1/2, Gdf15, and amino acid‐responsive genes, Fgf21, Asns, Trib3, Mthfd2, were strikingly increased by mTOR activation. Conclusions The switch from FA to glucose use causes mTOR‐dependent alterations in cardiac metabolism. We identified cardiac mTOR‐regulated genes not previously identified in other cellular models, suggesting heart‐specific mTOR signaling. Increased glucose use also changed glutathione‐related pathways and compensation by mTOR. The hypertrophy, oxidative stress, and metabolic changes that occur within the heart when glucose supplants FA as a major energy source suggest that substrate switching to glucose is not entirely benign. PMID:25713290

  5. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    SciTech Connect

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Kojori, Eshan Shokri; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-¹⁸FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal.

  6. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    DOE PAGES

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; ...

    2015-02-18

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET-¹⁸FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared tomore » placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal.« less

  7. Alcohol Decreases Baseline Brain Glucose Metabolism More in Heavy Drinkers Than Controls But Has No Effect on Stimulation-Induced Metabolic Increases

    PubMed Central

    Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S.; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-18FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. PMID:25698759

  8. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

    PubMed

    Volkow, Nora D; Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal.

  9. Glucose metabolism and cardiac hypertrophy

    PubMed Central

    Kolwicz, Stephen C.; Tian, Rong

    2011-01-01

    The most notable change in the metabolic profile of hypertrophied hearts is an increased reliance on glucose with an overall reduced oxidative metabolism, i.e. a reappearance of the foetal metabolic pattern. In animal models, this change is attributed to the down-regulation of the transcriptional cascades promoting gene expression for fatty acid oxidation and mitochondrial oxidative phosphorylation in adult hearts. Impaired myocardial energetics in cardiac hypertrophy also triggers AMP-activated protein kinase (AMPK), leading to increased glucose uptake and glycolysis. Aside from increased reliance on glucose as an energy source, changes in other glucose metabolism pathways, e.g. the pentose phosphate pathway, the glucosamine biosynthesis pathway, and anaplerosis, are also noted in the hypertrophied hearts. Studies using transgenic mouse models and pharmacological compounds to mimic or counter the switch of substrate preference in cardiac hypertrophy have demonstrated that increased glucose metabolism in adult heart is not harmful and can be beneficial when it provides sufficient fuel for oxidative metabolism. However, improvement in the oxidative capacity and efficiency rather than the selection of the substrate is likely the ultimate goal for metabolic therapies. PMID:21502371

  10. Antihypertensive drugs and glucose metabolism

    PubMed Central

    Rizos, Christos V; Elisaf, Moses S

    2014-01-01

    Hypertension plays a major role in the development and progression of micro- and macrovascular disease. Moreover, increased blood pressure often coexists with additional cardiovascular risk factors such as insulin resistance. As a result the need for a comprehensive management of hypertensive patients is critical. However, the various antihypertensive drug categories have different effects on glucose metabolism. Indeed, angiotensin receptor blockers as well as angiotensin converting enzyme inhibitors have been associated with beneficial effects on glucose homeostasis. Calcium channel blockers (CCBs) have an overall neutral effect on glucose metabolism. However, some members of the CCBs class such as azelnidipine and manidipine have been shown to have advantageous effects on glucose homeostasis. On the other hand, diuretics and β-blockers have an overall disadvantageous effect on glucose metabolism. Of note, carvedilol as well as nebivolol seem to differentiate themselves from the rest of the β-blockers class, being more attractive options regarding their effect on glucose homeostasis. The adverse effects of some blood pressure lowering drugs on glucose metabolism may, to an extent, compromise their cardiovascular protective role. As a result the effects on glucose homeostasis of the various blood pressure lowering drugs should be taken into account when selecting an antihypertensive treatment, especially in patients which are at high risk for developing diabetes. PMID:25068013

  11. Increased interictal cerebral glucose metabolism in a cortical-subcortical network in drug naive patients with cryptogenic temporal lobe epilepsy.

    PubMed Central

    Franceschi, M; Lucignani, G; Del Sole, A; Grana, C; Bressi, S; Minicucci, F; Messa, C; Canevini, M P; Fazio, F

    1995-01-01

    Positron emission tomography with [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG) has been used to assess the pattern of cerebral metabolism in different types of epilepsies. However, PET with [18F]FDG has never been used to evaluate drug naive patients with cryptogenic temporal lobe epilepsy, in whom the mechanism of origin and diffusion of the epileptic discharge may differ from that underlying other epilepsies. In a group of patients with cryptogenic temporal lobe epilepsy, never treated with antiepileptic drugs, evidence has been found of significant interictal glucose hypermetabolism in a bilateral neural network including the temporal lobes, thalami, basal ganglia, and cingular cortices. The metabolism in these areas and frontal lateral cortex enables the correct classification of all patients with temporal lobe epilepsy and controls by discriminant function analysis. Other cortical areas--namely, frontal basal and lateral, temporal mesial, and cerebellar cortices--had bilateral increases of glucose metabolism ranging from 10 to 15% of normal controls, although lacking stringent statistical significance. This metabolic pattern could represent a pathophysiological state of hyperactivity predisposing to epileptic discharge generation or diffusion, or else a network of inhibitory circuits activated to prevent the diffusion of the epileptic discharge. PMID:7561924

  12. High Glucose-Induced PC12 Cell Death by Increasing Glutamate Production and Decreasing Methyl Group Metabolism

    PubMed Central

    Chen, Minjiang; Zheng, Hong; Wei, Tingting; Wang, Dan; Xia, Huanhuan; Zhao, Liangcai; Ji, Jiansong

    2016-01-01

    Objective. High glucose- (HG-) induced neuronal cell death is responsible for the development of diabetic neuropathy. However, the effect of HG on metabolism in neuronal cells is still unclear. Materials and Methods. The neural-crest derived PC12 cells were cultured for 72 h in the HG (75 mM) or control (25 mM) groups. We used NMR-based metabolomics to examine both intracellular and extracellular metabolic changes in HG-treated PC12 cells. Results. We found that the reduction in intracellular lactate may be due to excreting more lactate into the extracellular medium under HG condition. HG also induced the changes of other energy-related metabolites, such as an increased succinate and creatine phosphate. Our results also reveal that the synthesis of glutamate from the branched-chain amino acids (isoleucine and valine) may be enhanced under HG. Increased levels of intracellular alanine, phenylalanine, myoinositol, and choline were observed in HG-treated PC12 cells. In addition, HG-induced decreases in intracellular dimethylamine, dimethylglycine, and 3-methylhistidine may indicate a downregulation of methyl group metabolism. Conclusions. Our metabolomic results suggest that HG-induced neuronal cell death may be attributed to a series of metabolic changes, involving energy metabolism, amino acids metabolism, osmoregulation and membrane metabolism, and methyl group metabolism. PMID:27413747

  13. Bone Gla protein increases HIF-1alpha-dependent glucose metabolism and induces cartilage and vascular calcification.

    PubMed

    Idelevich, Anna; Rais, Yoach; Monsonego-Ornan, Efrat

    2011-09-01

    Bone Gla Protein (BGP, osteocalcin) is commonly present in the calcified vasculature and was recently shown as energy metabolism-regulating hormone. This study investigates the role of BGP in cartilage and vasculature mineralization. We established an in vitro BGP-overexpression model in chondrocytes (ATDC5) and vascular smooth muscle cells (MOVAS). BGP overexpression upregulated markers of chondrogenic differentiation and intensified staining for minerals. BGP overexpression enhanced glucose uptake and increased expression of glucose transporters and glycolysis enzymes while decreasing gluconeogenesis enzymes. Treatment with purified BGP activated insulin signaling pathway and upregulated genes of glucose transport and utilization. Both BGP overexpression and treatment with purified BGP resulted in stabilization of hypoxia-inducible factor 1α (HIF-1α) in chondrocytes and vascular smooth muscle cells, shown essential in mediating the direct metabolic effect of BGP. The in vivo model of 1,25(OH)(2)D(3)-induced vascular calcification in rats revealed a correlation between calcification, elevated BGP levels, and increased HIF-1α expression in aortas and bone growth plates. The in vivo introduction of BGP siRNA, coadministered with 1,25(OH)(2)D(3), prevented 1,25(OH)(2)D(3)-induced HIF-1α stabilization, and diminished osteochondrogenic differentiation and mineralization of aortas. This study demonstrates novel mechanism by which BGP locally shifts cells toward glycolytic breakdown of glucose, in a HIF-1α-dependent manner, and stimulates calcification of cartilage and vasculature.

  14. Ketamine promotes increased freezing behavior in rats with experimental PTSD without changing brain glucose metabolism or BDNF.

    PubMed

    Saur, Lisiani; Neves, Laura Tartari; Greggio, Samuel; Venturin, Gianina Teribele; Jeckel, Cristina Maria Moriguchi; Costa Da Costa, Jaderson; Bertoldi, Karine; Schallenberger, Bruna; Siqueira, Ionara Rodrigues; Mestriner, Régis Gemerasca; Xavier, Léder Leal

    2017-08-18

    Acute treatment with ketamine, an NMDA receptor antagonist, has been reported to be efficacious in treating depression. The goal of our study was to evaluate ketamine treatment in an animal model of another important psychiatric disease, post-traumatic stress disorder (PTSD). Fifty-eight male rats were initially divided into four groups: Control+Saline (CTRL+SAL), Control+Ketamine (CTRL+KET), PTSD+Saline (PTSD+SAL) and PTSD+Ketamine (PTSD+KET). To mimic PTSD we employed the inescapable footshock protocol. The PTSD animals were classified according to freezing behavior duration into "extreme behavioral response" (EBR) or "minimal behavioral response" (MBR). Afterwards, the glucose metabolism and BDNF were evaluated in the hippocampus, frontal cortex, and amygdala. Our results show that animals classified as EBR exhibited increased freezing behavior and that ketamine treatment further increased freezing duration. Glucose metabolism and BDNF levels showed no significant differences. These results suggest ketamine might aggravate PTSD symptoms and that this effect is unrelated to alterations in glucose metabolism or BDNF protein levels. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Effects of increased transaldolase activity on D-xylulose and D-glucose metabolism in Saccharomyces cerevisiae cell extracts.

    PubMed Central

    Senac, T; Hahn-Hägerdal, B

    1991-01-01

    In vitro metabolism of D-xylulose and D-glucose in extracts obtained from D-glucose- and D-xylulose-fermenting Saccharomyces cerevisiae cells was investigated with 10- and 100-fold-increased activity of the enzyme transaldolase (EC 2.2.1.2). The rate of sugar consumption was the same in most cases, whereas the rate of ethanol formation decreased with increased levels of transaldolase. The formation of glycerol, pentitols, and acetic acid was not dependent on added transaldolase but was dependent on the sugar used as the growth substrate and on the sugar used in the in vitro metabolism experiments. The carbon balance showed that the dissimilated carbon could not be accounted for in products when transaldolase was added. The concentration of D-fructose-1,6.-diphosphate in the extracts was not influenced by added transaldolase but was higher with D-xylulose than with D-glucose. Levels of pyruvate, comparable with the two substrates, decreased with increasing levels of transaldolase. Exogenously added transaldolase decreased D-sedoheptulose-7-phosphate levels when D-xylulose was the substrate. The results are discussed in relation to the dissimilation of carbon through the upper part of glycolysis and the pentose phosphate pathway. PMID:1831338

  16. Plasmid-encoded biosynthetic genes alleviate metabolic disadvantages while increasing glucose conversion to shikimate in an engineered Escherichia coli strain.

    PubMed

    Rodriguez, Alberto; Martínez, Juan A; Millard, Pierre; Gosset, Guillermo; Portais, Jean-Charles; Létisse, Fabien; Bolivar, Francisco

    2017-06-01

    Metabolic engineering strategies applied over the last two decades to produce shikimate (SA) in Escherichia coli have resulted in a battery of strains bearing many expression systems. However, the effects that these systems have on the host physiology and how they impact the production of SA are still not well understood. In this work we utilized an engineered E. coli strain to determine the consequences of carrying a vector that promotes SA production from glucose with a high-yield but that is also expected to impose a significant cellular burden. Kinetic comparisons in fermentors showed that instead of exerting a negative effect, the sole presence of the plasmid increased glucose consumption without diminishing the growth rate. By constitutively expressing a biosynthetic operon from this vector, the more active glycolytic metabolism was exploited to redirect intermediates toward the production of SA, which further increased the glucose consumption rate and avoided excess acetate production. Fluxomics and metabolomics experiments revealed a global remodeling of the carbon and energy metabolism in the production strain, where the increased SA production reduced the carbon available for oxidative and fermentative pathways. Moreover, the results showed that the production of SA relies on a specific setup of the pentose phosphate pathway, where both its oxidative and non-oxidative branches are strongly activated to supply erythrose-4-phosphate and balance the NADPH requirements. This work improves our understanding of the metabolic reorganization observed in E. coli in response to the plasmid-based expression of the SA biosynthetic pathway. Biotechnol. Bioeng. 2017;114: 1319-1330. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  17. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome.

    PubMed

    Kaska, Lukasz; Sledzinski, Tomasz; Chomiczewska, Agnieszka; Dettlaff-Pokora, Agnieszka; Swierczynski, Julian

    2016-10-21

    Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission.

  18. Improved glucose metabolism following bariatric surgery is associated with increased circulating bile acid concentrations and remodeling of the gut microbiome

    PubMed Central

    Kaska, Lukasz; Sledzinski, Tomasz; Chomiczewska, Agnieszka; Dettlaff-Pokora, Agnieszka; Swierczynski, Julian

    2016-01-01

    Clinical studies have indicated that circulating bile acid (BA) concentrations increase following bariatric surgery, especially following malabsorptive procedures such as Roux-en-Y gastric bypasses (RYGB). Moreover, total circulating BA concentrations in patients following RYGB are positively correlated with serum glucagon-like peptide-1 concentrations and inversely correlated with postprandial glucose concentrations. Overall, these data suggest that the increased circulating BA concentrations following bariatric surgery - independently of calorie restriction and body-weight loss - could contribute, at least in part, to improvements in insulin sensitivity, incretin hormone secretion, and postprandial glycemia, leading to the remission of type-2 diabetes (T2DM). In humans, the primary and secondary BA pool size is dependent on the rate of biosynthesis and the enterohepatic circulation of BAs, as well as on the gut microbiota, which play a crucial role in BA biotransformation. Moreover, BAs and gut microbiota are closely integrated and affect each other. Thus, the alterations in bile flow that result from anatomical changes caused by bariatric surgery and changes in gut microbiome may influence circulating BA concentrations and could subsequently contribute to T2DM remission following RYGB. Research data coming largely from animal and cell culture models suggest that BAs can contribute, via nuclear farnezoid X receptor (FXR) and membrane G-protein-receptor (TGR-5), to beneficial effects on glucose metabolism. It is therefore likely that FXR, TGR-5, and BAs play a similar role in glucose metabolism following bariatric surgery in humans. The objective of this review is to discuss in detail the results of published studies that show how bariatric surgery affects glucose metabolism and subsequently T2DM remission. PMID:27818587

  19. A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly.

    PubMed

    Shah, T; Verdile, G; Sohrabi, H; Campbell, A; Putland, E; Cheetham, C; Dhaliwal, S; Weinborn, M; Maruff, P; Darby, D; Martins, R N

    2014-12-02

    Physical exercise interventions and cognitive training programs have individually been reported to improve cognition in the healthy elderly population; however, the clinical significance of using a combined approach is currently lacking. This study evaluated whether physical activity (PA), computerized cognitive training and/or a combination of both could improve cognition. In this nonrandomized study, 224 healthy community-dwelling older adults (60-85 years) were assigned to 16 weeks home-based PA (n=64), computerized cognitive stimulation (n=62), a combination of both (combined, n=51) or a control group (n=47). Cognition was assessed using the Rey Auditory Verbal Learning Test, Controlled Oral Word Association Test and the CogState computerized battery at baseline, 8 and 16 weeks post intervention. Physical fitness assessments were performed at all time points. A subset (total n=45) of participants underwent [(18)F] fluorodeoxyglucose positron emission tomography scans at 16 weeks (post-intervention). One hundred and ninety-one participants completed the study and the data of 172 participants were included in the final analysis. Compared with the control group, the combined group showed improved verbal episodic memory and significantly higher brain glucose metabolism in the left sensorimotor cortex after controlling for age, sex, premorbid IQ, apolipoprotein E (APOE) status and history of head injury. The higher cerebral glucose metabolism in this brain region was positively associated with improved verbal memory seen in the combined group only. Our study provides evidence that a specific combination of physical and mental exercises for 16 weeks can improve cognition and increase cerebral glucose metabolism in cognitively intact healthy older adults.

  20. A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly

    PubMed Central

    Shah, T; Verdile, G; Sohrabi, H; Campbell, A; Putland, E; Cheetham, C; Dhaliwal, S; Weinborn, M; Maruff, P; Darby, D; Martins, R N

    2014-01-01

    Physical exercise interventions and cognitive training programs have individually been reported to improve cognition in the healthy elderly population; however, the clinical significance of using a combined approach is currently lacking. This study evaluated whether physical activity (PA), computerized cognitive training and/or a combination of both could improve cognition. In this nonrandomized study, 224 healthy community-dwelling older adults (60–85 years) were assigned to 16 weeks home-based PA (n=64), computerized cognitive stimulation (n=62), a combination of both (combined, n=51) or a control group (n=47). Cognition was assessed using the Rey Auditory Verbal Learning Test, Controlled Oral Word Association Test and the CogState computerized battery at baseline, 8 and 16 weeks post intervention. Physical fitness assessments were performed at all time points. A subset (total n=45) of participants underwent [18F] fluorodeoxyglucose positron emission tomography scans at 16 weeks (post-intervention). One hundred and ninety-one participants completed the study and the data of 172 participants were included in the final analysis. Compared with the control group, the combined group showed improved verbal episodic memory and significantly higher brain glucose metabolism in the left sensorimotor cortex after controlling for age, sex, premorbid IQ, apolipoprotein E (APOE) status and history of head injury. The higher cerebral glucose metabolism in this brain region was positively associated with improved verbal memory seen in the combined group only. Our study provides evidence that a specific combination of physical and mental exercises for 16 weeks can improve cognition and increase cerebral glucose metabolism in cognitively intact healthy older adults. PMID:25463973

  1. Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

    PubMed Central

    Choi, Cheol Soo; Befroy, Douglas E.; Codella, Roberto; Kim, Sheene; Reznick, Richard M.; Hwang, Yu-Jin; Liu, Zhen-Xiang; Lee, Hui-Young; Distefano, Alberto; Samuel, Varman T.; Zhang, Dongyan; Cline, Gary W.; Handschin, Christoph; Lin, Jiandie; Petersen, Kitt F.; Spiegelman, Bruce M.; Shulman, Gerald I.

    2008-01-01

    Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1α in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an ≈60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1α expression on whole-body energy expenditure, and PGC-1α transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKCθ, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance. PMID:19066218

  2. Liver glucose metabolism in humans

    PubMed Central

    Adeva-Andany, María M.; Pérez-Felpete, Noemi; Fernández-Fernández, Carlos; Donapetry-García, Cristóbal; Pazos-García, Cristina

    2016-01-01

    Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and connected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic pathways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP–glucose. Minor amounts of UDP–glucose are used to form UDP–glucuronate and UDP–galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway. Glucose metabolism supplies intermediates for glycosylation, a post-translational modification of proteins and lipids that modulates their activity. Congenital deficiency of phosphoglucomutase (PGM)-1 and PGM-3 is associated with impaired glycosylation. In addition to metabolize carbohydrates, the liver produces glucose to be used by other tissues, from glycogen breakdown or from de novo synthesis using primarily lactate and alanine (gluconeogenesis). PMID:27707936

  3. Early maternal undernutrition programs increased feed intake, altered glucose metabolism and insulin secretion, and liver function in aged female offspring

    PubMed Central

    George, Lindsey A.; Zhang, Liren; Tuersunjiang, Nuermaimaiti; Ma, Yan; Long, Nathan M.; Uthlaut, Adam B.; Smith, Derek T.; Nathanielsz, Peter W.

    2012-01-01

    Insulin resistance and obesity are components of the metabolic syndrome that includes development of cardiovascular disease and diabetes with advancing age. The thrifty phenotype hypothesis suggests that offspring of poorly nourished mothers are predisposed to the various components of the metabolic syndrome due to adaptations made during fetal development. We assessed the effects of maternal nutrient restriction in early gestation on feeding behavior, insulin and glucose dynamics, body composition, and liver function in aged female offspring of ewes fed either a nutrient-restricted [NR 50% National Research Council (NRC) recommendations] or control (C: 100% NRC) diet from 28 to 78 days of gestation, after which both groups were fed at 100% of NRC from day 79 to lambing and through lactation. Female lambs born to NR and C dams were reared as a single group from weaning, and thereafter, they were fed 100% NRC recommendations until assigned to this study at 6 yr of age. These female offspring were evaluated by a frequently sampled intravenous glucose tolerance test, followed by dual-energy X-ray absorptiometry for body composition analysis prior to and after ad libitum feeding of a highly palatable pelleted diet for 11 wk with automated monitoring of feed intake (GrowSafe Systems). Aged female offspring born to NR ewes demonstrated greater and more rapid feed intake, greater body weight gain, and efficiency of gain, lower insulin sensitivity, higher insulin secretion, and greater hepatic lipid and glycogen content than offspring from C ewes. These data confirm an increased metabolic “thriftiness” of offspring born to NR mothers, which continues into advanced age, possibly predisposing these offspring to metabolic disease. PMID:22277936

  4. Clozapine and quetiapine acutely reduce glucagon-like peptide-1 production and increase glucagon release in obese rats: implications for glucose metabolism and food choice behaviour.

    PubMed

    Smith, Greg C; Vickers, Mark H; Cognard, Emmanuelle; Shepherd, Peter R

    2009-11-01

    Second generation antipsychotic drug (SGA) treatment is associated with detrimental effects on glucose metabolism which is often attributed to the development of obesity and insulin resistance. However, we have recently demonstrated that clozapine and quetiapine also have direct effects of glucose metabolism in animals. This study compares clozapine and quetiapine and investigates the effects of these on the development of obesity and the direct effects of these drugs on glucose metabolism compared with those caused by the obesity per se. Three groups of male Sprague-Dawley rats were fed a high fat/high sugar diet to induce obesity while another three groups were fed a chow diet. One group on each diet was injected daily with vehicle, clozapine or quetiapine and effects on glucose metabolism were monitored. Clozapine and quetiapine treatment did not directly cause obesity or potentiate diet induced obesity but did induce a preference for the high fat/high sugar diet. Neither drug caused a impairment in insulin tolerance over that caused by obesity but both drugs acutely induced impairments in glucose tolerance that were additive with the effects induced by the diet induced obesity. Both drugs caused increases in glucagon levels and a suppression of GLP-1. We investigated two strategies for restoring GLP-1 signalling. The DPP-IV inhibitor sitagliptin only partially restored GLP-1 levels and did not overcome the deleterious effects on glucose tolerance whereas the GLP-1 receptor agonist exendin-4 normalised both glucagon levels and glucose metabolism. Our findings indicate that the clozapine and quetiapine induced impairments in glucose tolerance in rats are independent of insulin resistance caused by obesity and that these defects are linked with a suppression of GLP-1 levels. These studies suggest the need to perform follow up studies in humans to determine whether clozapine and quetiapine induce acute derangements in glucose metabolism and whether GLP-1

  5. Cadmium stimulates glucose metabolism in rat adipocytes

    SciTech Connect

    Yamamoto, A.; Wada, O.; Ono, T.; Ono, H.

    1986-07-01

    Cd/sup 2 +/ caused an increase in CO/sub 2/ formation from glucose in rat adipocytes. The apparent Km value for glucose was 2.02 mM for control condition, with Cd/sup 2 +/, and with insulin. Cd/sup 2 +/ stimulates glucose metabolism even though specific diffusion of glucose is blocked. A possible site effected by Cd/sup 2 +/ is discussed.

  6. Improved Glucose Metabolism In Vitro and In Vivo by an Allosteric Monoclonal Antibody That Increases Insulin Receptor Binding Affinity

    PubMed Central

    Corbin, John A.; Bhaskar, Vinay; Goldfine, Ira D.; Bedinger, Daniel H.; Lau, Angela; Michelson, Kristen; Gross, Lisa M.; Maddux, Betty A.; Kuan, Hua F.; Tran, Catarina; Lao, Llewelyn; Handa, Masahisa; Watson, Susan R.; Narasimha, Ajay J.; Zhu, Shirley; Levy, Raphael; Webster, Lynn; Wijesuriya, Sujeewa D.; Liu, Naichi; Wu, Xiaorong; Chemla-Vogel, David; Lee, Steve R.; Wong, Steve; Wilcock, Diane; White, Mark L.

    2014-01-01

    Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory

  7. Pair bond formation leads to a sustained increase in global cerebral glucose metabolism in monogamous male titi monkeys (Callicebus cupreus).

    PubMed

    Maninger, Nicole; Hinde, Katie; Mendoza, Sally P; Mason, William A; Larke, Rebecca H; Ragen, Benjamin J; Jarcho, Michael R; Cherry, Simon R; Rowland, Douglas J; Ferrer, Emilio; Bales, Karen L

    2017-04-21

    Social bonds, especially attachment relationships, are crucial to our health and happiness. However, what we know about the neural substrates of these bonds is almost exclusively limited to rodent models and correlational experiments in humans. Here, we used socially monogamous non-human primates, titi monkeys (Callicebus cupreus) to experimentally examine changes in regional and global cerebral glucose metabolism (GCGM) during the formation and maintenance of pair bonds. Baseline positron emission tomography (PET) scans were taken of thirteen unpaired male titi monkeys. Seven males were then experimentally paired with females, scanned and compared, after one week, to six age-matched control males. Five of the six control males were then also paired and scanned after one week. Scans were repeated on all males after four months of pairing. PET scans were coregistered with structural magnetic resonance imaging (MRI), and region of interest (ROI) analysis was carried out. A primary finding was that paired males showed a significant increase in [(18)F]-fluorodeoxyglucose (FDG) uptake in whole brain following one week of pairing, which is maintained out to four months. Dopaminergic, "motivational" areas and those involved in social behavior showed the greatest change in glucose uptake. In contrast, control areas changed only marginally more than GCGM. These findings confirm the large effects of social bonds on GCGM. They also suggest that more studies should examine how social manipulations affect whole-brain FDG uptake, as opposed to assuming that it does not change across condition.

  8. Glucose Transporters in Cardiac Metabolism and Hypertrophy

    PubMed Central

    Shao, Dan; Tian, Rong

    2016-01-01

    The heart is adapted to utilize all classes of substrates to meet the high-energy demand, and it tightly regulates its substrate utilization in response to environmental changes. Although fatty acids are known as the predominant fuel for the adult heart at resting stage, the heart switches its substrate preference toward glucose during stress conditions such as ischemia and pathological hypertrophy. Notably, increasing evidence suggests that the loss of metabolic flexibility associated with increased reliance on glucose utilization contribute to the development of cardiac dysfunction. The changes in glucose metabolism in hypertrophied hearts include altered glucose transport and increased glycolysis. Despite the role of glucose as an energy source, changes in other nonenergy producing pathways related to glucose metabolism, such as hexosamine biosynthetic pathway and pentose phosphate pathway, are also observed in the diseased hearts. This article summarizes the current knowledge regarding the regulation of glucose transporter expression and translocation in the heart during physiological and pathological conditions. It also discusses the signaling mechanisms governing glucose uptake in cardiomyocytes, as well as the changes of cardiac glucose metabolism under disease conditions. PMID:26756635

  9. Oxidative metabolism: glucose versus ketones.

    PubMed

    Prince, Allison; Zhang, Yifan; Croniger, Colleen; Puchowicz, Michelle

    2013-01-01

    The coupling of upstream oxidative processes (glycolysis, beta-oxidation, CAC turnover) to mitochondrial oxidative phosphorylation (OXPHOS) under the driving conditions of energy demand by the cell results in the liberation of free energy as ATP. Perturbations in glycolytic CAC or OXPHOS can result in pathology or cell death. To better understand whole body energy expenditure during chronic ketosis, we used a diet-induced rat model of ketosis to determine if high-fat-carbohydrate-restricted "ketogenic" diet results in changes in total energy expenditure (TEE). Consistent with previous reports of increased energy expenditure in mice, we hypothesized that rats fed ketogenic diet for 3 weeks would result in increased resting energy expenditure due to alterations in metabolism associated with a "switch" in energy substrate from glucose to ketone bodies. The rationale is ketone bodies are a more efficient fuel than glucose. Indirect calorimetric analysis revealed a moderate increase in VO2 and decreased VCO2 and heat with ketosis. These results suggest ketosis induces a moderate uncoupling state and less oxidative efficiency compared to glucose oxidation.

  10. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats

    PubMed Central

    Russell, J C; Proctor, S D

    2007-01-01

    Background and purpose: The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome. Experimental approach: Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake. Key results: Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1β. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction. Conclusions and implications: Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG. PMID:17375078

  11. Increased insulin sensitivity and reduced micro and macro vascular disease induced by 2-deoxy-D-glucose during metabolic syndrome in obese JCR: LA-cp rats.

    PubMed

    Russell, J C; Proctor, S D

    2007-05-01

    The metabolic syndrome, characterized by obesity, insulin resistance and dyslipidemia, is a major cause of cardiovascular disease. The origins of the syndrome have been hypothesized to lie in continuous availability of energy dense foods in modern societies. In contrast, human physiology has evolved in an environment of sporadic food supply and frequent food deprivation. Intermittent food restriction in rats has previously been shown to lead to reduction of cardiovascular risk and a greater life span. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG) is taken up by cells and induces pharmacological inhibition of metabolism of glucose. We hypothesized that intermittent inhibition of glucose metabolism, a metabolic deprivation, may mimic intermittent food deprivation and ameliorate metabolic and pathophysiological aspects of the metabolic syndrome. Insulin resistant, atherosclerosis-prone JCR:LA-cp rats were treated with 2-DG (0.3% w/w in chow) on an intermittent schedule (2 days treated, one day non-treated, two days treated and two days non-treated) or continuously at a dose to give an equivalent averaged intake. Intermittent 2-DG-treatment improved insulin sensitivity, which correlated with increased adiponectin concentrations. Further, intermittent treatment (but not continuous treatment) reduced plasma levels of leptin and the inflammatory cytokine IL-1 beta. Both 2-DG treatments reduced micro-vascular glomerular sclerosis, but only the intermittent schedule improved macro-vascular dysfunction. Our findings are consistent with reduction in severity of the metabolic syndrome and protection against end stage micro- and macro-vascular disease through intermittent metabolic deprivation at a cellular level by inhibition of glucose oxidation with 2-DG.

  12. PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation in 3T3L1 adipocytes.

    PubMed

    Manna, Prasenjit; Jain, Sushil K

    2013-09-01

    Phosphatidylinositol-3,4,5-triphosphate (PIP3) and phosphatidylinositol-4,5-biphosphate (PIP2) are two well-known membrane bound polyphosphoinositides. Diabetes is associated with impaired glucose metabolism. Using a 3T3L1 adipocyte cell model, this study investigated the role of PIP3 and PIP2 on insulin stimulated glucose metabolism in high glucose (HG) treated cells. Exogenous PIP3 supplementation (1, 5, or 10 nM) increased the phosphorylation of AKT and PKCζ/λ, which in turn upregulated GLUT4 total protein expression as well as its surface expression, glucose uptake, and glucose utilization in cells exposed to HG (25 mM); however, PIP2 had no effect. Comparative signal silencing studies with antisense AKT2 and antisense PKCζ revealed that phosphorylation of PKCζ/λ is more effective in PIP3 mediated GLUT4 activation and glucose utilization than in AKT phosphorylation. Supplementation with PIP3 in combination with insulin enhanced glucose uptake and glucose utilization compared to PIP2 with insulin, or insulin alone, in HG-treated adipocytes. This suggests that a decrease in cellular PIP3 levels may cause impaired insulin sensitivity in diabetes. PIP3 supplementation also prevented HG-induced MCP-1 and resistin secretion and lowered adiponectin levels. This study for the first time demonstrates that PIP3 but not PIP2 plays an important role in GLUT4 upregulation and glucose metabolism mediated by AKT/PKCζ/λ phosphorylation. Whether PIP3 levels in blood can be used as a biomarker of insulin resistance in diabetes needs further investigation.

  13. Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways

    SciTech Connect

    Liu, Yansong; Xu, Dan; Feng, Jianghua; Kou, Hao; Liang, Gai; Yu, Hong; He, Xiaohua; Zhang, Baifang; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-07-15

    The aims of this study were to clarify the metabonome alteration in fetal rats after prenatal caffeine ingestion and to explore the underlying mechanism pertaining to the increased fetal circulatory glucocorticoid (GC). Pregnant Wistar rats were daily intragastrically administered with different doses of caffeine (0, 20, 60 and 180 mg/kg) from gestational days (GD) 11 to 20. Metabonome of fetal plasma and amniotic fluid on GD20 were analyzed by {sup 1}H nuclear magnetic resonance-based metabonomics. Gene and protein expressions involved in the GC metabolism, glucose and lipid metabolic pathways in fetal liver and gastrocnemius were measured by real-time RT-PCR and immunohistochemistry. Fetal plasma metabonome were significantly altered by caffeine, which presents as the elevated α- and β‐glucose, reduced multiple lipid contents, varied apolipoprotein contents and increased levels of a number of amino acids. The metabonome of amniotic fluids showed a similar change as that in fetal plasma. Furthermore, the expressions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) were decreased, while the level of blood GC and the expressions of 11β-HSD-1 and glucocorticoid receptor (GR) were increased in fetal liver and gastrocnemius. Meanwhile, the expressions of insulin-like growth factor 1 (IGF-1), IGF-1 receptor and insulin receptor were decreased, while the expressions of adiponectin receptor 2, leptin receptors and AMP-activated protein kinase α2 were increased after caffeine treatment. Prenatal caffeine ingestion characteristically change the fetal metabonome, which is probably attributed to the alterations of glucose and lipid metabolic pathways induced by increased circulatory GC, activated GC metabolism and enhanced GR expression in peripheral metabolic tissues. -- Highlights: ► Prenatal caffeine ingestion altered the metabonome of IUGR fetal rats. ► Caffeine altered the glucose and lipid metabolic pathways of IUGR fetal rats. ► Prenatal caffeine

  14. Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism

    NASA Astrophysics Data System (ADS)

    Lam, Tony K. T.; Gutierrez-Juarez, Roger; Pocai, Alessandro; Rossetti, Luciano

    2005-08-01

    The brain keenly depends on glucose for energy, and mammalians have redundant systems to control glucose production. An increase in circulating glucose inhibits glucose production in the liver, but this negative feedback is impaired in type 2 diabetes. Here we report that a primary increase in hypothalamic glucose levels lowers blood glucose through inhibition of glucose production in rats. The effect of glucose requires its conversion to lactate followed by stimulation of pyruvate metabolism, which leads to activation of adenosine triphosphate (ATP)-sensitive potassium channels. Thus, interventions designed to enhance the hypothalamic sensing of glucose may improve glucose homeostasis in diabetes.

  15. Glucose metabolism in rat retinal pigment epithelium.

    PubMed

    Coffe, Víctor; Carbajal, Raymundo C; Salceda, Rocío

    2006-01-01

    The retinal pigment epithelium (RPE) is the major transport pathway for exchange of metabolites and ions between choroidal blood supply and the neural retina. To gain insight into the mechanisms controlling glucose metabolism in RPE and its possible relationship to retinopathy, we studied the influence of different glucose concentrations on glycogen and lactate levels and CO(2) production in RPE from normal and streptozotocin-treated diabetic rats. Incubation of normal RPE in the absence of glucose caused a decrease in lactate production and glycogen content. In normal RPE, increasing glucose concentrations from 5.6 mM to 30 mM caused a four-fold increase in glucose accumulation and CO(2) yield, as well as reduction in lactate and glycogen production. In RPE from diabetic rats glucose accumulation did not increase in the presence of high glucose substrate, but it showed a four- and a seven-fold increase in CO(2) production through the mitochondrial and pentose phosphate pathways, respectively. We found high glycogen levels in RPE which can be used as an energy reserve for RPE itself and/or neural retina. Findings further show that the RPE possesses a high oxidative capacity. The large increase in glucose shunting to the pentose phosphate pathway in diabetic retina exposed to high glucose suggests a need for reducing capacity, consistent with increased oxidative stress.

  16. Circadian control of glucose metabolism.

    PubMed

    Kalsbeek, Andries; la Fleur, Susanne; Fliers, Eric

    2014-07-01

    The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis.

  17. Circadian control of glucose metabolism

    PubMed Central

    Kalsbeek, Andries; la Fleur, Susanne; Fliers, Eric

    2014-01-01

    The incidence of obesity and type 2 diabetes mellitus (T2DM) has risen to epidemic proportions. The pathophysiology of T2DM is complex and involves insulin resistance, pancreatic β-cell dysfunction and visceral adiposity. It has been known for decades that a disruption of biological rhythms (which happens the most profoundly with shift work) increases the risk of developing obesity and T2DM. Recent evidence from basal studies has further sparked interest in the involvement of daily rhythms (and their disruption) in the development of obesity and T2DM. Most living organisms have molecular clocks in almost every tissue, which govern rhythmicity in many domains of physiology, such as rest/activity rhythms, feeding/fasting rhythms, and hormonal secretion. Here we present the latest research describing the specific role played by the molecular clock mechanism in the control of glucose metabolism and speculate on how disruption of these tissue clocks may lead to the disturbances in glucose homeostasis. PMID:24944897

  18. Impaired glucose metabolism is a risk factor for increased thyroid volume and nodule prevalence in a mild-to-moderate iodine deficient area.

    PubMed

    Anil, Cuneyd; Akkurt, Aysen; Ayturk, Semra; Kut, Altug; Gursoy, Alptekin

    2013-07-01

    Insulin resistance (IR) is a key factor involved in the pathogenesis of impaired glucose metabolism. IR is associated with increased thyroid volume and nodule prevalence in patients with metabolic syndrome. Data on the association of thyroid morphology and abnormal glucose metabolism are limited. This prospective study was carried out to evaluate thyroid volume and nodule prevalence in patients with pre-diabetes and type 2 diabetes mellitus (DM) in a mild-to-moderate iodine deficient area. Data were gathered on all newly diagnosed patients with pre-diabetes and type 2 diabetes mellitus between May 2008 and February 2010. 156 patients with pre-diabetes and 123 patients with type 2 DM were randomly matched for age, gender, and smoking habits with 114 subjects with normal glucose metabolism. Serum thyroid-stimulating hormone (TSH) and thyroid ultrasonography was performed in all participants. Mean TSH level in the diabetes group (1.9±0.9 mIU/L) was higher than in the control group (1.4±0.8 mIU/L) and the pre-diabetes group (1.5±0.8 mIU/L) (P<0.0001 for both). Mean thyroid volume was higher in the pre-diabetes (18.2±9.2mL) and diabetes (20.0±8.2mL) groups than in controls (11.4±3.8mL) (P<0.0001 for both). Percentage of patients with thyroid nodules was also higher in the pre-diabetes (51.3%) and diabetes groups (61.8%) than in controls (23.7%) (P<0.0001 for both). The results suggest that patients with impaired glucose metabolism have significantly increased thyroid volume and nodule prevalence. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. [Glucose metabolism in the basal ganglia].

    PubMed

    Yamada, Katsuya

    2009-04-01

    GABAergic neurons in the substantia nigra pars reticulata (SNr) -a major output nucleus of the basal ganglia- are involved in sensing severe hypoglycemic and hypoxic conditions in the brain via the ATP-sensitive potassium (KATP) channels that are abundantly expressed in these neurons. However, these neurons are also sensitive to mild changes in extracellular glucose concentrations through KATP channel-independent, yet unknown mechanisms. Lenard et al. reported that globus pallidus (GP) -another output nucleus of the basal ganglia- also senses glucose concentrations in the brain. It is unclear why these two major output nuclei sense glucose concentrations. It has been reported that some SNr and GP neurons respond to feeding-related, jaw or hand movement. Interestingly, Nishino demonstrated that SNr neurons responded oppositely, i.e., increased or decreased in their firings, to the same sweet food depending on blood glucose levels. Thus, glucose levels might influence feeding-related information processing in the basal ganglia through SNr and GP. Other issues reviewed are regarding associations between glucose metabolism and motor diseases in the basal ganglia. These include mutation in glucose transporter (GLUT) 1 causing paroxysmal kinesigenic choreoarthetosis, abnormal glycolysis in Huntington's disease, and a study showing increased glucose metabolism in SNr and GP in Parkinson's disease using high-resolution research positron emission tomography (HRRT). Although glucose is the sole energy source for the brain, its utilization at the single-cell level remains elusive. Modern methods for investigating intercellular metabolic communication might help understanding the selective vulnerability seen in the basal ganglia of patients suffering from such neurodegenerative disorders in near future.

  20. BClI polymorphism of the glucocorticoid receptor gene is associated with increased obesity, impaired glucose metabolism and dyslipidaemia in patients with Addison's disease.

    PubMed

    Giordano, Roberta; Marzotti, Stefania; Berardelli, Rita; Karamouzis, Ioannis; Brozzetti, Annalisa; D'Angelo, Valentina; Mengozzi, Giulio; Mandrile, Giorgia; Giachino, Daniela; Migliaretti, Giuseppe; Bini, Vittorio; Falorni, Alberto; Ghigo, Ezio; Arvat, Emanuela

    2012-12-01

    Although glucocorticoids are essential for health, several studies have shown that glucocorticoids replacement in Addison's disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 patients with Addison's disease (34 women and 16 men, age 20-82 year) under glucocorticoids replacement. Neither N363S nor ER22/23EK variants were significantly associated with anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n = 4) showed higher (P < 0·05) BMI, waist circumference, HOMA and 2-h glucose levels after OGTT, as well as total cholesterol and triglycerides than those with wild-type genotype CC (n = 28) or heterozygous CG (n = 18). The totality of GG patients was connoted by abdominal adiposity, impaired glucose tolerance/diabetes mellitus or dyslipidaemia, while a lower percentage of CC or CG patients showed some anthropometric and metabolic alterations. These results suggest that BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addison's disease and may contribute, along with other factors, to the increase in central adiposity, impaired glucose metabolism and dyslipidaemia. © 2012 Blackwell Publishing Ltd.

  1. Interaction between bone and glucose metabolism [Review].

    PubMed

    Kanazawa, Ippei

    2017-09-30

    Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DM-induced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling. On the other hand, bone is recently recognized as an endocrine organ. Previous studies based on in vitro and animal studies showed that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, may regulate glucose homeostasis. Although several clinical studies reported the relationship between osteocalcin and glucose metabolism, further large-scale and intervention studies are necessary to confirm the beneficial effects of osteocalcin on glucose metabolism in human. It has been shown that adenosine monophosphate-activated protein kinase (AMPK), an intracellular energy sensor, is involved in bone metabolism. Adiponectin and metformin stimulate osteocalcin expression and the differentiation of osteoblasts via AMPK activation. Also, AMPK activation protects against oxidative stress-induced apoptosis of osteocytes. These findings suggest that AMPK in osteoblasts and osteocytes may be a therapeutic target for DM-induced bone fragility.

  2. Dexamethasone increases glucose cycling, but not glucose production, in healthy subjects

    SciTech Connect

    Wajngot, A.; Khan, A.; Giacca, A.; Vranic, M.; Efendic, S. )

    1990-11-01

    We established that measurement of glucose fluxes through glucose-6-phosphatase (G-6-Pase; hepatic total glucose output, HTGO), glucose cycling (GC), and glucose production (HGP), reveals early diabetogenic changes in liver metabolism. To elucidate the mechanism of the diabetogenic effect of glucocorticoids, we treated eight healthy subjects with oral dexamethasone (DEX; 15 mg over 48 h) and measured HTGO with (2-3H)glucose and HGP with (6-3H)glucose postabsorptively and during a 2-h glucose infusion (11.1 mumol.kg-1.min-1). (2-3H)- minus (6-3H)glucose equals GC. DEX significantly increased plasma glucose, insulin, C peptide, and HTGO, while HGP was unchanged. In controls and DEX, glucose infusion suppressed HTGO (82 vs. 78%) and HGP (87 vs. 91%). DEX increased GC postabsorptively (three-fold) P less than 0.005 and during glucose infusion (P less than 0.05) but decreased metabolic clearance and glucose uptake (Rd), which eventually normalized, however. Because DEX increased HTGO (G-6-Pase) and not HGP (glycogenolysis + gluconeogenesis), we assume that DEX increases HTGO and GC in humans by activating G-6-Pase directly, rather than by expanding the glucose 6-phosphate pool. Hyperglycemia caused by peripheral effects of DEX can also contribute to an increase in GC by activating glucokinase. Therefore, measurement of glucose fluxes through G-6-Pase and GC revealed significant early effects of DEX on hepatic glucose metabolism, which are not yet reflected in HGP.

  3. PPARδ regulates glucose metabolism and insulin sensitivity

    PubMed Central

    Lee, Chih-Hao; Olson, Peter; Hevener, Andrea; Mehl, Isaac; Chong, Ling-Wa; Olefsky, Jerrold M.; Gonzalez, Frank J.; Ham, Jungyeob; Kang, Heonjoong; Peters, Jeffrey M.; Evans, Ronald M.

    2006-01-01

    The metabolic syndrome is a collection of obesity-related disorders. The peroxisome proliferator-activated receptors (PPARs) regulate transcription in response to fatty acids and, as such, are potential therapeutic targets for these diseases. We show that PPARδ (NR1C2) knockout mice are metabolically less active and glucose-intolerant, whereas receptor activation in db/db mice improves insulin sensitivity. Euglycemic–hyperinsulinemic-clamp experiments further demonstrate that a PPARδ-specific agonist suppresses hepatic glucose output, increases glucose disposal, and inhibits free fatty acid release from adipocytes. Unexpectedly, gene array and functional analyses suggest that PPARδ ameliorates hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis. Coupling increased hepatic carbohydrate catabolism with its ability to promote β-oxidation in muscle allows PPARδ to regulate metabolic homeostasis and enhance insulin action by complementary effects in distinct tissues. The combined hepatic and peripheral actions of PPARδ suggest new therapeutic approaches to treat type II diabetes. PMID:16492734

  4. Increased Muscular 5α-Dihydrotestosterone in Response to Resistance Training Relates to Skeletal Muscle Mass and Glucose Metabolism in Type 2 Diabetic Rats

    PubMed Central

    Horii, Naoki; Sato, Koji; Mesaki, Noboru; Iemitsu, Motoyuki

    2016-01-01

    Regular resistance exercise induces skeletal muscle hypertrophy and improvement of glycemic control in type 2 diabetes patients. Administration of dehydroepiandrosterone (DHEA), a sex steroid hormone precursor, increases 5α-dihydrotestosterone (DHT) synthesis and is associated with improvements in fasting blood glucose level and skeletal muscle hypertrophy. Therefore, the aim of this study was to investigate whether increase in muscle DHT levels, induced by chronic resistance exercise, can contribute to skeletal muscle hypertrophy and concomitant improvement of muscular glucose metabolism in type 2 diabetic rats. Male 20-week-old type 2 diabetic rats (OLETF) were randomly divided into 3 groups: sedentary control, resistance training (3 times a week on alternate days for 8 weeks), or resistance training with continuous infusion of a 5α-reductase inhibitor (n = 8 each group). Age-matched, healthy nondiabetic Long-Evans Tokushima Otsuka (LETO) rats (n = 8) were used as controls. The results indicated that OLETF rats showed significant decrease in muscular DHEA, free testosterone, DHT levels, and protein expression of steroidogenic enzymes, with loss of skeletal muscle mass and hyperglycemia, compared to that of LETO rats. However, 8-week resistance training in OLETF rats significantly increased the levels of muscle sex steroid hormones and protein expression of steroidogenic enzymes with a concomitant increase in skeletal muscle mass, improved fasting glucose level, and insulin sensitivity index. Moreover, resistance training accelerated glucose transporter-4 (GLUT-4) translocation and protein kinase B and C-ζ/λ phosphorylation. Administering the 5α-reductase inhibitor in resistance-trained OLETF rats resulted in suppression of the exercise-induced effects on skeletal muscle mass, fasting glucose level, insulin sensitivity index, and GLUT-4 signaling, with a decline in muscular DHT levels. These findings suggest that resistance training-induced elevation of

  5. Sex steroids and glucose metabolism.

    PubMed

    Allan, Carolyn A

    2014-01-01

    Testosterone levels are lower in men with metabolic syndrome and type 2 diabetes mellitus (T2DM) and also predict the onset of these adverse metabolic states. Body composition (body mass index, waist circumference) is an important mediator of this relationship. Sex hormone binding globulin is also inversely associated with insulin resistance and T2DM but the data regarding estrogen are inconsistent. Clinical models of androgen deficiency including Klinefelter's syndrome and androgen deprivation therapy in the treatment of advanced prostate cancer confirm the association between androgens and glucose status. Experimental manipulation of the insulin/glucose milieu and suppression of endogenous testicular function suggests the relationship between androgens and insulin sensitivity is bidirectional. Androgen therapy in men without diabetes is not able to differentiate the effect on insulin resistance from that on fat mass, in particular visceral adiposity. Similarly, several small clinical studies have examined the efficacy of exogenous testosterone in men with T2DM, however, the role of androgens, independent of body composition, in modifying insulin resistance is uncertain.

  6. Inhibitory effects of fatty acids on glucose-regulated B-cell function: association with increased islet triglyceride stores and altered effect of fatty acid oxidation on glucose metabolism.

    PubMed

    Zhou, Y P; Ling, Z C; Grill, V E

    1996-08-01

    Long-term exposure to fatty acids (FA) inhibits B-cell function. We tested whether the inhibitory effects are associated with increased islet triglycerides (TG). Rat pancreatic islets were cultured for 48 hours in RPMI 1640 medium with 10% fetal calf serum (FCS) and 11 mmol/L glucose in the presence or absence of the long-chain FA, palmitate. Palmitate (0.125 mmol/L) exposure successively increased islet TG 70% after 6 hours and 200% after 48 hours of culture. The dose-response for palmitate was similar for the increase in TG and inhibition of glucose-induced insulin secretion. Reversal of elevated islet TG in RPMI medium (after 48 hours of palmitate) was 29% after 6 hours and 84% after 24 hours. A more rapid decline of TG was observed in Krebs-Ringer bicarbonate (KRB) medium in the absence of nutrients. This decline was totally prevented by 1 mumol/L of the carnitine palmitoyl transferase-I (CPT-I) inhibitor, etomoxir. Etomoxir enhanced glucose-induced insulin secretion from palmitate-cultured islets; however, this effect was lost when TG were normalized. Under conditions when oxidation of FA from islet TG stores was blocked with etomoxir, we tested the effects of octanoate, the oxidation of which is not blocked by etomoxir. Oxidation of [1-14C]octanoate from islets precultured with palmitate (48 hours) did not differ from that in control islets. Conversely, after palmitate, octanoate inhibited glucose oxidation (14CO2 production from [U-14C]glucose, 613 +/- 41 pmol/10 islets/90 min v 1,129 +/- 87 after control conditions, P < .01). In conclusion, (1) palmitate induces increases in islet TG that are associated with inhibition of B-cell function, and (2) long-term exposure to palmitate also induces an inhibitory effect of FA oxidation on glucose metabolism that is independent of TG.

  7. Increased beta-oxidation in muscle cells enhances insulin-stimulated glucose metabolism and protects against fatty acid-induced insulin resistance despite intramyocellular lipid accumulation.

    PubMed

    Perdomo, German; Commerford, S Renee; Richard, Ann-Marie T; Adams, Sean H; Corkey, Barbara E; O'Doherty, Robert M; Brown, Nicholas F

    2004-06-25

    Skeletal muscle insulin resistance may be aggravated by intramyocellular accumulation of fatty acid-derived metabolites that inhibit insulin signaling. We tested the hypothesis that enhanced fatty acid oxidation in myocytes should protect against fatty acid-induced insulin resistance by limiting lipid accumulation. L6 myotubes were transduced with adenoviruses encoding carnitine palmitoyltransferase I (CPT I) isoforms or beta-galactosidase (control). Two to 3-fold overexpression of L-CPT I, the endogenous isoform in L6 cells, proportionally increased oxidation of the long-chain fatty acids palmitate and oleate and increased insulin stimulation of [(14)C]glucose incorporation into glycogen by 60% while enhancing insulin-stimulated phosphorylation of p38MAPK. Incubation of control cells with 0.2 mm palmitate for 18 h caused accumulation of triacylglycerol, diacylglycerol, and ceramide (but not long-chain acyl-CoA) and decreased insulin-stimulated [(14)C]glucose incorporation into glycogen (60%), [(3)H]deoxyglucose uptake (60%), and protein kinase B phosphorylation (20%). In the context of L-CPT I overexpression, palmitate preincubation produced a relative decrease in insulin-stimulated incorporation of [(14)C]glucose into glycogen (60%) and [(3)H]deoxyglucose uptake (40%) but did not inhibit phosphorylation of protein kinase B. Due to the enhancement of insulin-stimulated glucose metabolism induced by L-CPT I overexpression itself, net insulin-stimulated incorporation of [(14)C]glucose into glycogen and [(3)H]deoxyglucose uptake in L-CPT I-transduced, palmitate-treated cells were significantly greater than in palmitate-treated control cells (71 and 75% greater, respectively). However, L-CPT I overexpression failed to decrease intracellular triacylglycerol, diacylglycerol, ceramide, or long-chain acyl-CoA. We propose that accelerated beta-oxidation in muscle cells exerts an insulin-sensitizing effect independently of changes in intracellular lipid content.

  8. Elderly women: homocysteine reduction by short-term folic acid supplementation resulting in increased glucose concentrations and affecting lipid metabolism (C677T MTHFR polymorphism).

    PubMed

    Chmurzynska, Agata; Malinowska, Anna M; Twardowska-Rajewska, Jolanta; Gawecki, Jan

    2013-06-01

    Serum homocysteine levels show interindividual variation and are determined by nutritional factors, such as B-vitamin intake, and by age and genetic influences, such as the genotype of the methylenetetrahydrofolate reductase (MTHFR) gene. Recently, the relation between one-carbon and lipid metabolism has been shown. Therefore, we hypothesized that folic acid supplementation would not only decrease homocysteine concentrations but also affect lipid metabolism. The aim of the present study was to evaluate the impact of short-term folic acid supplementation on homocysteine and lipid metabolism in Polish women older than 60 y with different C677T MTHFR genotypes. One hundred twenty-two volunteers were supplemented with folic acid 400 μg/d for 8 wk. Folate intake was assessed using a food-frequency questionnaire. The serum homocysteine level was analyzed using high-performance liquid chromatography. Serum biomarkers were measured with a Vitalab Flexor biochemical analyzer. MTHFR genotyping was performed using the polymerase chain reaction restriction fragment length polymorphism method. In the studied group, the MTHFR genotype frequencies were 0.14 for TT, 0.43 for CT, 0.43 for CC carriers. At baseline, the average folic acid and homocysteine concentrations were 12.16 ± 0.23 ng/mL and 7.94 ± 0.3 μmol/L, respectively. Folic acid supplementation lowered the serum homocysteine concentration. However, the dietary intervention also led to an increase in glucose concentrations (P < 0.01). The T-allele carriers had a larger waist circumference (P < 0.05) and a higher waist-to-hip ratio (P < 0.01). In elderly women, a short-term, low-dose folic acid supplementation lowered the serum homocysteine level but also increased glucose concentrations. The C677T MTHFR polymorphism affects the waist-to-hip ratio and lipid metabolism. Copyright © 2013 Elsevier Inc. All rights reserved.

  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. Glucose intolerance, metabolic syndrome, and neuropathy.

    PubMed

    Cortez, Melissa; Singleton, J Robinson; Smith, A Gordon

    2014-01-01

    There is increasing evidence that impaired glucose tolerance (IGT) or metabolic syndrome may result in peripheral nerve injury, although the exact relationship between the conditions is still being characterized. There is animal model, epidemiologic, and clinical evidence to suggest a pathophysiologic relationship between neuropathy and metabolic syndrome, along with its components including obesity, dyslipidemia, and insulin resistance. IGT and metabolic syndrome are associated with subclinical nerve damage or are typically painful and sensory predominant, although autonomic involvement may also occur. Because there is often preferential small fiber injury and nerve conduction studies may be relatively insensitive, skin biopsy with assessment of intraepidermal nerve fiber density is often used to confirm the diagnosis. Treatment of metabolic syndrome and IGT-associated neuropathies should include diet and exercise counseling, maintenance of normoglycemia, and targeted pharmacologic therapy for modifiable risk factors. Further research is required to fully elucidate the complex pathophysiology, as well as identify optimal diagnostic and treatment approaches.

  11. Melatonin and glucose metabolism: clinical relevance.

    PubMed

    Lardone, P J; Alvarez-Sanchez, Sanchez N; Guerrero, J M; Carrillo-Vico, A

    2014-01-01

    The role of melatonin in glucose homeostasis is an active area of investigation. There is a growing body of evidence suggesting a link between disturbances in melatonin production and impaired insulin, glucose, lipid metabolism, and antioxidant capacity. Furthermore, melatonin has been found to influence insulin secretion both in vivo and in vitro, and night-time melatonin levels are related to night-time insulin concentrations in patients with diabetes. In several recent studies, a single nucleotide polymorphism of the human melatonin receptor 1B has been described as being causally linked to an increased risk of developing type 2 diabetes. Taken together, these data suggest that endogenous as well as exogenous melatonin may play a role in diabetes and associated metabolic disturbances not only by regulating insulin secretion but also by providing protection against reactive oxygen species, considering pancreatic β-cells are particularly susceptible to oxidative stress because they possess only low-antioxidative capacity.

  12. Fructose vs. glucose and metabolism: do the metabolic differences matter?

    PubMed

    Sievenpiper, John L; de Souza, Russell J; Cozma, Adrian I; Chiavaroli, Laura; Ha, Vanessa; Mirrahimi, Arash

    2014-02-01

    Fructose is seen as uniquely contributing to the pandemics of obesity and its cardiometabolic complications. Much of the evidence for this view derives from the unique biochemical, metabolic, and endocrine responses that differentiate fructose from glucose. To understand whether these proposed mechanisms result in clinically meaningful modification of cardiovascular risk in humans, we update a series of systematic reviews and meta-analyses of controlled feeding trials to assess the cardiometabolic effects of fructose in isocaloric replacement for glucose. A total of 20 controlled feeding trials (n = 344) have investigated the effect of fructose in/on cardiometabolic endpoints. Pooled analyses show that although fructose may increase total cholesterol, uric acid, and postprandial triglycerides in isocaloric replacement for glucose, it does not appear to be any worse than glucose in its effects on other aspects of the lipid profile, insulin, or markers of nonalcoholic fatty liver disease. It may also have important advantages over glucose for body weight, glycemic control, and blood pressure. Depending on the cardiometabolic endpoint in question, fructose has variable effects when replacing glucose. In the absence of clear evidence of net harm, there is no justification to replace fructose with glucose in the diet.

  13. Evidence for central regulation of glucose metabolism.

    PubMed

    Carey, Michelle; Kehlenbrink, Sylvia; Hawkins, Meredith

    2013-12-06

    Evidence for central regulation of glucose homeostasis is accumulating from both animal and human studies. Central nutrient and hormone sensing in the hypothalamus appears to coordinate regulation of whole body metabolism. Central signals activate ATP-sensitive potassium (KATP) channels, thereby down-regulating glucose production, likely through vagal efferent signals. Recent human studies are consistent with this hypothesis. The contributions of direct and central inputs to metabolic regulation are likely of comparable magnitude, with somewhat delayed central effects and more rapid peripheral effects. Understanding central regulation of glucose metabolism could promote the development of novel therapeutic approaches for such metabolic conditions as diabetes mellitus.

  14. Increased insulin binding to adipocytes and monocytes and increased insulin sensitivity of glucose transport and metabolism in adipocytes from non-insulin-dependent diabetics after a low-fat/high-starch/high-fiber diet.

    PubMed

    Hjøllund, E; Pedersen, O; Richelsen, B; Beck-Nielsen, H; Sørensen, N S

    1983-11-01

    Nine non-insulin-dependent diabetics were studied before and after 3 weeks on an isoenergetic high-fiber/high-starch/low-fat diet (alternative diet), and nine non-insulin-dependent diabetics were studied on their usual diet. In the group that ate the alternative diet, the intake of fiber and starch increased 120% and 53%, whereas fat intake decreased 31%. Diabetes control improved as demonstrated by decreased fasting plasma glucose (P less than 0.05) and 24-hour urinary glucose excretion (P less than 0.05). The in vivo insulin action increased (KIVITT increased, P less than 0.05) with no change in fasting serum insulin levels. In fat cells obtained from patients in the alternative-diet group, insulin receptor binding increased (P less than 0.05) after the change of diet. Insulin binding to purified monocytes (more than 95% monocytes) also increased (P less than 0.05), whereas no change was found in insulin binding to erythrocytes. When lipogenesis was studied at a tracer glucose concentration at which glucose transport seems to be rate limiting, insulin sensitivity increased (P less than 0.02). This is the predicted consequence of increased receptor binding. Moreover, when CO2 production and lipogenesis were studied at a higher glucose concentration, where steps beyond transport seem to be rate limiting for glucose metabolism, increased insulin sensitivity was also observed. In contrast, no change was found in maximal insulin responsiveness. Fat and blood cells from the patients who continued on their usual diet showed no changes of the mentioned quantities.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Effect of increasing amounts of milk replacer powder added to whole milk on postweaning performance, reproduction, glucose metabolism, and mammary fat pad in dairy heifers.

    PubMed

    Lage, C F A; Azevedo, R A; Machado, F S; Campos, M M; Pereira, L G R; Tomich, T R; Carvalho, B C; Alves, B R C; Santos, G B; Brandão, F Z; Coelho, S G

    2017-09-06

    The aim of this study was to evaluate the effects of increasing the total solids (TS) content of liquid feed, by adding increasing amounts of milk replacer powder to whole milk, on age at puberty and postweaning performance, glucose metabolism, and mammary fat pad of dairy heifers. Crossbreed Holstein × Gyr heifers (n = 58) were distributed into 4 different treatments during the preweaning period. Treatments consisted of liquid feeds with TS content of 12.5 (actual TS = 13.5 ± 0.53%; n = 15), 15.0 (actual TS = 16.1 ± 0.03%; n = 15), 17.5 (actual TS = 18.2 ± 0.14%; n = 13), or 20.0% (actual TS = 20.4 ± 0.24%; n = 15), which were provided up to 59 d old. From 60 to 89 d old, the animals received the same starter offered during the preweaning period in addition to corn silage ad libitum starting at 70 d old. From 90 to 104 d old, the animals were adapted to a total mixed ration. At 105 d old, the animals were distributed in 4 paddocks equipped with electronic feed and water bins and were fed the same total mixed ration ad libitum. A period of adaptation to the electronic feed bins occurred from 105 to 119 d old. Feed and water intake and body weight and body frame development were assessed until puberty. Mammary gland evaluations were performed monthly by ultrasonography from 120 d of age until puberty onset. Puberty onset was determined as plasma progesterone concentration greater than 1 ng/mL in 2 consecutive samples collected 7 d apart. The date of puberty onset was recorded as the collection day of the first of these samples. A glucose tolerance test was performed at 280 d of age. The increased TS content of the liquid feed fed during the preweaning period did not affect dry matter intake, performance, age at puberty, glucose metabolism, or mammary gland fat pad at later stages of rearing process. Conversely, hip width and heart girth increased linearly up to 150 and 240 d of age, respectively, as a result of the increased TS concentration of the liquid feed

  16. An anthocyanin-rich extract from Kamchatka honeysuckle increases enzymatic activity within the gut and ameliorates abnormal lipid and glucose metabolism in rats.

    PubMed

    Jurgoński, Adam; Juśkiewicz, Jerzy; Zduńczyk, Zenon

    2013-06-01

    The berries of blue honeysuckle (Lonicera caerulea L.), including an edible Kamchatka variety (var. kamtschatica Sevast.), are a potential but relatively unknown source of anthocyanins, which are thought to have favorable effects on diabetes and cardiovascular disease (CVD). The aim of this study was to examine whether the dietary addition of a Kamchatka honeysuckle berry extract (KHBE, 327 mg anthocyanins/g) is able to limit the disorders related to these diseases induced by a high-fructose diet in rats. The experiment was conducted using 24 adult male Wistar rats distributed into 3 groups of 8 animals each and fed semipurified casein diets differentiated by the carbohydrate source for 4 wk, as follows: a control cornstarch diet (681 g/kg) or a high-fructose diet (633 g/kg), with or without the addition of KHBE (2 g/kg). The mucosal lactase activity in the small intestine was increased in the rats fed the KHBE-containing diet compared with the rats fed the control diet. In the cecal digesta, the dietary KHBE considerably increased bacterial α- and β-glucosidase activity. Furthermore, hyperlipidemia, hyperinsulinemia, insulin resistance, and impaired glucose tolerance were detected in the rats fed the high-fructose diet. The dietary KHBE normalized the plasma triglyceride concentration and atherogenicity, whereas plasma non-HDL cholesterol, insulin concentration, and insulin resistance were ameliorated to levels comparable with the rats fed the control diet. An anthocyanin-rich Kamchatka honeysuckle berry extract supplemented to an unbalanced diet is able to ameliorate the disturbances in lipid and glucose metabolism that are the fundamental risk factors for CVD and diabetes. Moreover, the extract stimulates enzymatic activity within the gut that seems to be related to the metabolism of polyphenols. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Sirtuins in glucose and lipid metabolism

    PubMed Central

    Ye, Xin; Li, Meiting; Hou, Tianyun; Gao, Tian; Zhu, Wei-guo; Yang, Yang

    2017-01-01

    Sirtuins are evolutionarily conserved protein, serving as nicotinamide adenine dinucleotide-dependent deacetylases or adenosine diphosphate-ribosyltransferases. The mammalian sirtuins family, including SIRT1~7, is involved in many biological processes such as cell survival, proliferation, senescence, stress response, genome stability and metabolism. Evidence accumulated over the past two decades has indicated that sirtuins not only serve as important energy status sensors but also protect cells against metabolic stresses. In this review, we summarize the background of glucose and lipid metabolism concerning sirtuins and discuss the functions of sirtuins in glucose and lipid metabolism. We also seek to highlight the biological roles of certain sirtuins members in cancer metabolism. PMID:27659520

  18. Persistent impaired glucose metabolism in a zebrafish hyperglycemia model.

    PubMed

    Capiotti, Katiucia Marques; Antonioli, Régis; Kist, Luiza Wilges; Bogo, Maurício Reis; Bonan, Carla Denise; Da Silva, Rosane Souza

    2014-05-01

    Diabetes mellitus (DM) affects over 10% of the world's population. Hyperglycemia is the main feature for the diagnosis of this disease. The zebrafish (Danio rerio) is an established model organism for the study of various metabolic diseases. In this paper, hyperglycemic zebrafish, when immersed in a 111 mM glucose solution for 14 days, developed increased glycation of proteins from the eyes, decreased mRNA levels of insulin receptors in the muscle, and a reversion of high blood glucose level after treatment with anti-diabetic drugs (glimepiride and metformin) even after 7 days of glucose withdrawal. Additionally, hyperglycemic zebrafish developed an impaired response to exogenous insulin, which was recovered after 7 days of glucose withdrawal. These data suggest that the exposure of adult zebrafish to high glucose concentration is able to induce persistent metabolic changes probably underlined by a hyperinsulinemic state and impaired peripheral glucose metabolism.

  19. Fast Food Intake Increases the Incidence of Metabolic Syndrome in Children and Adolescents: Tehran Lipid and Glucose Study.

    PubMed

    Asghari, Golaleh; Yuzbashian, Emad; Mirmiran, Parvin; Mahmoodi, Behnaz; Azizi, Fereidoun

    2015-01-01

    The aim of the study was to evaluate the association between fast food consumption and incidence of metabolic syndrome (MetS) and its components among children and adolescents over a 3.6 year follow-up. Dietary data of 424 healthy subjects, aged 6-18 years, was collected using a valid and reliable food frequency questionnaire. Metabolic syndrome was defined according to the Cook et al criteria. Consumption of fast foods including hamburgers, sausages, bologna (beef), and fried potatoes was calculated and further categorized to quartiles. Multiple logistic regression models were used to estimate the incidence of MetS and its components in each quartile of fast food intake. The incidence of MetS was 11.3% after a 3.6 year follow up. In the fully adjusted model, compared to the lowest quartile of fast food intake, individuals in the highest had odds ratios of 2.96 (95% CI: 1.02-8.63; P for trend<0.001), 2.82 (95% CI: 1.01-7.87; P for trend = 0.037), and 2.58 (95% CI: 1.01-6.61; P for trend = 0.009) for incidence of MetS, hypertriglyceridemia, and abdominal obesity, respectively. No significant association was found between fast food intakes and other components of MetS. Fast food consumption is associated with the incidence of MetS, abdominal obesity, and hypertriglyceridemia in Tehranian children and adolescents.

  20. Progesterone impairs cell respiration and suppresses a compensatory increase in glucose transport in isolated rat skeletal muscle: a non-genomic mechanism contributing to metabolic adaptation to late pregnancy?

    PubMed

    Gras, F; Brunmair, B; Quarré, L; Szöcs, Z; Waldhäusl, W; Fürnsinn, C

    2007-12-01

    The aim of the study was to gain better insight into the mechanisms responsible for impaired glucose metabolism during late pregnancy. We explored the direct effects of progesterone on glucose metabolism of skeletal muscle. Specimens of skeletal muscle from untreated rats were incubated with progesterone and rates of substrate fluxes through the various pathways of glucose metabolism were analysed. Progesterone dose-dependently reduced the rates of glucose and pyruvate oxidation (insulin-stimulated rates after 5 h of exposure to 1 and 10 mumol/l progesterone: glucose oxidation, -6 +/- 4%, NS, and -39 +/- 4%, p < 0.001; pyruvate oxidation, -28 +/- 2% and -55 +/- 4%, p < 0.001 each) and increased lactate release (+28 +/- 4% and +58 +/- 9%, p < 0.005 each), which indicated inhibition of mitochondrial respiratory function. Impairment of cell respiration, e.g. by the specific inhibitor rotenone, is known to trigger a compensatory increase in glucose transport, but this response was blunted in the case of progesterone (change of glucose transport in response to 10 mumol/l progesterone vs 60 nmol/l rotenone, both causing a reduction in glucose oxidation by -39%: progesterone, +14 +/- 8% vs rotenone, +84 +/- 23%, p < 0.03). Further experiments dealt with the underlying mechanisms and revealed a rapid mode of action (50 mumol/l progesterone, reduction in insulin-stimulated glucose oxidation after 30 min: -29 +/- 7%, p < 0.01) not affected by blockers of gene expression or the nuclear progesterone receptor. Progesterone inhibits cell respiration and at the same time suppresses a compensatory increase in glucose transport, causing cellular carbohydrate deficiency in isolated rat skeletal muscle. This effect is mediated by a direct, rapid and non-genomic mechanism and could contribute to pregnancy-associated changes in glucose homeostasis.

  1. Fast Food Intake Increases the Incidence of Metabolic Syndrome in Children and Adolescents: Tehran Lipid and Glucose Study

    PubMed Central

    Asghari, Golaleh; Yuzbashian, Emad; Mirmiran, Parvin; Mahmoodi, Behnaz; Azizi, Fereidoun

    2015-01-01

    The aim of the study was to evaluate the association between fast food consumption and incidence of metabolic syndrome (MetS) and its components among children and adolescents over a 3.6 year follow-up. Dietary data of 424 healthy subjects, aged 6–18 years, was collected using a valid and reliable food frequency questionnaire. Metabolic syndrome was defined according to the Cook et al criteria. Consumption of fast foods including hamburgers, sausages, bologna (beef), and fried potatoes was calculated and further categorized to quartiles. Multiple logistic regression models were used to estimate the incidence of MetS and its components in each quartile of fast food intake. The incidence of MetS was 11.3% after a 3.6 year follow up. In the fully adjusted model, compared to the lowest quartile of fast food intake, individuals in the highest had odds ratios of 2.96 (95% CI: 1.02–8.63; P for trend<0.001), 2.82 (95% CI: 1.01–7.87; P for trend = 0.037), and 2.58 (95% CI: 1.01–6.61; P for trend = 0.009) for incidence of MetS, hypertriglyceridemia, and abdominal obesity, respectively. No significant association was found between fast food intakes and other components of MetS. Fast food consumption is associated with the incidence of MetS, abdominal obesity, and hypertriglyceridemia in Tehranian children and adolescents. PMID:26447855

  2. Regulation of glucose metabolism and the skeleton.

    PubMed

    Ng, Kong Wah

    2011-08-01

    Complex interactions occur among adipose tissue, the central nervous system, bone and pancreas to integrate bone remodelling, glucose, lipid and energy metabolism. Data obtained largely from the judicious use of gain-of-function and loss-of-function genetic mouse models show that leptin, an adipocyte-secreted product, indirectly inhibits bone accrual through a central pathway comprising the hypothalamus and central nervous system. Increased sympathetic output acting via β2-adrenergic receptors present in osteoblasts decreases bone formation and causes increased bone resorption. Insulin is a key molecular link between bone remodelling and energy metabolism. Insulin signalling in the osteoblasts increases bone formation and resorption as well as the release of undercarboxylated osteocalcin. An increase in the release of bone-derived undercarboxylated osteocalcin into the systemic circulation enables it to act as a circulating hormone to stimulate insulin production and secretion by pancreatic β-cells and adiponectin by adipocytes. Insulin sensitivity increases, lipolysis and fat accumulation decreases while energy expenditure increases. Whether this model of integrative physiology involving the skeleton, pancreas and adipose tissue, so elegantly demonstrated in rodents, is applicable to humans is controversial. The mouse Esp gene, encoding an intracellular tyrosine phosphatase that negatively regulates insulin signalling in osteoblasts, is a pseudogene in humans, and a homolog for the Esp gene has so far not been identified in humans. A close homologue of Esp, PTP1B, is expressed in human osteoblasts and could take the role of Esp in humans. Data available from the limited number of clinical studies do not provide a sufficient body of evidence to determine whether osteocalcin or undercarboxylated osteocalcin affects glucose metabolism in humans. © 2011 Blackwell Publishing Ltd.

  3. Hypothalamic Leucine Metabolism Regulates Liver Glucose Production

    PubMed Central

    Su, Ya; Lam, Tony K.T.; He, Wu; Pocai, Alessandro; Bryan, Joseph; Aguilar-Bryan, Lydia; Gutiérrez-Juárez, Roger

    2012-01-01

    Amino acids profoundly affect insulin action and glucose metabolism in mammals. Here, we investigated the role of the mediobasal hypothalamus (MBH), a key center involved in nutrient-dependent metabolic regulation. Specifically, we tested the novel hypothesis that the metabolism of leucine within the MBH couples the central sensing of leucine with the control of glucose production by the liver. We performed either central (MBH) or systemic infusions of leucine in Sprague-Dawley male rats during basal pancreatic insulin clamps in combination with various pharmacological and molecular interventions designed to modulate leucine metabolism in the MBH. We also examined the role of hypothalamic ATP-sensitive K+ channels (KATP channels) in the effects of leucine. Enhancing the metabolism of leucine acutely in the MBH lowered blood glucose through a biochemical network that was insensitive to rapamycin but strictly dependent on the hypothalamic metabolism of leucine to α-ketoisocaproic acid and, further, insensitive to acetyl- and malonyl-CoA. Functional KATP channels were also required. Importantly, molecular attenuation of this central sensing mechanism in rats conferred susceptibility to developing hyperglycemia. We postulate that the metabolic sensing of leucine in the MBH is a previously unrecognized mechanism for the regulation of hepatic glucose production required to maintain glucose homeostasis. PMID:22187376

  4. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism

    PubMed Central

    Greer, Renee L.; Dong, Xiaoxi; Moraes, Ana Carolina F.; Zielke, Ryszard A.; Fernandes, Gabriel R.; Peremyslova, Ekaterina; Vasquez-Perez, Stephany; Schoenborn, Alexi A.; Gomes, Everton P.; Pereira, Alexandre C.; Ferreira, Sandra R. G.; Yao, Michael; Fuss, Ivan J.; Strober, Warren; Sikora, Aleksandra E.; Taylor, Gregory A.; Gulati, Ajay S.; Morgun, Andrey; Shulzhenko, Natalia

    2016-01-01

    Cross-talk between the gut microbiota and the host immune system regulates host metabolism, and its dysregulation can cause metabolic disease. Here, we show that the gut microbe Akkermansia muciniphila can mediate negative effects of IFNγ on glucose tolerance. In IFNγ-deficient mice, A. muciniphila is significantly increased and restoration of IFNγ levels reduces A. muciniphila abundance. We further show that IFNγ-knockout mice whose microbiota does not contain A. muciniphila do not show improvement in glucose tolerance and adding back A. muciniphila promoted enhanced glucose tolerance. We go on to identify Irgm1 as an IFNγ-regulated gene in the mouse ileum that controls gut A. muciniphila levels. A. muciniphila is also linked to IFNγ-regulated gene expression in the intestine and glucose parameters in humans, suggesting that this trialogue between IFNγ, A. muciniphila and glucose tolerance might be an evolutionally conserved mechanism regulating metabolic health in mice and humans. PMID:27841267

  5. Exenatide Regulates Cerebral Glucose Metabolism in Brain Areas Associated With Glucose Homeostasis and Reward System.

    PubMed

    Daniele, Giuseppe; Iozzo, Patricia; Molina-Carrion, Marjorie; Lancaster, Jack; Ciociaro, Demetrio; Cersosimo, Eugenio; Tripathy, Devjit; Triplitt, Curtis; Fox, Peter; Musi, Nicolas; DeFronzo, Ralph; Gastaldelli, Amalia

    2015-10-01

    Glucagon-like peptide 1 receptors (GLP-1Rs) have been found in the brain, but whether GLP-1R agonists (GLP-1RAs) influence brain glucose metabolism is currently unknown. The study aim was to evaluate the effects of a single injection of the GLP-1RA exenatide on cerebral and peripheral glucose metabolism in response to a glucose load. In 15 male subjects with HbA1c of 5.7 ± 0.1%, fasting glucose of 114 ± 3 mg/dL, and 2-h glucose of 177 ± 11 mg/dL, exenatide (5 μg) or placebo was injected in double-blind, randomized fashion subcutaneously 30 min before an oral glucose tolerance test (OGTT). The cerebral glucose metabolic rate (CMRglu) was measured by positron emission tomography after an injection of [(18)F]2-fluoro-2-deoxy-d-glucose before the OGTT, and the rate of glucose absorption (RaO) and disposal was assessed using stable isotope tracers. Exenatide reduced RaO0-60 min (4.6 ± 1.4 vs. 13.1 ± 1.7 μmol/min ⋅ kg) and decreased the rise in mean glucose0-60 min (107 ± 6 vs. 138 ± 8 mg/dL) and insulin0-60 min (17.3 ± 3.1 vs. 24.7 ± 3.8 mU/L). Exenatide increased CMRglu in areas of the brain related to glucose homeostasis, appetite, and food reward, despite lower plasma insulin concentrations, but reduced glucose uptake in the hypothalamus. Decreased RaO0-60 min after exenatide was inversely correlated to CMRglu. In conclusion, these results demonstrate, for the first time in man, a major effect of a GLP-1RA on regulation of brain glucose metabolism in the absorptive state.

  6. MicroRNA 33 Regulates Glucose Metabolism

    PubMed Central

    Ramírez, Cristina M.; Goedeke, Leigh; Rotllan, Noemi; Yoon, Je-Hyun; Cirera-Salinas, Daniel; Mattison, Julie A.; Suárez, Yajaira; de Cabo, Rafael; Gorospe, Myriam

    2013-01-01

    Metabolic diseases are characterized by the failure of regulatory genes or proteins to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators, recent discoveries have shown the remarkable role of small noncoding RNAs (microRNAs [miRNAs]) in the posttranscriptional regulation of gene expression. In this regard, we have recently demonstrated that miR-33a and miR33b, intronic miRNAs located within the sterol regulatory element-binding protein (SREBP) genes, regulate lipid metabolism in concert with their host genes. Here, we show that miR-33b also cooperates with SREBP1 in regulating glucose metabolism by targeting phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), key regulatory enzymes of hepatic gluconeogenesis. Overexpression of miR-33b in human hepatic cells inhibits PCK1 and G6PC expression, leading to a significant reduction of glucose production. Importantly, hepatic SREBP1c/miR-33b levels correlate inversely with the expression of PCK1 and G6PC upon glucose infusion in rhesus monkeys. Taken together, these results suggest that miR-33b works in concert with its host gene to ensure a fine-tuned regulation of lipid and glucose homeostasis, highlighting the clinical potential of miR-33a/b as novel therapeutic targets for a range of metabolic diseases. PMID:23716591

  7. Glucose and fructose metabolism in Zymomonas anaerobia

    PubMed Central

    McGill, D. J.; Dawes, E. A.

    1971-01-01

    Isotopic and enzymic evidence indicates that Zymomonas anaerobia ferments glucose via the Entner–Doudoroff pathway. The molar growth yields with glucose (5.89) and fructose (5.0) are lower than those for the related organism Zymomonas mobilis and the observed linear growth suggests that energetically uncoupled growth occurs. A survey of enzymes of carbohydrate metabolism revealed the presence of weak phosphofructokinase and fructose 1,6-diphosphate aldolase activities but phosphoketolase, transketolase and transaldolase were not detected. Fermentation balances for glucose and fructose are reported; acetaldehyde accumulated in both fermentations, to a greater extent with fructose which also yielded glycerol and dihydroxyacetone as minor products. PMID:4259336

  8. Patterns of human local cerebral glucose metabolism during epileptic seizures

    SciTech Connect

    Engel, J. Jr.; Kuhl, D.E.; Phelps, M.E.

    1982-10-01

    Ictal patterns of local cerebral metabolic rate have been studied in epileptic patients by positron computed tomography with /sup 18/F-labeled 2-fluoro-2-deoxy-D-glucose. Partial seizures were associated with activation of anatomic structures unique to each patient studied. Ictal increases and decreases in local cerebral metabolism were observed. Scans performed during generalized convulsions induced by electroshock demonstrated a diffuse ictal increase and postictal decrease in cerebral metabolism. Petit mal absences were associated with a diffuse increase in cerebral metabolic rate. The ictal fluorodeoxyglucose patterns obtained from patients do not resemble autoradiographic patterns obtained from common experimental animal models of epilepsy.

  9. Utilization of dietary glucose in the metabolic syndrome

    PubMed Central

    2011-01-01

    This review is focused on the fate of dietary glucose under conditions of chronically high energy (largely fat) intake, evolving into the metabolic syndrome. We are adapted to carbohydrate-rich diets similar to those of our ancestors. Glucose is the main energy staple, but fats are our main energy reserves. Starvation drastically reduces glucose availability, forcing the body to shift to fatty acids as main energy substrate, sparing glucose and amino acids. We are not prepared for excess dietary energy, our main defenses being decreased food intake and increased energy expenditure, largely enhanced metabolic activity and thermogenesis. High lipid availability is a powerful factor decreasing glucose and amino acid oxidation. Present-day diets are often hyperenergetic, high on lipids, with abundant protein and limited amounts of starchy carbohydrates. Dietary lipids favor their metabolic processing, saving glucose, which additionally spares amino acids. The glucose excess elicits hyperinsulinemia, which may derive, in the end, into insulin resistance. The available systems of energy disposal could not cope with the excess of substrates, since they are geared for saving not for spendthrift, which results in an unbearable overload of the storage mechanisms. Adipose tissue is the last energy sink, it has to store the energy that cannot be used otherwise. However, adipose tissue growth also has limits, and the excess of energy induces inflammation, helped by the ineffective intervention of the immune system. However, even under this acute situation, the excess of glucose remains, favoring its final conversion to fat. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic syndrome traits: insulin resistance, obesity, diabetes, liver steatosis, hyperlipidemia and their compounded combined effects. Thus, a maintained excess of energy in the diet may result in difficulties in the disposal of glucose, eliciting inflammation and the

  10. Glucose metabolism in fish: a review.

    PubMed

    Polakof, Sergio; Panserat, Stéphane; Soengas, José L; Moon, Thomas W

    2012-12-01

    Teleost fishes represent a highly diverse group consisting of more than 20,000 species living across all aquatic environments. This group has significant economical, societal and environmental impacts, yet research efforts have concentrated primarily on salmonid and cyprinid species. This review examines carbohydrate/glucose metabolism and its regulation in these model species including the role of hormones and diet. Over the past decade, molecular tools have been used to address some of the downstream components of these processes and these are incorporated to better understand the roles played by carbohydrates and their regulatory paths. Glucose metabolism remains a contentious area as many fish species are traditionally considered glucose intolerant and, therefore, one might expect that the use and storage of glucose would be considered of minor importance. However, the actual picture is not so clear since the apparent intolerance of fish to carbohydrates is not evident in herbivorous and omnivorous species and even in carnivorous species, glucose is important for specific tissues and/or for specific activities. Thus, our aim is to up-date carbohydrate metabolism in fish, placing it to the context of these new experimental tools and its relationship to dietary intake. Finally, we suggest that new research directions ultimately will lead to a better understanding of these processes.

  11. In vivo metabolic response of glucose to dichloroacetate in humans.

    PubMed

    Brown, J A; Gore, D C

    1996-03-01

    Hyperglycemia is common in severely ill patients and is related principally to an increase in glucose production. Dichloroacetate (DCA), which is known to increase the rate of pyruvate oxidation, has been shown to lower plasma glucose concentrations in normal fasting subjects and in diabetics and thus may be efficacious in treating stress induced hyperglycemia. However, the mechanism by which DCA lowers the plasma glucose concentration in humans has not been elucidated. To examine the human in vivo metabolic alterations induced by DCA, six fasting volunteers were infused with 6,6-D2-glucose and indirect calorimetry was performed prior to and following DCA administration. Glucose, lactate, and alanine net balance across the leg were also quantitated. Following DCA administration, plasma glucose concentrations decreased by 9% due to a proportional decrease in the rate of glucose production (P < 0.05). DCA had no affect on glucose clearance or leg net balance; however, the rate of glucose oxidation increased by 24% from baseline (P < 0.05). This increase in glucose oxidation without a compensatory change in peripheral glucose consumption suggests an improved efficiency in peripheral glucose utilization induced by DCA. Plasma concentrations of lactate and alanine were also lowered by DCA (56% for lactate, 66% for alanine, P < 0.05) without a significant alteration in leg net balance. These results suggest that DCA may decrease gluconeogenesis by limiting the availability of the precursor substrates lactate and alanine. Thus dichloroacetate may be an appropriate alternative to insulin in correcting mild elevations in plasma glucose concentrations. Furthermore, DCA may be especially effective in severely ill patients where hyperglycemia is largely due to increases in gluconeogenesis.

  12. Platelet-activating factor-induced increases in glucose kinetics

    SciTech Connect

    Lang, C.H.; Dobrescu, C.; Hargrove, D.M.; Bagby, G.J.; Spitzer, J.J. )

    1988-02-01

    Platelet-activating factor (PAF) is a postulated mediator of many of the early hemodynamic effects of endotoxin. The aim of the present study was to determine whether in vivo administration of PAF could produce alterations in whole-body glucose metabolism that would mimic those seen during endotoxemia. Glucose kinetics were assessed in chronically catheterized conscious rats by the constant infusion of (6-{sup 3}H)- and (U-{sup 14}C)glucose before and for 4 h after either a bolus injection or a constant infusion of PAF. The bolus injection of PAF elevated the rate of glucose appearance (R{sub a}; 44%) for 1.5 h. The lower PAF infusion rate decreased blood pressure 11% to 104 mmHg, whereas the higher infusion rate decreased pressure 34% to 77 mmHg. Both PAF infusion rates produced elevations in plasma glucose and glucose R{sub a} throughout the 4-h infusion period in a dose-related manner. The PAF infusions also induced dose-related increases in plasma glucagon and catecholamine levels throughout the infusion period. Because the constant infusion of PAF did stimulate many of the hemodynamic and metabolic alterations produced by endotoxin, this study provides additional support for the potential importance of PAF as a mediator of the early hemodynamic and metabolic sequela of endotoxin shock. Furthermore, the PAF-induced changes in glucose metabolism appear to be mediated by the resultant elevation in plasma catecholamines.

  13. A link between sleep loss, glucose metabolism and adipokines.

    PubMed

    Padilha, H G; Crispim, C A; Zimberg, I Z; De-Souza, D A; Waterhouse, J; Tufik, S; de-Mello, M T

    2011-10-01

    The present review evaluates the role of sleep and its alteration in triggering problems of glucose metabolism and the possible involvement of adipokines in this process. A reduction in the amount of time spent sleeping has become an endemic condition in modern society, and a search of the current literature has found important associations between sleep loss and alterations of nutritional and metabolic contexts. Studies suggest that sleep loss is associated with problems in glucose metabolism and a higher risk for the development of insulin resistance and type 2 diabetes mellitus. The mechanism involved may be associated with the decreased efficacy of regulation of the hypothalamus-pituitary-adrenal axis by negative feedback mechanisms in sleep-deprivation conditions. In addition, changes in the circadian pattern of growth hormone (GH) secretion might also contribute to the alterations in glucose regulation observed during sleep loss. On the other hand, sleep deprivation stress affects adipokines - increasing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and decreasing leptin and adiponectin -, thus establishing a possible association between sleep-debt, adipokines and glucose metabolism. Thus, a modified release of adipokines resulting from sleep deprivation could lead to a chronic sub-inflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes mellitus. Further studies are necessary to investigate the role of sleep loss in adipokine release and its relationship with glucose metabolism.

  14. A link between hepatic glucose production and peripheral energy metabolism via hepatokines.

    PubMed

    Abdul-Wahed, Aya; Gautier-Stein, Amandine; Casteras, Sylvie; Soty, Maud; Roussel, Damien; Romestaing, Caroline; Guillou, Hervé; Tourette, Jean-André; Pleche, Nicolas; Zitoun, Carine; Gri, Blandine; Sardella, Anne; Rajas, Fabienne; Mithieux, Gilles

    2014-08-01

    Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes.

  15. Glucose metabolism in cultured trophoblasts from human placenta

    SciTech Connect

    Moe, A.J.; Farmer, D.R.; Nelson, D.M.; Smith, C.H. )

    1990-02-26

    The development of appropriate placental trophoblast isolation and culture techniques enables the study of pathways of glucose utilization by this important cell layer in vitro. Trophoblasts from normal term placentas were isolated and cultured 24 hours and 72 hours in uncoated polystyrene culture tubes or tubes previously coated with a fibrin matrix. Trophoblasts cultured on fibrin are morphologically distinct from those cultured on plastic or other matrices and generally resemble in vivo syncytium. Cells were incubated up to 3 hours with {sup 14}C-labeled glucose and reactions were stopped by addition of perchloric acid. {sup 14}CO{sub 2} production by trophoblasts increased linearly with time however the largest accumulation of label was in organic acids. Trophoblasts cultured in absence of fibrin utilized more glucose and accumulated more {sup 14}C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO{sub 2} by the phosphogluconate (PG) pathway was estimated from specific yields of {sup 14}CO{sub 2} from (1-{sup 14}C)-D-glucose and (6-{sup 14}C)-D-glucose. Approximately 6% of glucose oxidation was by the PG pathway when cells were cultured on fibrin compared to approximately 1% by cells cultured in the absence of fibrin. The presence of a fibrin growth matrix appears to modulate the metabolism of glucose by trophoblast from human placenta in vitro.

  16. Diabetes and Altered Glucose Metabolism with Aging

    PubMed Central

    Kalyani, Rita Rastogi; Egan, Josephine M.

    2013-01-01

    I. Synopsis Diabetes and impaired glucose tolerance affect a substantial proportion of older adults. While the aging process can be associated with alterations in glucose metabolism, including both relative insulin resistance and islet cell dysfunction, abnormal glucose metabolism is not a necessary component of aging. Instead, older adults with diabetes and altered glucose status likely represent a vulnerable subset of the population at high-risk for complications and adverse geriatric syndromes such as accelerated muscle loss, functional disability, frailty, and early mortality. Goals for treatment of diabetes in the elderly include control of hyperglycemia, prevention and treatment of diabetic complications, avoidance of hypoglycemia and preservation of quality of life. Given the heterogeneity of the elderly population with regards to the presence of comorbidities, life expectancy, and functional status, an individualized approach to diabetes management is often appropriate. A growing area of research seeks to explore associations of dysglycemia and insulin resistance with the development of adverse outcomes in the elderly and may ultimately inform guidelines on the use of future glucose-lowering therapies in this population. PMID:23702405

  17. Metabolic Profiling of the Response to an Oral Glucose Tolerance Test Detects Subtle Metabolic Changes

    PubMed Central

    Wopereis, Suzan; Rubingh, Carina M.; van Erk, Marjan J.; Verheij, Elwin R.; van Vliet, Trinette; Cnubben, Nicole H. P.; Smilde, Age K.; van der Greef, Jan; van Ommen, Ben; Hendriks, Henk F. J.

    2009-01-01

    Background The prevalence of overweight is increasing globally and has become a serious health problem. Low-grade chronic inflammation in overweight subjects is thought to play an important role in disease development. Novel tools to understand these processes are needed. Metabolic profiling is one such tool that can provide novel insights into the impact of treatments on metabolism. Methodology To study the metabolic changes induced by a mild anti-inflammatory drug intervention, plasma metabolic profiling was applied in overweight human volunteers with elevated levels of the inflammatory plasma marker C-reactive protein. Liquid and gas chromatography mass spectrometric methods were used to detect high and low abundant plasma metabolites both in fasted conditions and during an oral glucose tolerance test. This is based on the concept that the resilience of the system can be assessed after perturbing a homeostatic situation. Conclusions Metabolic changes were subtle and were only detected using metabolic profiling in combination with an oral glucose tolerance test. The repeated measurements during the oral glucose tolerance test increased statistical power, but the metabolic perturbation also revealed metabolites that respond differentially to the oral glucose tolerance test. Specifically, multiple metabolic intermediates of the glutathione synthesis pathway showed time-dependent suppression in response to the glucose challenge test. The fact that this is an insulin sensitive pathway suggests that inflammatory modulation may alter insulin signaling in overweight men. PMID:19242536

  18. 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

  19. HDL and glucose metabolism: current evidence and therapeutic potential

    PubMed Central

    Siebel, Andrew L.; Heywood, Sarah Elizabeth; Kingwell, Bronwyn A.

    2015-01-01

    High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies. PMID:26582989

  20. HDL and glucose metabolism: current evidence and therapeutic potential.

    PubMed

    Siebel, Andrew L; Heywood, Sarah Elizabeth; Kingwell, Bronwyn A

    2015-01-01

    High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

  1. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress.

    PubMed

    Kim, Nam Hee; Cha, Yong Hoon; Lee, Jueun; Lee, Seon-Hyeong; Yang, Ji Hye; Yun, Jun Seop; Cho, Eunae Sandra; Zhang, Xianglan; Nam, Miso; Kim, Nami; Yuk, Young-Su; Cha, So Young; Lee, Yoonmi; Ryu, Joo Kyung; Park, Sunghyouk; Cheong, Jae-Ho; Kang, Sang Won; Kim, Soo-Youl; Hwang, Geum-Sook; Yook, Jong In; Kim, Hyun Sil

    2017-02-08

    Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial-mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of phosphofructokinase, platelet (PFKP), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP.

  2. Snail reprograms glucose metabolism by repressing phosphofructokinase PFKP allowing cancer cell survival under metabolic stress

    PubMed Central

    Kim, Nam Hee; Cha, Yong Hoon; Lee, Jueun; Lee, Seon-Hyeong; Yang, Ji Hye; Yun, Jun Seop; Cho, Eunae Sandra; Zhang, Xianglan; Nam, Miso; Kim, Nami; Yuk, Young-Su; Cha, So Young; Lee, Yoonmi; Ryu, Joo Kyung; Park, Sunghyouk; Cheong, Jae-Ho; Kang, Sang Won; Kim, Soo-Youl; Hwang, Geum-Sook; Yook, Jong In; Kim, Hyun Sil

    2017-01-01

    Dynamic regulation of glucose flux between aerobic glycolysis and the pentose phosphate pathway (PPP) during epithelial–mesenchymal transition (EMT) is not well-understood. Here we show that Snail (SNAI1), a key transcriptional repressor of EMT, regulates glucose flux toward PPP, allowing cancer cell survival under metabolic stress. Mechanistically, Snail regulates glycolytic activity via repression of phosphofructokinase, platelet (PFKP), a major isoform of cancer-specific phosphofructokinase-1 (PFK-1), an enzyme involving the first rate-limiting step of glycolysis. The suppression of PFKP switches the glucose flux towards PPP, generating NADPH with increased metabolites of oxidative PPP. Functionally, dynamic regulation of PFKP significantly potentiates cancer cell survival under metabolic stress and increases metastatic capacities in vivo. Further, knockdown of PFKP rescues metabolic reprogramming and cell death induced by loss of Snail. Thus, the Snail-PFKP axis plays an important role in cancer cell survival via regulation of glucose flux between glycolysis and PPP. PMID:28176759

  3. Glucose regulates lipid metabolism in fasting king penguins.

    PubMed

    Bernard, Servane F; Orvoine, Jord; Groscolas, René

    2003-08-01

    This study aims to determine whether glucose intervenes in the regulation of lipid metabolism in long-term fasting birds, using the king penguin as an animal model. Changes in the plasma concentration of various metabolites and hormones, and in lipolytic fluxes as determined by continuous infusion of [2-3H]glycerol and [1-14C]palmitate, were examined in vivo before, during, and after a 2-h glucose infusion under field conditions. All the birds were in the phase II fasting status (large fat stores, protein sparing) but differed by their metabolic and hormonal statuses, being either nonstressed (NSB; n = 5) or stressed (SB; n = 5). In both groups, glucose infusion at 5 mg.kg-1.min-1 induced a twofold increase in glycemia. In NSB, glucose had no effect on lipolysis (maintenance of plasma concentrations and rates of appearance of glycerol and nonesterified fatty acids) and no effect on the plasma concentrations of triacylglycerols (TAG), glucagon, insulin, or corticosterone. However, it limited fatty acid (FA) oxidation, as indicated by a 25% decrease in the plasma level of beta-hydroxybutyrate (beta-OHB). In SB, glucose infusion induced an approximately 2.5-fold decrease in lipolytic fluxes and a large decrease in FA oxidation, as reflected by a 64% decrease in the plasma concentration of beta-OHB. There were also a 35% decrease in plasma TAG, a 6.5- and 2.8-fold decrease in plasma glucagon and corticosterone, respectively, and a threefold increase in insulinemia. These data show that in fasting king penguins, glucose regulates lipid metabolism (inhibition of lipolysis and/or of FA oxidation) and affects hormonal status differently in stressed vs. nonstressed individuals. The results also suggest that in birds, as in humans, the availability of glucose, not of FA, is an important determinant of the substrate mix (glucose vs. FA) that is oxidized for energy production.

  4. Enhanced hydrogen production from glucose by metabolically engineered Escherichia coli.

    PubMed

    Maeda, Toshinari; Sanchez-Torres, Viviana; Wood, Thomas K

    2007-12-01

    To utilize fermentative bacteria for producing the alternative fuel hydrogen, we performed successive rounds of P1 transduction from the Keio Escherichia coli K-12 library to introduce multiple, stable mutations into a single bacterium to direct the metabolic flux toward hydrogen production. E. coli cells convert glucose to various organic acids (such as succinate, pyruvate, lactate, formate, and acetate) to synthesize energy and hydrogen from formate by the formate hydrogen-lyase (FHL) system that consists of hydrogenase 3 and formate dehydrogenase-H. We altered the regulation of FHL by inactivating the repressor encoded by hycA and by overexpressing the activator encoded by fhlA, removed hydrogen uptake activity by deleting hyaB (hydrogenase 1) and hybC (hydrogenase 2), redirected glucose metabolism to formate by using the fdnG, fdoG, narG, focA, focB, poxB, and aceE mutations, and inactivated the succinate and lactate synthesis pathways by deleting frdC and ldhA, respectively. The best of the metabolically engineered strains, BW25113 hyaB hybC hycA fdoG frdC ldhA aceE, increased hydrogen production 4.6-fold from glucose and increased the hydrogen yield twofold from 0.65 to 1.3 mol H(2)/mol glucose (maximum, 2 mol H(2)/mol glucose).

  5. Impaired glucose metabolism in hypertensive patients.

    PubMed

    Fragachan, F; Perez-Acuña, F; Monsalve, P; Sanabria, A

    1990-01-01

    the free glucose pool at zero time. A significantly higher level was found in hypertensives with pathological Kg values, again indicating an impairment in glucose metabolism in this group: 90.6 +/- 26.5 vs. 65.0 +/- 5.4 g (p less than 0.0001). Another study showed an estimate of the mean cellular glucose uptake (MCUg) per minute and per kilogram body weight. The MCUg following glucose loading decreased considerably in hypertensives with pathological Kg values. The percentage reduction ranged between 50 and 55% hypertensives with pathological Kg values 4.1 +/- 0.8, and normotensives with normal Kg values, 8.0 +/- 0.6 (p less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

  6. Adult glucose metabolism in extremely birthweight-discordant monozygotic twins.

    PubMed

    Frost, M; Petersen, I; Brixen, K; Beck-Nielsen, H; Holst, J J; Christiansen, L; Højlund, K; Christensen, K

    2012-12-01

    Low birthweight (BW) is associated with increased risk of type 2 diabetes. We compared glucose metabolism in adult BW-discordant monozygotic (MZ) twins, thereby controlling for genetic factors and rearing environment. Among 77,885 twins in the Danish Twin Registry, 155 of the most BW-discordant MZ twin pairs (median BW difference 0.5 kg) were assessed using a 2 h oral glucose tolerance test with sampling of plasma (p-)glucose, insulin, C-peptide, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. HOMA for beta cell function (HOMA-β) and insulin resistance (HOMA-IR), and also insulin sensitivity index (BIGTT-SI) and acute insulin response (BIGTT-AIR), were calculated. Subgroup analyses were performed in those with: (1) double verification of BW difference; (2) difference in BW >0.5 kg; and (3) no overt metabolic disease (type 2 diabetes, hyperlipidaemia or thyroid disease). No intra-pair differences in p-glucose, insulin, C-peptide, incretin hormones, HOMA-β, HOMA-IR or BIGTT-SI were identified. p-Glucose at 120 min was higher in the twins with the highest BW without metabolic disease, and BIGTT-AIR was higher in those with the highest BW although not in pairs with a BW difference of >0.5 kg. BW-discordant MZ twins provide no evidence for a detrimental effect of low BW on glucose metabolism in adulthood once genetic factors and rearing environment are controlled for.

  7. Cerebral glucose metabolism in the course of subacute sclerosing panencephalitis

    SciTech Connect

    Huber, M.; Herholz, K.; Pawlik, G.; Szelies, B.; Juergens, R.H.; Heiss, W.D.

    1989-01-01

    Regional cerebral glucose metabolism was studied in a 15-year-old boy with subacute sclerosing panencephalitis before and after therapy with human interferon beta, using positron emission tomography of fluorine 18-2-fluoro-2-deoxyglucose. At first examination, metabolism was symmetrically decreased in the thalamus, cerebellum, and all cortical areas except prerolandic motor cortex, but increased in lentiform nucleus. A computed tomographic scan was normal. Six months later, bilateral focal necrosis centered in the previously hypermetabolic putamen was demonstrated by computed tomography and magnetic resonance imaging. The caudate nucleus and the superoposterior part of the putamen were spared, still showing increased metabolism. Corresponding with some clinical improvement, cortical glucose consumption rates had returned to a normal level.

  8. Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine.

    PubMed

    Leke, Renata; Bak, Lasse K; Anker, Malene; Melø, Torun M; Sørensen, Michael; Keiding, Susanne; Vilstrup, Hendrik; Ott, Peter; Portela, Luis V; Sonnewald, Ursula; Schousboe, Arne; Waagepetersen, Helle S

    2011-04-01

    Cerebral hyperammonemia is believed to play a pivotal role in the development of hepatic encephalopathy (HE), a debilitating condition arising due to acute or chronic liver disease. In the brain, ammonia is thought to be detoxified via the activity of glutamine synthetase, an astrocytic enzyme. Moreover, it has been suggested that cerebral tricarboxylic acid (TCA) cycle metabolism is inhibited and glycolysis enhanced during hyperammonemia. The aim of this study was to characterize the ammonia-detoxifying mechanisms as well as the effects of ammonia on energy-generating metabolic pathways in a mouse neuronal-astrocytic co-culture model of the GABAergic system. We found that 5 mM ammonium chloride affected energy metabolism by increasing the neuronal TCA cycle activity and switching the astrocytic TCA cycle toward synthesis of substrate for glutamine synthesis. Furthermore, ammonia exposure enhanced the synthesis and release of alanine. Collectively, our results demonstrate that (1) formation of glutamine is seminal for detoxification of ammonia; (2) neuronal oxidative metabolism is increased in the presence of ammonia; and (3) synthesis and release of alanine is likely to be important for ammonia detoxification as a supplement to formation of glutamine.

  9. Effects of oral glucose on systemic glucose metabolism during hyperinsulinemic hypoglycemia in normal man.

    PubMed

    Poulsen, P L; Orskov, L; Grøfte, T; Møller, J; Holst, J J; Schmitz, O; Møller, N

    2000-12-01

    The widespread use of oral glucose in the treatment of hypoglycemia is mainly empirically based, and little is known about the time lag and subsequent magnitude of effects following its administration. To define the systemic impact and time course of effects following oral glucose during hypoglycemia, we investigated 7 healthy young men twice. On both occasions, a 6-hour hyperinsulinemic (1.5 mU/kg/min)-hypoglycemic clamp was performed to ensure similar plasma glucose profiles during a stepwise decrease toward a nadir less than 50 mg/100 mL after 3 hours. On the first occasion, subjects ingested 40 g glucose and 4 g 3-ortho-methylglucose ([3-OMG] to trace glucose absorption) dissolved in 400 mL tap water after 3.5 hours. The second examination was identical except for the omission of 40 g oral glucose, and glucose levels were clamped at hypoglycemic concentrations similar to those recorded on the first examination. Plasma glucose curves were superimposable, and all participants reached a nadir less than 50 mg/100 mL. Similar increases in growth hormone (GH) and glucagon were observed in both situations. The glucose infusion rates (GIRs) were lower after oral glucose, with the difference starting after 5 to 10 minutes, being statistically significant after 20 minutes, and reaching a maximum of 8.5 +/- 1.6 mg/kg/min after 40 minutes. Circulating 3-OMG increased after 20 minutes. In both situations, infusion of insulin resulted in insulin levels of approximately 150 microU/mL and a suppression of C-peptide levels from 2.0 to 1.1 nmol/L (P < .01). After glucose ingestion, both serum C-peptide and glucagon-like peptide-1 (GLP-1) increased (C-peptide from 1.1 +/- 0.05 to 1.4 +/- 0.05 nmol/L and GLP-1 from 3.2 +/- 0.8 to 18.1 +/- 3.3 pmol/L), in contrast to the situation without oral glucose (P < .05). Isotopically determined glucose turnover was similar. In conclusion, our data suggest that oral glucose affects systemic glucose metabolism rapidly after 5 to 10 minutes

  10. Effect of specific growth rate and glucose concentration on growth and glucose metabolism of Escherichia coli K-12.

    PubMed

    Hollywood, N; Doelle, H W

    1976-01-01

    Chemostat cultures of E. coli K-12 revealed that the metabolic change from respiration to aerobic fermentation can be obtained with increasing specific growth rate at low glucose input concentration (0.1%), or increasing glucose input concentrations at low specific growth rate (0.1 h-1). Both effects do not affect biomass formation. The metabolic change is not related to a pathway switch of glucose utilization. The increase in specific growth rate causes suppression of succinate dehydrogenase, and NADH oxidase, whereas glucose increases cause suppression of succinate dehydrogenase, cytochrome a and 2-ketoglutarate dehydrogenase. Both phenomena are reflected in the specific oxygen uptake rate, specific carbon dioxide production rate and respiratory quotient values. Growth limitation could be related to a maximal glucose uptake rate of the cell and thus constitutes an entirely different effect caused by high glucose input concentration.

  11. Ghrelin in the control of energy, lipid, and glucose metabolism.

    PubMed

    Heppner, Kristy M; Müller, Timo D; Tong, Jenny; Tschöp, Matthias H

    2012-01-01

    The discovery of ghrelin as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) led to subsequent studies characterizing the endogenous action of this gastrointestinal hormone. Accordingly, exogenous administration of ghrelin was found to increase food intake and adiposity in a variety of species, including rodents, nonhuman primates, and humans. Later work supported these findings and confirmed that ghrelin acts through hypothalamic neurons to mediate its effects on energy metabolism. Ghrelin acts specifically through GHS-R to promote a positive energy balance as demonstrated by loss of ghrelin action after pharmacological blockade or genetic deletion of GHS-R. More recently, ghrelin was found to be a mediator of glucose metabolism and acts to inhibit insulin secretion from pancreatic β-cells. Together, the literature highlights a predominant role of ghrelin in regulating energy and glucose metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. LncRNA ANRIL is up-regulated in nasopharyngeal carcinoma and promotes the cancer progression via increasing proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells

    PubMed Central

    Zou, Zhen Wei; Ma, Charlie; Medoro, Lorraine; Chen, Lili; Wang, Bin; Gupta, Roohi; Liu, Ting; Yang, Xian Zi; Chen, Tian Tian; Wang, Ruo Zhen; Zhang, Wen Jie; Li, Pin Dong

    2016-01-01

    Long noncoding RNAs play a vital role in diverse biological processes such as embryonic development, cell growth, and tumorigenesis. In this study, we report that LncRNA ANRIL, which encodes a 3834-nt RNA that contains 19 exons at the antisense orientation of the INK4B-ARF-INK4A gene cluster, generally up-regulated in nasopharyngeal carcinoma [1]. In a cohort of 88 NPC patients, ANRIL was highly expressed in advanced-stage cancer. Multivariate analyses revealed that ANRIL expression could serve as an independent predictor of overall survival (P = 0.027) and disease-free survival (P = 0.033). Further investigation showed that knockdown of ANRIL significantly repressed NPC cell proliferation and transformation. We also found that ANRIL could induce the percentage of side population cells (SP cells) in NPC. To meet the urgent needs of energy provision, ANRIL can also reprogram glucose metabolism via increasing glucose uptake for glycolysis, which was regulated by the mTOR signal pathway to affect the expression of essential genes in glycolysis. We concluded that ANRIL could promote NPC progression via increasing cell proliferation, reprograming cell glucose metabolism and inducing side-population stem-like cancer cells. Our results also suggested that ANRIL may serve as a novel diagnostic or prognostic biomarker and a candidate target for new therapies in NPC. PMID:27557514

  13. Remodeling of Oxidative Energy Metabolism by Galactose Improves Glucose Handling and Metabolic Switching in Human Skeletal Muscle Cells

    PubMed Central

    Kase, Eili Tranheim; Nikolić, Nataša; Bakke, Siril Skaret; Bogen, Kaja Kamilla; Aas, Vigdis; Thoresen, G. Hege; Rustan, Arild Christian

    2013-01-01

    Cultured human myotubes have a low mitochondrial oxidative potential. This study aims to remodel energy metabolism in myotubes by replacing glucose with galactose during growth and differentiation to ultimately examine the consequences for fatty acid and glucose metabolism. Exposure to galactose showed an increased [14C]oleic acid oxidation, whereas cellular uptake of oleic acid uptake was unchanged. On the other hand, both cellular uptake and oxidation of [14C]glucose increased in myotubes exposed to galactose. In the presence of the mitochondrial uncoupler carbonylcyanide p-trifluormethoxy-phenylhydrazone (FCCP) the reserve capacity for glucose oxidation was increased in cells grown with galactose. Staining and live imaging of the cells showed that myotubes exposed to galactose had a significant increase in mitochondrial and neutral lipid content. Suppressibility of fatty acid oxidation by acute addition of glucose was increased compared to cells grown in presence of glucose. In summary, we show that cells grown in galactose were more oxidative, had increased oxidative capacity and higher mitochondrial content, and showed an increased glucose handling. Interestingly, cells exposed to galactose showed an increased suppressibility of fatty acid metabolism. Thus, galactose improved glucose metabolism and metabolic switching of myotubes, representing a cell model that may be valuable for metabolic studies related to insulin resistance and disorders involving mitochondrial impairments. PMID:23560061

  14. Targeting glucose metabolism for healthy aging

    PubMed Central

    Brewer, Rachel A.; Gibbs, Victoria K.; Smith, Daniel L.

    2016-01-01

    Advancing age is the greatest single risk factor for numerous chronic diseases. Thus, the ability to target the aging process can facilitate improved healthspan and potentially lifespan. Lack of adequate glucoregulatory control remains a recurrent theme accompanying aging and chronic disease, while numerous longevity interventions result in maintenance of glucoregulatory control. In this review, we propose targeting glucose metabolism to enhance regulatory control as a means to ameliorate the aging process. We highlight that calorie restriction improves glucoregulatory control and extends both lifespan and healthspan in model organisms, but we also indicate more practical interventions (i.e., calorie restriction mimetics) are desirable for clinical application in humans. Of the calorie restriction mimetics being investigated, we focus on the type 2 diabetes drug acarbose, an α-glucosidase inhibitor that when taken with a meal, results in reduced enzymatic degradation and absorption of glucose from complex carbohydrates. We discuss alternatives to acarbose that yield similar physiologic effects and describe dietary sources (e.g., sweet potatoes, legumes, and berries) of bioactive compounds with α-glucosidase inhibitory activity. We indicate future research should include exploration of how non-caloric compounds like α-glucosidase inhibitors modify macronutrient metabolism prior to disease onset, which may guide nutritional/lifestyle interventions to support health and reduce age-related disease risk. PMID:28035340

  15. Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease

    PubMed Central

    Protas, Hillary D.; Chen, Kewei; Langbaum, Jessica B. S.; Fleisher, Adam S.; Alexander, Gene E.; Lee, Wendy; Bandy, Daniel; de Leon, Mony J.; Mosconi, Lisa; Buckley, Shannon; Truran-Sacrey, Diana; Schuff, Norbert; Weiner, Michael W.; Caselli, Richard J.; Reiman, Eric M.

    2013-01-01

    Objective To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease. Design Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers. Setting Academic medical center. Participants A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level. Main Outcome Measures The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume. Results Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05, determined by use of pairwise Fisher z tests). Conclusions Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or

  16. Proton pump inhibitors: impact on glucose metabolism.

    PubMed

    Boj-Carceller, Diana

    2013-02-01

    Diabetes mellitus is a complex chronic disease associated with an absolute insulin deficiency in type 1 diabetes (T1D) and a progressive deterioration of β-cell function in type 2 diabetes (T2D). T2D pathophysiology has numerous defects including incretin deficiency/resistance. Gastrin has demonstrated to be an islet growth factor (like glucagon-like peptide-1, epidermal growth factor, transforming growth factor-α,…) and be able to restore a functional β-cell mass in diabetic animals. This hormone is likely to stimulate insulin secretion during an ordinary protein-rich meal, this is, to have an incretin-like effect. Proton pump inhibitors (PPIs) can raise serum gastrin concentration significantly and therefore, affect to glucose metabolism through promoting β-cell regeneration/expansion and also enhancing insulin secretion. The present paper aims to review studies concerning the effect of PPIs on glucose metabolism. Several research groups have recently explored the potential role of this class of drugs on glycemic control, mainly in T2D. The results show antidiabetic properties for the PPIs with a global glucose-lowering power around 0.6-0.7 % points of HbA1c, but the level of evidence for the available literature is still not high. If these data start to become demonstrated in the ongoing clinical trials, PPIs could become a new antidiabetic agent with a good and safe profile for T2D and even useful for T1D, particularly in the area of islet transplantation to preserve β-cell mass.

  17. Serotonin modulation of cerebral glucose metabolism: sex and age effects.

    PubMed

    Munro, Cynthia A; Workman, Clifford I; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S

    2012-11-01

    The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20-79 years) underwent two resting positron emission tomography studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([(18)F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. Copyright © 2012 Wiley Periodicals, Inc.

  18. SEROTONIN MODULATION OF CEREBRAL GLUCOSE METABOLISM: SEX AND AGE EFFECTS

    PubMed Central

    Munro, Cynthia A.; Workman, Clifford; Kramer, Elisse; Hermann, Carol; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S.

    2012-01-01

    The serotonin system is implicated in a variety of psychiatric disorders whose clinical presentation and response to treatment differ between males and females, as well as with aging. However, human neurobiological studies are limited. Sex differences in the cerebral metabolic response to an increase in serotonin concentrations were measured, as well as the effect of aging, in men compared to women. Thirty-three normal healthy individuals (14 men/19 women, age range 20–79 years) underwent two resting positron emission tomography (PET) studies with the radiotracer [18F]-2-deoxy-2-fluoro-D-glucose ([18F]-FDG) after placebo and selective serotonin reuptake inhibitor (SSRI, citalopram) infusions on two separate days. Results indicated that women demonstrated widespread areas of increased cortical glucose metabolism with fewer areas of decrease in metabolism in response to citalopram. Men, in contrast, demonstrated several regions of decreased cortical metabolism, but no regions of increased metabolism. Age was associated with greater increases in women and greater decreases in men in most brain regions. These results support prior studies indicating that serotonin function differs in men and women across the lifespan. Future studies aimed at characterizing the influences of age and sex on the serotonin system in patients with psychiatric disorders are needed to elucidate the relationship between sex and age differences in brain chemistry and associated differences in symptom presentation and treatment response. PMID:22836227

  19. Glucose Metabolism of the Isolated Eccrine Sweat Gland

    PubMed Central

    Sato, Kenzo; Dobson, Richard L.

    1973-01-01

    This paper attempts to further clarify the characteristics of Mecholyl- or epinephrine-stimulated glucose metabolism in the isolated monkey eccrine sweat gland with special emphasis on its relationship to increased sodium transport. The Mecholyl- or epinephrine-stimulated glucose metabolism (as estimated by either lactate or 14CO2 production or both) is seen only in the secretory coil and not in the duct. It is markedly suppressed in the absence of glucose, Na+, or K+. It is inhibited by ouabain (10−3 M) and partially suppressed in a low-sodium (40 mM), high-potassium (100 mM) medium. 2,4-dinitrophenol (10−4 M) reverses ouabain-induced inhibition of lactate and 14CO2 production but only partially reverses inhibition induced by Na+ + K+ deprivation, indicating that metabolic inhibition by ouabain is secondary to the inhibition of sodium transport. There is no synergism between Mecholyl and epinephrine. The absence of any significant inhibitory effects by acetazolamide (Diamox) or HCO3−-free media suggests that H+ transport may not be important in sweat gland function. In contrast to a report by Wolfe et al., human eccrine sweat glands show considerable oxidative activity (14CO2 production of 0.42-0.72 nmol/gland/h). These observations are discussed in terms of the linkage between sweat gland energy metabolism and sodium transport. PMID:4269528

  20. Linking neuronal brain activity to the glucose metabolism

    PubMed Central

    2013-01-01

    Background Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. Methods First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Results Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. Conclusions The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID:23988084

  1. Cerebral glucose metabolic differences in patients with panic disorder

    SciTech Connect

    Nordahl, T.E.; Semple, W.E.; Gross, M.; Mellman, T.A.; Stein, M.B.; Goyer, P.; King, A.C.; Uhde, T.W.; Cohen, R.M. )

    1990-08-01

    Regional glucose metabolic rates were measured in patients with panic disorder during the performance of auditory discrimination. Those regions examined by Reiman and colleagues in their blood flow study of panic disorder were examined with a higher resolution positron emission tomography (PET) scanner and with the tracer (F-18)-2-fluoro-2-deoxyglucose (FDG). In contrast to the blood flow findings of Reiman et al., we did not find global gray metabolic differences between patients with panic disorder and normal controls. Consistent with the findings of Reiman et al., we found hippocampal region asymmetry. We also found metabolic decreases in the left inferior parietal lobule and in the anterior cingulate (trend), as well as an increase in the metabolic rate of the medial orbital frontal cortex (trend) of panic disorder patients. It is unclear whether the continuous performance task (CPT) enhanced or diminished findings that would have been noted in a study performed without task.

  2. Circadian system and glucose metabolism: implications for physiology and disease

    PubMed Central

    Qian, Jingyi; Scheer, Frank AJL

    2016-01-01

    The circadian system serves one of the most fundamental properties present in nearly all organisms: it generates 24-hr rhythms in behavioral and physiological processes and enables anticipating and adapting to daily environmental changes. Recent studies indicate that the circadian system is important in regulating the daily rhythm in glucose metabolism. Disturbance of this circadian control or of its coordination relative to the environmental/behavioral cycle, such as in shift work, eating late or due to genetic changes, results in disturbed glucose control and increased type 2 diabetes risk. Therefore, an in-depth understanding of the mechanisms underlying glucose regulation by the circadian system and its disturbance may help in the development of therapeutic interventions against the deleterious health consequences of circadian disruption. PMID:27079518

  3. Decaffeinated Coffee and Glucose Metabolism in Young Men

    PubMed Central

    Greenberg, James A.; Owen, David R.; Geliebter, Allan

    2010-01-01

    OBJECTIVE The epidemiological association between coffee drinking and decreased risk of type 2 diabetes is strong. However, caffeinated coffee acutely impairs glucose metabolism. We assessed acute effects of decaffeinated coffee on glucose and insulin levels. RESEARCH DESIGN AND METHODS This was a randomized, cross-over, placebo-controlled trial of the effects of decaffeinated coffee, caffeinated coffee, and caffeine on glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels during a 2-h oral glucose tolerance test (OGTT) in 11 young men. RESULTS Within the first hour of the OGTT, glucose and insulin were higher for decaffeinated coffee than for placebo (P < 0.05). During the whole OGTT, decaffeinated coffee yielded higher insulin than placebo and lower glucose and a higher insulin sensitivity index than caffeine. Changes in GIP could not explain any beverage effects on glucose and insulin. CONCLUSIONS Some types of decaffeinated coffee may acutely impair glucose metabolism but less than caffeine. PMID:19918017

  4. Rpl13a small nucleolar RNAs regulate systemic glucose metabolism

    PubMed Central

    Lee, Jiyeon; Harris, Alexis N.; Holley, Christopher L.; Mahadevan, Jana; Pyles, Kelly D.; Lavagnino, Zeno; Scherrer, David E.; Fujiwara, Hideji; Sidhu, Rohini; Zhang, Jessie; Huang, Stanley Ching-Cheng; Piston, David W.; Remedi, Maria S.; Urano, Fumihiko; Ory, Daniel S.

    2016-01-01

    Small nucleolar RNAs (snoRNAs) are non-coding RNAs that form ribonucleoproteins to guide covalent modifications of ribosomal and small nuclear RNAs in the nucleus. Recent studies have also uncovered additional non-canonical roles for snoRNAs. However, the physiological contributions of these small RNAs are largely unknown. Here, we selectively deleted four snoRNAs encoded within the introns of the ribosomal protein L13a (Rpl13a) locus in a mouse model. Loss of Rpl13a snoRNAs altered mitochondrial metabolism and lowered reactive oxygen species tone, leading to increased glucose-stimulated insulin secretion from pancreatic islets and enhanced systemic glucose tolerance. Islets from mice lacking Rpl13a snoRNAs demonstrated blunted oxidative stress responses. Furthermore, these mice were protected against diabetogenic stimuli that cause oxidative stress damage to islets. Our study illuminates a previously unrecognized role for snoRNAs in metabolic regulation. PMID:27820699

  5. Abnormal glucose metabolism: diagnosis and management in the ambulatory setting.

    PubMed

    Hawkins, Josiah Z S; Wing, Deborah

    2012-09-01

    Abnormal glucose metabolism in pregnancy is a spectrum. This spectrum stretches from mild forms of glucose intolerance that do not rise to the level of diabetes, to diabetes that first occurs in pregnancy, as well as to pregravid forms of diabetes associated with end-organ disease. In this review, we first discuss risk factors common to all forms of abnormal glucose metabolism in pregnancy. A review of how abnormal glucose metabolism in pregnancy is diagnosed precedes discussion of perinatal risks associated with different degrees of glycemic aberration. We discuss how to intervene in the ambulatory setting to mitigate these risks.

  6. Brain areas and pathways in the regulation of glucose metabolism.

    PubMed

    Diepenbroek, Charlene; Serlie, Mireille J; Fliers, Eric; Kalsbeek, Andries; la Fleur, Susanne E

    2013-01-01

    Glucose is the most important source of fuel for the brain and its concentration must be kept within strict boundaries to ensure the organism's optimal fitness. To maintain glucose homeostasis, an optimal balance between glucose uptake and glucose output is required. Besides managing acute changes in plasma glucose concentrations, the brain controls a daily rhythm in glucose concentrations. The various nuclei within the hypothalamus that are involved in the control of both these processes are well known. However, novel studies indicate an additional role for brain areas that are originally appreciated in other processes than glucose metabolism. Therefore, besides the classic hypothalamic pathways, we will review cortico-limbic brain areas and their role in glucose metabolism.

  7. Advances in glucose metabolism research in colorectal cancer

    PubMed Central

    Fang, Sitian; Fang, Xiao

    2016-01-01

    Cancer cells uptake glucose at a higher rate and produce lactic acid rather than metabolizing pyruvate through the tricarboxylic acid cycle. This adaptive metabolic shift is termed the Warburg effect. Recently progress had been made regarding the mechanistic understanding of glucose metabolism and associated diagnostic and therapeutic methods, which have been investigated in colorectal cancer. The majority of novel mechanisms involve important glucose metabolism associated genes and miRNA regulation. The present review discusses the contribution of these research results to facilitate with the development of novel diagnosis and anticancer treatment options. PMID:27602209

  8. Engineering glucose metabolism of Escherichia coli under nitrogen starvation.

    PubMed

    Chubukov, Victor; Desmarais, John James; Wang, George; Chan, Leanne Jade G; Baidoo, Edward Ek; Petzold, Christopher J; Keasling, Jay D; Mukhopadhyay, Aindrila

    2017-01-01

    A major aspect of microbial metabolic engineering is the development of chassis hosts that have favorable global metabolic phenotypes, and can be further engineered to produce a variety of compounds. In this work, we focus on the problem of decoupling growth and production in the model bacterium Escherichia coli, and in particular on the maintenance of active metabolism during nitrogen-limited stationary phase. We find that by overexpressing the enzyme PtsI, a component of the glucose uptake system that is inhibited by α-ketoglutarate during nitrogen limitation, we are able to achieve a fourfold increase in metabolic rates. Alternative systems were also tested: chimeric PtsI proteins hypothesized to be insensitive to α-ketoglutarate did not improve metabolic rates under the conditions tested, whereas systems based on the galactose permease GalP suffered from energy stress and extreme sensitivity to expression level. Overexpression of PtsI is likely to be a useful arrow in the metabolic engineer's quiver as productivity of engineered pathways becomes limited by central metabolic rates during stationary phase production processes.

  9. Muscle glucose metabolism in chronic obstructive pulmonary disease patients.

    PubMed

    Sancho-Muñoz, Antonio; Trampal, Carlos; Pascual, Sergi; Martínez-Llorens, Juana; Chalela, Roberto; Gea, Joaquim; Orozco-Levi, Mauricio

    2014-06-01

    Muscle dysfunction is one of the most extensively studied manifestations of COPD. Metabolic changes in muscle are difficult to study in vivo, due to the lack of non-invasive techniques. Our aim was to evaluate metabolic activity simultaneously in various muscle groups in COPD patients. Thirty-nine COPD patients and 21 controls with normal lung function, due to undergo computed axial and positron emission tomography for staging of localized lung lesions were included. After administration of 18-fluordeoxyglucose, images of 2 respiratory muscles (costal and crural diaphragm, and rectus abdominus) and 2 peripheral muscles (brachial biceps and quadriceps) were obtained, using the standard uptake value as the glucose metabolism index. Standard uptake value was higher in both portions of the diaphragm than in the other muscles of all subjects. Moreover, the crural diaphragm and rectus abdominus showed greater activity in COPD patients than in the controls (1.8±0.7 vs 1.4±0.8; and 0.78±0.2 vs 0.58±0.1; respectively, P<.05). A similar trend was observed with the quadriceps. In COPD patients, uptake in the two respiratory muscles and the quadriceps correlated directly with air trapping (r=0.388, 0.427 and 0.361, respectively, P<.05). There is greater glucose uptake and metabolism in the human diaphragm compared to other muscles when the subject is at rest. Increased glucose metabolism in the respiratory muscles (with a similar trend in their quadriceps) of COPD patients is confirmed quantitatively, and is directly related to the mechanical loads confronted. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

  10. Glucose metabolic gene expression in growth hormone transgenic coho salmon.

    PubMed

    Panserat, Stéphane; Kamalam, Biju Sam; Fournier, Jeanne; Plagnes-Juan, Elisabeth; Woodward, Krista; Devlin, Robert H

    2014-04-01

    Salmonids are generally known to be glucose intolerant. However, previous studies have shown that growth hormone (GH) transgenic coho salmon display modified nutritional regulation of glycolysis and lipogenesis compared to non-transgenic fish, suggesting the potential for better use of glucose in GH transgenic fish. To examine this in detail, GH transgenic and non-transgenic coho salmon were subjected to glucose tolerance test and subsequent metabolic assessments. After intra-peritoneal injection of 250mg/kg glucose, we analysed post-injection kinetics of glycaemia and expression of several key target genes highly involved in glucose homeostasis in muscle and liver tissues. Our data show no significant differences in plasma glucose levels during peak hyperglycaemia (3-6h after injection), demonstrating a similar glucose tolerance between transgenic and non transgenic. However, and unrelated to the hyperglycaemic episode, GH transgenic fish return to a slightly lower basal glycaemia values 24h after injection. Correspondingly, GH transgenic fish exhibited higher mRNA levels of glucokinase (GK) and glucose-6-phosphate dehydrogenase (G6PDH) in liver, and glucose transporter (GLUT4) in muscle. These data suggest that these metabolic actors may be involved in different glucose use in GH transgenic fish, which would be expected to influence the glucose challenge response. Overall, our data demonstrate that GH transgenic coho salmon may be a pertinent animal model for further study of glucose metabolism in carnivorous fish.

  11. [Metabolism of labeled exogenous glucose in fiber flax tissues].

    PubMed

    Chikov, V I; Avvakumova, N Iu; Bakirova, G G; Khamidullina, L A

    2005-01-01

    A labeled glucose solution was introduced into cut fiber flax plants (45-50 cm high) using a special unit under a pressure of 0.1 atm for 30 min, 1, and 2 h. The highest quantities of labeled carbon were revealed in the woody tissue. Sucrose made up a considerable proportion in low molecular weight products of [ [2-14C]-glucose transformation (23.5%). Metabolism of labeled glucose in the leaves exposed to sunlight yielded a set of metabolites similar to products of 14CO2 photoassimilation. In the shade, the pattern of 14C distribution in labeled compounds of the water/alcohol soluble fraction remained similar in mature leaves, while in juvenile leaves, 14C content decreased in sucrose and increased in organic and amino acids. In the shade, the incorporation of 14C into starch and hot water soluble polysaccharides increased at the expense of the acetone fraction (lipids and pigments), water/salt soluble proteins, and cellulose. Low light conditions increased the radioactivity ratio of sparingly soluble (KOH and Triton X-100 soluble) proteins to albumins and globulins. We propose that the synthesis of components of the photosynthetic apparatus in juvenile leaves is directly powered by photosynthesis and the photosynthesis of glucose and the polymers compete for ATP energy. Appearance of sucrose in the woody tissue is due to its release from the phloem to the stem apoplast and the radial transfer to the xylem, where it is transported to the upper shoot with the transpiration flow.

  12. Dysregulation of glucose metabolism in preclinical type 1 diabetes.

    PubMed

    Veijola, Riitta; Koskinen, Maarit; Helminen, Olli; Hekkala, Anne

    2016-07-01

    Long-term prospective studies have provided valuable information about preclinical type 1 diabetes (T1D). Children who have seroconverted to positive for islet autoantibodies have also, in follow-up, had metabolic tests to understand the timing and development of abnormal glucose tolerance and declining insulin secretion before the clinical diagnosis of T1D. First phase insulin response (FPIR) in the intravenous glucose tolerance test (IVGTT) is lower in the progressors positive for multiple islet autoantibodies in all age groups and as early as 4-6 years before the diagnosis when compared with the non-progressors positive for only islet cell antibodies (ICA). An accelerated decline in FPIR is seen in the progressors during the last 1.5 years before the diagnosis. These results indicate that the progressors may have an early intrinsic defect in beta cell development or function. In the oral glucose tolerance test (OGTT) the peak C-peptide response is delayed in the progressors at least 2 years before diagnosis. Glucose levels and HbA1c are increasing about 2 years before clinical diagnosis. An increase in HbA1c and detection of abnormal glucose tolerance in OGTT are useful in the prediction of the timing of clinical onset of T1D. Continuous glucose monitoring (CGM) may be useful in the prediction of T1D as an early indicator of increased glycemic variability but more data from larger series are needed for confirmation. Children followed in the prospective studies are diagnosed earlier and have a decreased frequency of ketoacidosis at the diagnosis of T1D when compared with age-matched cases from the population.

  13. Design of the Glucose Rate Increase Detector

    PubMed Central

    Harvey, Rebecca A.; Dassau, Eyal; Zisser, Howard; Seborg, Dale E.

    2014-01-01

    The Glucose Rate Increase Detector (GRID), a module of the Health Monitoring System (HMS), has been designed to operate in parallel to the glucose controller to detect meal events and safely trigger a meal bolus. The GRID algorithm was tuned on clinical data with 40-70 g CHO meals and tested on simulation data with 50-100 g CHO meals. Active closed- and open-loop protocols were executed in silico with various treatments, including automatic boluses based on a 75 g CHO meal and boluses based on simulated user input of meal size. An optional function was used to reduce the recommended bolus using recent insulin and glucose history. For closed-loop control of a 3-meal scenario (50, 75, and 100 g CHO), the GRID improved median time in the 80-180 mg/dL range by 17% and in the >180 range by 14% over unannounced meals, using an automatic bolus for a 75 g CHO meal at detection. Under open-loop control of a 75 g CHO meal, the GRID shifted the median glucose peak down by 73 mg/dL and earlier by 120 min and reduced the time >180 mg/dL by 57% over a missed-meal bolus scenario, using a full meal bolus at detection. The GRID improved closed-loop control in the presence of large meals, without increasing late postprandial hypoglycemia. Users of basal-bolus therapy could also benefit from GRID as a safety alert for missed meal corrections. PMID:24876583

  14. Mechanisms Linking the Gut Microbiome and Glucose Metabolism

    PubMed Central

    Kratz, Mario; Damman, Chris J.; Hullarg, Meredith

    2016-01-01

    Context: Type 2 diabetes mellitus is associated with gastrointestinal dysbiosis involving both compositional and functional changes in the gut microbiome. Changes in diet and supplementation with probiotics and prebiotics (ie, fermentable fibers) can induce favorable changes in gut bacterial species and improve glucose homeostasis. Objective: This paper will review the data supporting several potential mechanisms whereby gut dysbiosis contributes to metabolic dysfunction, including microbiota driven increases in systemic lipopolysaccharide concentrations, changes in bile acid metabolism, alterations in short chain fatty acid production, alterations in gut hormone secretion, and changes in circulating branched-chain amino acids. Methods: Data for this review were identified by searching English language references from PubMed and relevant articles. Conclusions: Understanding the mechanisms linking the gut microbiome to glucose metabolism, and the relevant compositional and functional characteristics of the gut microbiome, will help direct future research to develop more targeted approaches or novel compounds aimed at restoring a more healthy gut microbiome as a new approach to prevent and treat type 2 diabetes mellitus and related metabolic conditions. PMID:26938201

  15. Osteoid osteoma is an osteocalcinoma affecting glucose metabolism.

    PubMed

    Confavreux, C B; Borel, O; Lee, F; Vaz, G; Guyard, M; Fadat, C; Carlier, M-C; Chapurlat, R; Karsenty, G

    2012-05-01

    Osteocalcin is a hormone secreted by osteoblasts, which regulates energy metabolism by increasing β-cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. This has been demonstrated in mice, but to date, the evidence implicating osteocalcin in the regulation of energy metabolism in humans are indirect. To address this question more directly, we asked whether a benign osteoblastic tumor, such as osteoma osteoid in young adults, may secrete osteocalcin. The study was designed to assess the effect of surgical resection of osteoid osteoma on osteocalcin and blood glucose levels in comparison with patients undergoing knee surgery and healthy volunteers. Blood collections were performed the day of surgery and the following morning after overnight fasting. Patients and controls were recruited in the orthopedic surgery department of New York Presbiterian Hospital, NY-USA and Hospices Civils de Lyon, France. Seven young males were included in the study: two had osteoid osteoma, two underwent knee surgery, and three were healthy volunteers. After resection of the osteoid osteomas, we observed a decrease of osteocalcin by 62% and 30% from the initial levels. Simultaneously, blood glucose increased respectively by 32% and 15%. Bone turnover markers were not affected. This case study shows for the first time that osteocalcin in humans affects blood glucose level. This study also suggests that ostoid osteoma may be considered, at least in part, as an osteocalcinoma.

  16. Berberine improves glucose metabolism through induction of glycolysis.

    PubMed

    Yin, Jun; Gao, Zhanguo; Liu, Dong; Liu, Zhijun; Ye, Jianping

    2008-01-01

    Berberine, a botanical alkaloid used to control blood glucose in type 2 diabetes in China, has recently been reported to activate AMPK. However, it is not clear how AMPK is activated by berberine. In this study, activity and action mechanism of berberine were investigated in vivo and in vitro. In dietary obese rats, berberine increased insulin sensitivity after 5-wk administration. Fasting insulin and HOMA-IR were decreased by 46 and 48%, respectively, in the rats. In cell lines including 3T3-L1 adipocytes, L6 myotubes, C2C12 myotubes, and H4IIE hepatocytes, berberine was found to increase glucose consumption, 2-deoxyglucose uptake, and to a less degree 3-O-methylglucose (3-OMG) uptake independently of insulin. The insulin-induced glucose uptake was enhanced by berberine in the absence of change in IRS-1 (Ser307/312), Akt, p70 S6, and ERK phosphorylation. AMPK phosphorylation was increased by berberine at 0.5 h, and the increase remained for > or =16 h. Aerobic and anaerobic respiration were determined to understand the mechanism of berberine action. The long-lasting phosphorylation of AMPK was associated with persistent elevation in AMP/ATP ratio and reduction in oxygen consumption. An increase in glycolysis was observed with a rise in lactic acid production. Berberine exhibited no cytotoxicity, and it protected plasma membrane in L6 myotubes in the cell culture. These results suggest that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria. Berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.

  17. Vitamins and glucose metabolism: The role of static magnetic fields.

    PubMed

    Lahbib, Aïda; Ghodbane, Soumaya; Sakly, Mohsen; Abdelmelek, Hafedh

    2014-12-01

    This review focuses on our own data and other data from the literature of static magnetic fields (SMF) bioeffects and vitamins and glucose metabolism. Three main areas of investigation have been covered: Static magnetic field and glucose metabolism, static magnetic field and vitamins and the role of vitamins on glucose metabolism. Considering these articles comprehensively, the conclusions are as follows: The primary cause of changes in cells after incubation in external SMF is disruption of free radical metabolism and elevation of their concentration. Such disruption causes oxidative stress leading to an unsteadiness of glucose level and insulin release. Moreover, based on available data, it was concluded that exposure to SMF alters plasma levels of vitamin A, C, D and E; these parameters can take part in disorder of glucose homeostasis and insulin release.

  18. Glucose metabolism as a target of histone deacetylase inhibitors.

    PubMed

    Wardell, Suzanne E; Ilkayeva, Olga R; Wieman, Heather L; Frigo, Daniel E; Rathmell, Jeffrey C; Newgard, Christopher B; McDonnell, Donald P

    2009-03-01

    The therapeutic efficacy of histone deacetylase inhibitors (HDACI) is generally attributed to their ability to alter gene expression secondary to their effects on the acetylation status of transcription factors and histones. However, because HDACIs exhibit similar transcriptional effects in most cells, the molecular basis for their therapeutic selectivity toward malignant cells is largely unknown. In this study, we report that HDACI, of distinct chemotypes, quantitatively inhibit glucose transporter 1 (GLUT1)-mediated glucose transport into multiple myeloma cells through both down-regulation of GLUT1 and inhibition of hexokinase 1 (HXK1) enzymatic activity. Unexpectedly, however, this inhibition of glucose utilization is accompanied by an increase in amino acid catabolism with no increase in fatty acid oxidation. Our findings suggest that an HDACI-induced change in carbon source preference could contribute to the therapeutic efficacy of these drugs by creating a pattern of fuel utilization that is incompatible with rapid tumor growth and survival. Furthermore, these results, which implicate glucose metabolism as a target of HDACI, suggest that caution should be exercised in attributing effects of this class of drug to primary alterations in gene transcription.

  19. Endothelial inflammation induced by excess glucose is associated with cytosolic glucose-6-phosphate but not increased mitochondrial respiration

    PubMed Central

    Sweet, Ian R; Gilbert, Merle; Maloney, Ezekiel; Hockenbery, David M.; Schwartz, Michael W.; Kim, Francis

    2009-01-01

    Aims/hypothesis Exposure of endothelial cells to high glucose levels suppresses responses to insulin, including induction of endothelial nitric oxide synthetase activity, through pro-inflammatory signaling via the IKKβ-NF-κB pathway. In the current study, we aimed to identify metabolic responses to glucose excess that mediate endothelial cell inflammation and insulin resistance. Since endothelial cells decrease their rate of oxygen consumption (OCR) in response to glucose, we hypothesized that increased mitochondrial function would not mediate these cell’s response to excess substrate. Methods The effects of glycolytic and mitochondrial fuels on metabolic intermediates and end products of glycolytic and oxidative metabolism, including glucose-6 phosphate (G6P), lactate, CO2, NAD(P)H, and OCR, were measured in cultured human microvascular endothelial cells and correlated with IKKβ activation. Results In response to increases in glucose concentration from low to physiological levels (0 to 5 mM), production of G6P, lactate, NAD(P)H and CO2 each increased as expected, while OCR was sharply reduced. IKKβ activation was detected at glucose concentrations above 5 mM, which was associated with parallel increases of G6P levels, whereas downstream metabolic pathways were insensitive to excess substrate. Conclusions/interpretation Activation of IKKβ by excess glucose correlates with increased levels of the glycolytic intermediate G6P, but not with lactate generation or OCR, which are inhibited well below saturation levels at physiologic glucose concentrations. These findings suggest that oxidative stress due to increased mitochondrial respiration is unlikely to mediate endothelial inflammation induced by excess glucose and suggests instead the involvement of G6P accumulation in the adverse effects of hyperglycemia on endothelial cells. PMID:19219423

  20. The UPR reduces glucose metabolism via IRE1 signaling.

    PubMed

    van der Harg, Judith M; van Heest, Jessica C; Bangel, Fabian N; Patiwael, Sanne; van Weering, Jan R T; Scheper, Wiep

    2017-04-01

    Neurons are highly dependent on glucose. A disturbance in glucose homeostasis therefore poses a severe risk that is counteracted by activation of stress responses to limit damage and restore the energy balance. A major stress response that is activated under conditions of glucose deprivation is the unfolded protein response (UPR) that is aimed to restore proteostasis in the endoplasmic reticulum. The key signaling of the UPR involves the transient activation of a transcriptional program and an overall reduction of protein synthesis. Since the UPR is strategically positioned to sense and integrate metabolic stress signals, it is likely that - apart from its adaptive response to restore proteostasis - it also directly affects metabolic pathways. Here we investigate the direct role of the UPR in glucose homeostasis. O-GlcNAc is a post-translational modification that is highly responsive to glucose fluctuations. We find that UPR activation results in decreased O-GlcNAc modification, in line with reduced glucose metabolism. Our data indicate that UPR activation has no direct impact on the upstream processes in glucose metabolism; glucose transporter expression, glucose uptake and hexokinase activity. In contrast, prolonged UPR activation decreases glycolysis and mitochondrial metabolism. Decreased mitochondrial respiration is not accompanied by apoptosis or a structural change in mitochondria indicating that the reduction in metabolic rate upon UPR activation is a physiological non-apoptotic response. Metabolic decrease is prevented if the IRE1 pathway of the UPR is inhibited. This indicates that activation of IRE1 signaling induces a reduction in glucose metabolism, as part of an adaptive response. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Comparing glucose and insulin data from the two-hour oral glucose tolerance test in metabolic syndrome subjects and marathon runners.

    PubMed

    Altuve, Miguel; Perpinan, Gilberto; Severeyn, Erika; Wong, Sara

    2016-08-01

    Glucose is the main energy source of the body's cells and is essential for normal metabolism. Two pancreatic hormones, insulin and glucagon, are involved in glucose home-ostasis. Alteration in the plasma glucose and insulin concentrations could lead to distinct symptoms and diseases, ranging from mental function impairment to coma and even death. Type 2 diabetes, insulin resistance and metabolic syndrome are typical examples of abnormal glucose metabolism that increase the risk for cardiovascular disease and mortality. The oral glucose tolerance test (OGTT) is a medical test used to screen for prediabetes, type 2 diabetes and insulin resistance. In the 5-sample 2-hour OGTT, plasma glucose and insulin concentrations are measured after a fast and then after oral intake of glucose, at intervals of 30 minutes. In this work, a statistical analysis is carried out to find significant differences between the five stages of the OGTT for plasma glucose and insulin data. In addition, the behavior of the glucose and insulin data is compared between subjects with the metabolic syndrome and marathon runners. Results show that marathon runners have plasma glucose and insulin levels significantly lower (p <; 0.05) than people with the metabolic syndrome in all the stages of the OGTT. Insulin secretion decreases in marathon runners due to a significant reduction in plasma glucose concentration, but insulin secretion does not decrease in metabolic syndrome subjects due to insulin resistance, consequently plasma glucose concentration does not achieve normal levels.

  2. Polysaccharides from Enteromorpha prolifera Improve Glucose Metabolism in Diabetic Rats

    PubMed Central

    Lin, Wenting; Wang, Wenxiang; Liao, Dongdong; Chen, Damiao; Zhu, Pingping; Cai, Guoxi; Kiyoshi, Aoyagi

    2015-01-01

    This study investigated the effects of polysaccharides from Enteromorpha prolifera (PEP) on glucose metabolism in a rat model of diabetes mellitus (DM). PEP (0, 150, 300, and 600 mg/kg) was administered intragastrically to rats for four weeks. After treatment, fasting blood glucose (FBG) and insulin (INS) levels were measured, and the insulin sensitivity index (ISI) was calculated. The morphopathological changes in the pancreas were observed. Serum samples were collected to measure the oxidant-antioxidant status. The mRNA expression levels of glucokinase (GCK) and insulin receptor (InsR) in liver tissue and glucose transporter type 4 (GLUT-4) and adiponectin (APN) in adipose tissue were determined. Compared with the model group, the FBG and INS levels were lower, the ISI was higher, and the number of islet β-cells was significantly increased in all the PEP groups. In the medium- and high-dose PEP groups, MDA levels decreased, and the enzymatic activities of SOD and GSH-Px increased. The mRNA expression of InsR and GCK increased in all the PEP groups; APN mRNA expression increased in the high-dose PEP group, and GLUT-4 mRNA expression increased in adipose tissue. These findings suggest that PEP is a potential therapeutic agent that can be utilized to treat DM. PMID:26347892

  3. Cell Based Metabolic Barriers to Glucose Diffusion: Macrophages and Continuous Glucose Monitoring

    PubMed Central

    Klueh, Ulrike; Frailey, Jackman; Qiao, Yi; Antar, Omar; Kreutzer, Donald L.

    2014-01-01

    It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance. We hypothesized that the accumulation of MQ at the glucose sensor-tissue interface will act as “Cell Based Metabolic Barriers” (CBMB) to glucose diffusing from the interstitial tissue compartment to the implanted glucose sensor and as such creating an artificially low sensor output, thereby compromising sensor function and CGM. Our studies demonstrated that 1) direct injections of MQ at in vivo sensor implantation sites dramatically decreased sensor output (measured in nA), 2) addition of MQ to glucose sensors in vitro resulted in a rapid and dramatic fall in sensor output and 3) lymphocytes did not affect sensor function in vitro or in vivo. These data support our hypothesis that MQ can act as metabolic barriers to glucose and O2 diffusion in vivo and in vitro. PMID:24461328

  4. Cell based metabolic barriers to glucose diffusion: macrophages and continuous glucose monitoring.

    PubMed

    Klueh, Ulrike; Frailey, Jackman T; Qiao, Yi; Antar, Omar; Kreutzer, Donald L

    2014-03-01

    It is assumed that MQ are central to glucose sensor bio-fouling and therefore have a major negative impact on continuous glucose monitoring (CGM) performance in vivo. However to our knowledge there is no data in the literature to directly support or refute this assumption. Since glucose and oxygen (O2) are key to glucose sensor function in vivo, understanding and controlling glucose and O2 metabolic activity of MQ is likely key to successful glucose sensor performance. We hypothesized that the accumulation of MQ at the glucose sensor-tissue interface will act as "Cell Based Metabolic Barriers" (CBMB) to glucose diffusing from the interstitial tissue compartment to the implanted glucose sensor and as such creating an artificially low sensor output, thereby compromising sensor function and CGM. Our studies demonstrated that 1) direct injections of MQ at in vivo sensor implantation sites dramatically decreased sensor output (measured in nA), 2) addition of MQ to glucose sensors in vitro resulted in a rapid and dramatic fall in sensor output and 3) lymphocytes did not affect sensor function in vitro or in vivo. These data support our hypothesis that MQ can act as metabolic barriers to glucose and O2 diffusion in vivo and in vitro.

  5. Glucosensing in the gastrointestinal tract: Impact on glucose metabolism.

    PubMed

    Fournel, Audren; Marlin, Alysson; Abot, Anne; Pasquio, Charles; Cirillo, Carla; Cani, Patrice D; Knauf, Claude

    2016-05-01

    The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases. Copyright © 2016 the American Physiological Society.

  6. Glucosensing in the gastrointestinal tract: Impact on glucose metabolism

    PubMed Central

    Fournel, Audren; Marlin, Alysson; Abot, Anne; Pasquio, Charles; Cirillo, Carla; Cani, Patrice D.

    2016-01-01

    The gastrointestinal tract is an important interface of exchange between ingested food and the body. Glucose is one of the major dietary sources of energy. All along the gastrointestinal tube, e.g., the oral cavity, small intestine, pancreas, and portal vein, specialized cells referred to as glucosensors detect variations in glucose levels. In response to this glucose detection, these cells send hormonal and neuronal messages to tissues involved in glucose metabolism to regulate glycemia. The gastrointestinal tract continuously communicates with the brain, especially with the hypothalamus, via the gut-brain axis. It is now well established that the cross talk between the gut and the brain is of crucial importance in the control of glucose homeostasis. In addition to receiving glucosensing information from the gut, the hypothalamus may also directly sense glucose. Indeed, the hypothalamus contains glucose-sensitive cells that regulate glucose homeostasis by sending signals to peripheral tissues via the autonomous nervous system. This review summarizes the mechanisms by which glucosensors along the gastrointestinal tract detect glucose, as well as the results of such detection in the whole body, including the hypothalamus. We also highlight how disturbances in the glucosensing process may lead to metabolic disorders such as type 2 diabetes. A better understanding of the pathways regulating glucose homeostasis will further facilitate the development of novel therapeutic strategies for the treatment of metabolic diseases. PMID:26939867

  7. Excess glucose induces hypoxia-inducible factor-1α in pancreatic cancer cells and stimulates glucose metabolism and cell migration

    PubMed Central

    Liu, Zhiwen; Jia, Xiaohui; Duan, Yijie; Xiao, Huijie; Sundqvist, Karl-Gösta; Permert, Johan; Wang, Feng

    2013-01-01

    Pancreatic cancer patients frequently show hyperglycemia, but it is uncertain whether hyperglycemia stimulates pancreatic cancer cells. We have investigated whether excess glucose induces hypoxia-inducible factor-1α (HIF-1α) and stimulates glucose metabolism and cell migration in pancreatic cancer cells. We studied wild-type (wt) MiaPaCa2 pancreatic cancer cells and a MiaPaCa2 subline (namely si-MiaPaCa2) that had HIF-1α-specific small interfering RNA. Wt-MiaPaCa2 cells are known to be HIF-1α-positive in hypoxia and HIF-1α-negative in normoxia, whereas si-MiaPaCa2 cells are devoid of HIF-1α in both normoxia and hypoxia. We incubated these cells with different amounts of glucose and determined HIF-1α mRNA and protein by real-time polymerase chain reaction and western blotting. We determined glucose consumption, lactate production and intracellular hexokinase-II and ATP to assess glucose metabolisms and determined pyruvate dehydrogenase kinase-1, reactive oxygen species and fumarate to assess mitochondrial activities. Further, we studied cell migration using a Boyden chamber. Excess glucose (16.7−22.2mM) increased HIF-1α in hypoxic wt-MiaPaCa2 cells. HIF-1α expression increased ATP contents and inhibited mitochondrial activities. Extracellular glucose and hypoxia stimulated glucose metabolisms independent of HIF-1α. Excess glucose stimulated the migration of wt- and si-MiaPaCa2 cells in both normoxia and hypoxia. Thus, glucose stimulated cell migration independent of HIF-1α. Nevertheless, hypoxic wt-MiaPaCa2 cells showed greater migrating ability than their si-MiaPaCa2 counterparts. We conclude that (1) excess glucose increases HIF-1α and ATP in hypoxic wt-MiaPaCa2 cells, (2) extracellular glucose and hypoxia regulate glucose metabolisms independent of HIF-1α and (3) glucose stimulates cell migration by mechanisms that are both dependent on HIF-1α and independent of it. PMID:23377827

  8. [Kinetics of glucose metabolism in central neurocytomas].

    PubMed

    Shioya, H; Mineura, K; Sasajima, T; Kowada, M; Iida, H; Ogawa, T; Hatazawa, J; Uemura, K

    1995-10-01

    To estimate proliferating activity of central neurocytoma, we measured kinetic rate constants and glucose metabolic rate (kinetic-rCMRGI) using dynamic positron emission tomography (PET), as well as autoradiographic rCMRG1 (arg-rCMRG1), in patients with histologically verified central neurocytoma. The subject included five patients, four males and one female, aged from 23 to 53 years with a mean age of 41 years old. All tumors were located in the lateral ventricle and two extended into the third ventricle through the forearm of Monro. Tumor lesion on the PET images was determined using CT or MRI, which was performed at levels equivalent to those for the PET scans. The kinetic rate constants of tracer transport from blood to brain (k1), reverse transport from brain to blood (k2), and phosphorylation (k3) were analyzed according to the three compartment 18F-fluorodeoxyglucose (FDG) model. For quantitative analysis, regions of interest (ROI) on PET images were delineated on the tumor and the contralateral gray matter. Tumor k1 and k2 values were similar to or higher than those of the contralateral gray matter, suggesting high permeability due to lack of blood-brain barrier. Tumor k3 value, an indicator of hexokinase activity, and kinetic-rCMRG1 were exceedingly lower in three of five patients. These three patients have been free from tumor recurrence or regrowth, postoperatively. The other two patients, tumor kinetic-rCMRG1 was similar to or higher than that of the contralateral gray matter. One patient suffered from tumor regrowth shortly after resection, and the other has been followed up postoperatively. Thus, k3 and kinetic-rCMRG1 are indicative parameters of proliferative activity in central neurocytoma.

  9. A link between hepatic glucose production and peripheral energy metabolism via hepatokines

    PubMed Central

    Abdul-Wahed, Aya; Gautier-Stein, Amandine; Casteras, Sylvie; Soty, Maud; Roussel, Damien; Romestaing, Caroline; Guillou, Hervé; Tourette, Jean-André; Pleche, Nicolas; Zitoun, Carine; Gri, Blandine; Sardella, Anne; Rajas, Fabienne; Mithieux, Gilles

    2014-01-01

    Type 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulin resistance of glucose uptake by peripheral tissues and increased endogenous glucose production. Here we report that the specific suppression of hepatic glucose production positively modulates whole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatase that is mandatory for endogenous glucose production. When they were fed a high fat/high sucrose diet, they resisted the development of diabetes and obesity due to the activation of peripheral glucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones like fibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepatic glucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapid restoration of glucose and body weight controls. Therefore, hepatic glucose production is an essential lever for the control of whole-body energy metabolism during the development of obesity and diabetes. PMID:25061558

  10. Peritoneal Dialysate Glucose Load and Systemic Glucose Metabolism in Non-Diabetics: Results from the GLOBAL Fluid Cohort Study

    PubMed Central

    Chess, James; Do, Jun-Young; Noh, Hyunjin; Lee, Hi-Bahl; Kim, Yong-Lim; Summers, Angela; Williams, Paul Ford; Davison, Sara; Dorval, Marc

    2016-01-01

    Background and Objectives Glucose control is a significant predictor of mortality in diabetic peritoneal dialysis (PD) patients. During PD, the local toxic effects of intra-peritoneal glucose are well recognized, but despite large amounts of glucose being absorbed, the systemic effects of this in non-diabetic patients are not clear. We sought to clarify whether dialysate glucose has an effect upon systemic glucose metabolism. Methods and Materials We analysed the Global Fluid Study cohort, a prospective, observational cohort study initiated in 2002. A subset of 10 centres from 3 countries with high data quality were selected (368 incident and 272 prevalent non-diabetic patients), with multilevel, multivariable analysis of the reciprocal of random glucose levels, and a stratified-by-centre Cox survival analysis. Results The median follow up was 5.6 and 6.4 years respectively in incident and prevalent patients. On multivariate analysis, serum glucose increased with age (β = -0.007, 95%CI -0.010, -0.004) and decreased with higher serum sodium (β = 0.002, 95%CI 0.0005, 0.003) in incident patients and increased with dialysate glucose (β = -0.0002, 95%CI -0.0004, -0.00006) in prevalent patients. Levels suggested undiagnosed diabetes in 5.4% of prevalent patients. Glucose levels predicted death in unadjusted analyses of both incident and prevalent groups but in an adjusted survival analysis they did not (for random glucose 6–10 compared with <6, Incident group HR 0.92, 95%CI 0.58, 1.46, Prevalent group HR 1.42, 95%CI 0.86, 2.34). Conclusions In prevalent non-diabetic patients, random glucose levels at a diabetic level are under-recognised and increase with dialysate glucose load. Random glucose levels predict mortality in unadjusted analyses, but this association has not been proven in adjusted analyses. PMID:27249020

  11. Glucose metabolism in pregnant sheep when placental growth is restricted

    SciTech Connect

    Owens, J.A.; Falconer, J.; Robinson, J.S. )

    1989-08-01

    The effect of restricting placental growth on glucose metabolism in pregnant sheep in late gestation was determined by primed constant infusions of D-(U-{sup 14}C)- and D-(2-{sup 3}H)glucose and antipyrine into fetuses of six control sheep and six sheep from which endometrial caruncles had been removed before pregnancy (caruncle sheep). In the latter, placental and fetal weights were reduced, as was the concentration of glucose in fetal arterial blood. Fetal glucose turnover in caruncle sheep was only 52-59% of that in controls, largely because of lower umbilical loss of glucose back to the placenta (38-39% of control) and lower fetal glucose utilization (61-74% of control). However, fetal glucose utilization on a weight-specific basis was similar in control and caruncle sheep. Significant endogenous glucose production occurred in control and caruncle fetal sheep. Maternal glucose production and partition of glucose between the gravid uterus and other maternal tissues were similar in control and caruncle sheep. In conclusion, when placental and fetal growth are restricted, fetal glucose utilization is maintained by reduced loss of glucose back to the placenta and mother and by maintaining endogenous glucose production.

  12. Regional glucose metabolism using PETT in normal and psychiatric populations

    SciTech Connect

    Brodie, J.D.; Wolf, A.P.; Volkow, N.

    1982-01-01

    The metabolism of /sup 18/F-2-deoxy-2-fluoro-D-glucose (/sup 18/FDG) in 150 subjects including normals, schizophrenics, senile dementias, and primary affective disorders was studied. Some of the data analyzed to date are discussed.

  13. JAK-STAT signaling and myocardial glucose metabolism

    PubMed Central

    Frias, Miguel A; Montessuit, Christophe

    2013-01-01

    JAK-STAT signaling occurs in virtually every tissue of the body, and so does glucose metabolism. In this review, we summarize the regulation of glucose metabolism in the myocardium and ponder whether JAK-STAT signaling participates in this regulation. Despite a paucity of data directly pertaining to cardiac myocytes, we conclude that JAK-STAT signaling may contribute to the development of insulin resistance in the myocardium in response to various hormones and cytokines. PMID:24416656

  14. Visualizing Sweetness: Increasingly Diverse Applications for Fluorescent-Tagged Glucose Bioprobes and Their Recent Structural Modifications

    PubMed Central

    Kim, Woong Hee; Lee, Jinho; Jung, Da-Woon; Williams, Darren R.

    2012-01-01

    Glucose homeostasis is a fundamental aspect of life and its dysregulation is associated with important diseases, such as cancer and diabetes. Traditionally, glucose radioisotopes have been used to monitor glucose utilization in biological systems. Fluorescent-tagged glucose analogues were initially developed in the 1980s, but it is only in the past decade that their use as a glucose sensor has increased significantly. These analogues were developed for monitoring glucose uptake in blood cells, but their recent applications include tracking glucose uptake by tumor cells and imaging brain cell metabolism. This review outlines the development of fluorescent-tagged glucose analogues, describes their recent structural modifications and discusses their increasingly diverse biological applications. PMID:22666073

  15. Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation

    PubMed Central

    Holmes, Andrew P; Turner, Philip J; Carter, Paul; Leadbeater, Wendy; Ray, Clare J; Hauton, David; Buckler, Keith J; Kumar, Prem

    2014-01-01

    The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge. PMID:25063821

  16. Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation.

    PubMed

    Holmes, Andrew P; Turner, Philip J; Carter, Paul; Leadbeater, Wendy; Ray, Clare J; Hauton, David; Buckler, Keith J; Kumar, Prem

    2014-10-15

    The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate PO2 led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ∼33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.

  17. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men.

    PubMed

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens J; Dela, Flemming; Madsbad, Sten; Vaag, Allan A

    2003-06-01

    We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.

  18. Cerebral glucose metabolism after portacaval shunting in the rat. Patterns of metabolism and implications for the pathogenesis of hepatic encephalopathy.

    PubMed Central

    Lockwood, A H; Ginsberg, M D; Rhoades, H M; Gutierrez, M T

    1986-01-01

    The regional cerebral metabolic rate for glucose was measured in normal and portacaval shunted rats and the effects of unilateral carotid infusions of "threshold" amounts of ammonia were assessed. 8 wk after shunting the glucose metabolic rate was increased in all 20 brain regions sampled. Effects on subcortical and phylogenetically older regions of the brain were most pronounced with a 74% increase observed in the reticular formation at the collicular level. Increases in the cerebral cortex ranged from 12 to 18%. Unilateral infusions of ammonia did not affect behavior but altered the electroencephalogram and selectively increased the glucose metabolic rate in the thalamus, hypothalamus, and substantia nigra in half of the animals, a pattern similar to that seen after a portacaval shunt, suggesting hyperammonemia as the cause of postshunt increases in glucose metabolism. Visual inspection of autoradiograms, computed correlation coefficients relating interregional metabolism, and principal component analysis suggest that normal cerebral metabolic and functional interrelationships are altered by shunting. Ammonia stimulation of the hypothalamic satiety centers may suppress appetite and lead to cachexia. Reductions in the ammonia detoxification capacity of skeletal muscle may increase the probability of developing future episodes of hyperammonemia, perpetuating the process. Direct effects of ammonia on specific brain centers such as the dorsomedial hypothalamus and reticular activating system may combine with global disruptions of cerebral metabolic-functional relationships to produce the protean manifestations of portal-systemic encephalopathy. Images PMID:3722388

  19. Signalling mechanisms linking hepatic glucose and lipid metabolism.

    PubMed

    Weickert, M O; Pfeiffer, A F H

    2006-08-01

    Fatty liver and hepatic triglyceride accumulation are strongly associated with obesity, insulin resistance and type 2 diabetes, and are subject to nutritional influences. Hepatic regulation of glucose and lipid homeostasis is influenced by a complex system of hormones, hormonally regulated signalling pathways and transcription factors. Recently, considerable progress has been made in elucidating molecular pathways and potential factors that are affected in insulin-resistant states. In this review we discuss some of the key factors that are involved in both the regulation of glucose and lipid metabolism in the liver. Understanding the molecular network that links hepatic lipid accumulation and impaired glucose metabolism may provide targets for dietary or pharmacological interventions.

  20. Insulin effect on glucose transport in thymocytes and splenocytes from rats with metabolic syndrome

    PubMed Central

    2010-01-01

    Metabolic syndrome (MS) may comprise several clinical conditions such as obesity, diabetes and inflammatory disorders, which are characterized by metabolic imbalances. The study of glucose transport and regulation by insulin in lymphocytes is important, since the way they increase inflammation and susceptibility to infections are common in MS. We studied glucose internalization in isolated thymocytes and splenocytes, its regulation by insulin, and the role of three glucose transporters (Gluts) in control and in MS rats. Control glucose internalization and insulin responses were lower in splenocytes than in thymocytes. Control and insulin-induced glucose internalization in thymocytes declined with age, while transport by splenocyte continued to respond to insulin. Control thymocyte glucose internalization was blocked by antibodies against Glut 1 and 4, while the insulin response also was blocked by an anti-Glut 3 antibody. On four month old control and insulin-induced response, splenocyte transport was only blocked by Glut 1 and 4 antibodies. At six months splenocyte glucose internalization depended on Glut 1 and was less sensitive to the effects of an anti-Glut 4 antibody. In MS splenocytes the capacity of anti-Glut 1 antibodies to inhibit control and insulin-dependent glucose transport was less significant, and we found that in MS rats, glucose internalization was dependent on Glut 3 and Glut 4. In summary, the altered metabolic state present in MS rats shows signs of modulation of glucose internalization by the Glut1, Glut 3 and Glut 4 transporters, compared with its own age control. PMID:21044347

  1. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder

    SciTech Connect

    Swedo, S.E.; Schapiro, M.B.; Grady, C.L.; Cheslow, D.L.; Leonard, H.L.; Kumar, A.; Friedland, R.; Rapoport, S.I.; Rapoport, J.L.

    1989-06-01

    The cerebral metabolic rate for glucose was studied in 18 adults with childhood-onset obsessive-compulsive disorder (OCD) and in age- and sex-matched controls using positron emission tomography and fludeoxyglucose F 18. Both groups were scanned during rest, with reduced auditory and visual stimulation. The group with OCD showed an increased glucose metabolism in the left orbital frontal, right sensorimotor, and bilateral prefrontal and anterior cingulate regions as compared with controls. Ratios of regional activity to mean cortical gray matter metabolism were increased for the right prefrontal and left anterior cingulate regions in the group with OCD as a whole. Correlations between glucose metabolism and clinical assessment measures showed a significant relationship between metabolic activity and both state and trait measurements of OCD and anxiety as well as the response to clomipramine hydrochloride therapy. These results are consistent with the suggestion that OCD may result from a functional disturbance in the frontal-limbic-basal ganglia system.

  2. The role of osteocalcin in human glucose metabolism: marker or mediator?

    PubMed Central

    Booth, Sarah L.; Centi, Amanda; Smith, Steven R.; Gundberg, Caren

    2015-01-01

    Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines and nutrients. Here, the evidence for a role of osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bone matrix protein that regulates hydroxyapatite size and shape through its vitamin-K-dependent γ-carboxylated form. In circulation, the concentration of osteocalcin is a measure of bone formation. The undercarboxylated form of osteocalcin is reported to be active in glucose metabolism in mice. Total serum osteocalcin concentrations in humans are inversely associated with measures of glucose metabolism; however, human data are inconclusive with regard to the role of uncarboxylated osteocalcin in glucose metabolism because most studies do not account for the influence of vitamin K on the proportion of undercarboxylated osteocalcin or differentiate between the total and uncarboxylated forms of osteocalcin. Furthermore, most human studies do not concomitantly measure other bone turnover markers to isolate the role of osteocalcin as a measure of bone formation from its effect on glucose metabolism. Carefully designed studies are required to define the role of osteocalcin and its carboxylated or undercarboxylated forms in the regulation of glucose metabolism in humans. PMID:23147574

  3. Reduced CD300LG mRNA tissue expression, increased intramyocellular lipid content and impaired glucose metabolism in healthy male carriers of Arg82Cys in CD300LG: a novel genometabolic cross-link between CD300LG and common metabolic phenotypes

    PubMed Central

    Støy, Julie; Kampmann, Ulla; Mengel, Annette; Magnusson, Nils E; Jessen, Niels; Grarup, Niels; Rungby, Jørgen; Stødkilde-Jørgensen, Hans; Brandslund, Ivan; Christensen, Cramer; Hansen, Torben; Pedersen, Oluf; Møller, Niels

    2015-01-01

    Background CD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability to recognize and interact with extracellular lipids. We tested whether this specific polymorphism results in abnormal lipid accumulation in skeletal muscle and liver and other indices of metabolic dysfunction. Methods 40 healthy men with a mean age of 55 years were characterized metabolically including assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) and intramyocellular lipid content (IMCL) by MR spectroscopy, and β-cell function by an intravenous glucose tolerance test. Changes in insulin signaling and CD300LG mRNA expression were determined by western blotting and quantitative PCR in muscle and adipose tissue. Results Compared with the 20 controls (CC carriers), the 20 CT carriers (polymorphism carriers) had higher IMCL (p=0.045), a reduced fasting forearm glucose uptake (p=0.011), a trend toward lower M-values during the clamp; 6.0 mg/kg/min vs 7.1 (p=0.10), and higher IHLC (p=0.10). CT carriers had lower CD300LG mRNA expression and CD300LG expression in muscle correlated with IMCL (β=−0.35, p=0.046), forearm glucose uptake (β=0.37, p=0.03), and tended to correlate with the M-value (β=0.33, p=0.06), independently of CD300LG genotype. β-cell function was unaffected. Conclusions The CD300LG polymorphism was associated with decreased CD300LG mRNA expression in muscle and adipose tissue, increased IMCL, and abnormalities of glucose metabolism. CD300LG mRNA levels correlated with IMCL and forearm glucose uptake. These findings link a specific CD300LG polymorphism with features of the metabolic syndrome suggesting a role for CD300LG in the regulation of common metabolic traits. Trial registration number NCT01571609. PMID:26336608

  4. Regional cerebral glucose metabolism in patients with alcoholic Korsakoff's syndrome

    SciTech Connect

    Kessler, R.M.; Parker, E.S.; Clark, C.M.; Martin, P.R.; George, D.T.; Weingartner, H.; Sokoloff, L.; Ebert, M.H.; Mishkin, M.

    1985-05-01

    Seven alcoholic male subjects diagnosed as having Korsakoff's syndrome and eight age-matched male normal volunteers were studied with /sup 18/F 2-fluoro-2-deoxy-D-glucose (2/sup 18/FDG). All subjects were examined at rest with eyes covered in a quiet, darkened room. Serial plasma samples were obtained following injection of 4 to 5 mCi of 2/sup 18/FDG. Tomographic slices spaced at 10mm axial increments were obtained (in-plane resolution = 1.75 cm, axial resolution = 1.78 cm). Four planes were selected from each subject, and a total of 46 regions of interest were sampled and glucose metabolic rates for each region calculated. The mean glucose metalbolic rate for the 46 regions in the Korsakoff subjects was significantly lower than that in the normal controls (5.17 +- .43 versus 6.6 +- 1.31). A Q-component analysis, which examined each subject's regional rates relative to his mean rate, revealed two distinct patterns in the Korsakoff group. Glucose metabolism was significantly reduced in 37 of the 46 regions sampled. Reduced cerebral glucose metabolism in a nondemented group of subjects has not previously been reported. The reduction in cortical metabolism may be the result of damage to sub-cortical projecting systems. The differing patterns of cerebral metabolism in Korsakoff's syndrome suggests subgroups with differing neuropathology. Regions implicated in memory function, medial temporal, thalamic and medial prefrontal were among the regions reduced in metabolism.

  5. Plasma Metanephrines Are Associated With Glucose Metabolism in Patients With Essential Hypertension.

    PubMed

    Wang, Weiqing; Mu, Liangshan; Su, Tingwei; Ye, Lei; Jiang, Yiran; Jiang, Lei; Zhou, Weiwei

    2015-09-01

    There is a high incidence of glucose intolerance in essential hypertension. Overactivation of the sympathetic system is one of important causes of essential hypertension. Whether sympathetic system affects glucose metabolism in patients with essential hypertension has never been reported previously. The aim of this study was to explore the association between the sympathetic system activity and glucose metabolism in patients with essential hypertension. A total of 202 essential hypertension inpatients without diabetes were recruited from Shanghai Ruijin Hospital between February 2006 and August 2013. Activity of sympathetic system was quantified by plasma metanephrines (MNs) levels. All subjects received an oral glucose tolerance test. Fasting plasma glucose and 2-hour plasma glucose increased significantly across the quartiles of plasma MNs. The multiple linear regression analysis revealed that plasma MNs were significantly associated with fasting plasma glucose and 2-hour plasma glucose. The area under curve of plasma glucose increased significantly from the lowest plasma MNs quartile across to the highest quartile. The multiple logistic regression analysis revealed that odds ratios (95% confidence interval) for prediabetes in the highest quartile compared with the lowest quartile of plasma MNs was 4.00 (95% confidence interval, 1.16-13.86). Plasma MNs levels are positively associated with plasma glucose in patients with essential hypertension. Patients with high plasma MNs levels had an increased risk of prediabetes.

  6. Plasma Metanephrines Are Associated With Glucose Metabolism in Patients With Essential Hypertension

    PubMed Central

    Wang, Weiqing; Mu, Liangshan; Su, Tingwei; Ye, Lei; Jiang, Yiran; Jiang, Lei; Zhou, Weiwei

    2015-01-01

    Abstract There is a high incidence of glucose intolerance in essential hypertension. Overactivation of the sympathetic system is one of important causes of essential hypertension. Whether sympathetic system affects glucose metabolism in patients with essential hypertension has never been reported previously. The aim of this study was to explore the association between the sympathetic system activity and glucose metabolism in patients with essential hypertension. A total of 202 essential hypertension inpatients without diabetes were recruited from Shanghai Ruijin Hospital between February 2006 and August 2013. Activity of sympathetic system was quantified by plasma metanephrines (MNs) levels. All subjects received an oral glucose tolerance test. Fasting plasma glucose and 2-hour plasma glucose increased significantly across the quartiles of plasma MNs. The multiple linear regression analysis revealed that plasma MNs were significantly associated with fasting plasma glucose and 2-hour plasma glucose. The area under curve of plasma glucose increased significantly from the lowest plasma MNs quartile across to the highest quartile. The multiple logistic regression analysis revealed that odds ratios (95% confidence interval) for prediabetes in the highest quartile compared with the lowest quartile of plasma MNs was 4.00 (95% confidence interval, 1.16–13.86). Plasma MNs levels are positively associated with plasma glucose in patients with essential hypertension. Patients with high plasma MNs levels had an increased risk of prediabetes. PMID:26376391

  7. Cerebral glucose metabolism in Wernicke's, Broca's, and conduction aphasia

    SciTech Connect

    Metter, E.J.; Kempler, D.; Jackson, C.; Hanson, W.R.; Mazziotta, J.C.; Phelps, M.E.

    1989-01-01

    Cerebral glucose metabolism was evaluated in patients with either Wernicke's (N = 7), Broca's (N = 11), or conduction (N = 10) aphasia using /sup 18/F-2-fluoro-2-deoxy-D-glucose with positron emission tomography. The three aphasic syndromes differed in the degree of left-to-right frontal metabolic asymmetry, with Broca's aphasia showing severe asymmetry and Wernicke's aphasia mild-to-moderate metabolic asymmetry, while patients with conduction aphasia were metabolically symmetric. On the other hand, the three syndromes showed the same degree of metabolic decline in the left temporal region. The parietal region appeared to separate conduction aphasia from both Broca's and Wernicke's aphasias. Common aphasic features in the three syndromes appear to be due to common changes in the temporal region, while unique features were associated with frontal and parietal metabolic differences.

  8. Glucose and fatty acid metabolism in normal and diabetic rabbit cerebral microvessels

    SciTech Connect

    Hingorani, V.; Brecher, P.

    1987-05-01

    Rabbit cerebral microvessels were used to study fatty acid metabolism and its utilization relative to glucose. Microvessels were incubated with either (6-/sup 14/C)glucose or (1-/sup 14/C)oleic acid and the incorporation of radioactivity into /sup 14/CO/sub 2/, lactate, triglyceride, cholesterol ester, and phospholipid was determined. The inclusion of 5.5 mM glucose in the incubation mixture reduced oleate oxidation by 50% and increased esterification into both phospholipid and triglyceride. Glucose oxidation to CO/sub 2/ was reduced by oleate addition, whereas lactate production was unaffected. 2'-Tetradecylglycidic acid, an inhibitor of carnitine acyltransferase I, blocked oleic acid oxidation in the presence and absence of glucose. It did not effect fatty acid esterification when glucose was absent and eliminated the inhibition of oleate on glucose oxidation. Glucose oxidation to /sup 14/CO/sub 2/ was markedly suppressed in microvessels from alloxan-treated diabetic rabbits but lactate formation was unchanged. Fatty acid oxidation to CO/sub 2/ and incorporation into triglyceride, phospholipid, and cholesterol ester remained unchanged in the diabetic state. The experiments show that both fatty acid and glucose can be used as a fuel source by the cerebral microvessels, and the interactions found between fatty acid and glucose metabolism are similar to the fatty acid-glucose cycle, described previously.

  9. Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma.

    PubMed

    Steiner, Johann; Bernstein, Hans-Gert; Schiltz, Kolja; Müller, Ulf J; Westphal, Sabine; Drexhage, Hemmo A; Bogerts, Bernhard

    2014-01-03

    Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-β) appear to be state markers, whereas IL-12, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia.

  10. Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: involvement of the GLP-1 pathway.

    PubMed

    Nguyen, Anh Thoai; Mandard, Stéphane; Dray, Cédric; Deckert, Valérie; Valet, Philippe; Besnard, Philippe; Drucker, Daniel J; Lagrost, Laurent; Grober, Jacques

    2014-02-01

    Lipopolysaccharides (LPS) of the cell wall of gram-negative bacteria trigger inflammation, which is associated with marked changes in glucose metabolism. Hyperglycemia is frequently observed during bacterial infection and it is a marker of a poor clinical outcome in critically ill patients. The aim of the current study was to investigate the effect of an acute injection or continuous infusion of LPS on experimentally induced hyperglycemia in wild-type and genetically engineered mice. The acute injection of a single dose of LPS produced an increase in glucose disposal and glucose-stimulated insulin secretion (GSIS). Continuous infusion of LPS through mini-osmotic pumps was also associated with increased GSIS. Finally, manipulation of LPS detoxification by knocking out the plasma phospholipid transfer protein (PLTP) led to increased glucose disposal and GSIS. Overall, glucose tolerance and GSIS tests supported the hypothesis that mice treated with LPS develop glucose-induced hyperinsulinemia. The effects of LPS on glucose metabolism were significantly altered as a result of either the accumulation or antagonism of glucagon-like peptide 1 (GLP-1). Complementary studies in wild-type and GLP-1 receptor knockout mice further implicated the GLP-1 receptor-dependent pathway in mediating the LPS-mediated changes in glucose metabolism. Hence, enhanced GLP-1 secretion and action underlies the development of glucose-mediated hyperinsulinemia associated with endotoxemia.

  11. Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation.

    PubMed

    Alarcon, Cristina; Wicksteed, Barton; Prentki, Marc; Corkey, Barbara E; Rhodes, Christopher J

    2002-08-01

    The secondary signals emanating from increased glucose metabolism, which lead to specific increases in proinsulin biosynthesis translation, remain elusive. It is known that signals for glucose-stimulated insulin secretion and proinsulin biosynthesis diverge downstream of glycolysis. Consequently, the mitochondrial products ATP, Krebs cycle intermediates, glutamate, and acetoacetate were investigated as candidate stimulus-coupling signals specific for glucose-induced proinsulin biosynthesis in rat islets. Decreasing ATP levels by oxidative phosphorylation inhibitors showed comparable effects on proinsulin biosynthesis and total protein synthesis. Although it is a cofactor, ATP is unlikely to be a metabolic stimulus-coupling signal specific for glucose-induced proinsulin biosynthesis. Neither glutamic acid methyl ester nor acetoacetic acid methyl ester showed a specific effect on glucose-stimulated proinsulin biosynthesis. Interestingly, among Krebs cycle intermediates, only succinic acid monomethyl ester specifically stimulated proinsulin biosynthesis. Malonic acid methyl ester, an inhibitor of succinate dehydrogenase, also specifically increased glucose-induced proinsulin biosynthesis without affecting islet ATP levels or insulin secretion. Glucose caused a 40% increase in islet intracellular succinate levels, but malonic acid methyl ester showed no further effect, probably due to efficient conversion of succinate to succinyl-CoA. In this regard, a GTP-dependent succinyl-CoA synthetase activity was found in cytosolic fractions of pancreatic islets. Thus, succinate and/or succinyl-CoA appear to be preferential metabolic stimulus-coupling factors for glucose-induced proinsulin biosynthesis translation.

  12. The role of osteocalcin in human glucose metabolism: marker or mediator?

    USDA-ARS?s Scientific Manuscript database

    Increasing evidence supports an association between the skeleton and energy metabolism. These interactions are mediated by a variety of hormones, cytokines, and nutrients. Here, the evidence for a role of osteocalcin in the regulation of glucose metabolism in humans is reviewed. Osteocalcin is a bon...

  13. Bypasses in intracellular glucose metabolism in iron-limited Pseudomonas putida.

    PubMed

    Sasnow, Samantha S; Wei, Hua; Aristilde, Ludmilla

    2016-02-01

    Decreased biomass growth in iron (Fe)-limited Pseudomonas is generally attributed to downregulated expression of Fe-requiring proteins accompanied by an increase in siderophore biosynthesis. Here, we applied a stable isotope-assisted metabolomics approach to explore the underlying carbon metabolism in glucose-grown Pseudomonas putida KT2440. Compared to Fe-replete cells, Fe-limited cells exhibited a sixfold reduction in growth rate but the glucose uptake rate was only halved, implying an imbalance between glucose uptake and biomass growth. This imbalance could not be explained by carbon loss via siderophore production, which accounted for only 10% of the carbon-equivalent glucose uptake. In lieu of the classic glycolytic pathway, the Entner-Doudoroff (ED) pathway in Pseudomonas is the principal route for glucose catabolism following glucose oxidation to gluconate. Remarkably, gluconate secretion represented 44% of the glucose uptake in Fe-limited cells but only 2% in Fe-replete cells. Metabolic (13) C flux analysis and intracellular metabolite levels under Fe limitation indicated a decrease in carbon fluxes through the ED pathway and through Fe-containing metabolic enzymes. The secreted siderophore was found to promote dissolution of Fe-bearing minerals to a greater extent than the high extracellular gluconate. In sum, bypasses in the Fe-limited glucose metabolism were achieved to promote Fe availability via siderophore secretion and to reroute excess carbon influx via enhanced gluconate secretion.

  14. High concentrations of glucose reduce the oxidative metabolism of dog neutrophils in vitro

    PubMed Central

    2013-01-01

    Background Dogs are commonly affected by hyperglycemic conditions. Hyperglycemia compromises the immune response and favors bacterial infections; however, reports on the effects of glucose on neutrophil oxidative metabolism and apoptosis are conflicting in humans and rare in dogs. Considering the many complex factors that affect neutrophil oxidative metabolism in vivo, we investigated in vitro the specific effect of high concentrations of glucose on superoxide production and apoptosis rate in neutrophils from healthy dogs. Results The capacity of the neutrophils to reduce tetrazolium nitroblue decreased significantly in the higher concentration of glucose (15.13 ± 9.73% (8 mmol/L) versus 8.93 ± 5.71% (16 mmol/L)). However, there were no changes in tetrazolium nitroblue reduction at different glucose concentrations when the neutrophils were first activated with phorbol myristate acetate. High concentrations of glucose did not affect the viability and apoptosis rate of canine neutrophils either with or without prior camptothecin stimulation. This study provides the first evidence that high concentrations of glucose inhibit the oxidative metabolism of canine neutrophils in vitro in a manner similar to that which occurs in humans, and that the decrease in superoxide production did not increase the apoptosis rate. Conclusions A high concentration of glucose reduces the oxidative metabolism of canine neutrophils in vitro. It is likely that glucose at high concentrations rapidly affects membrane receptors responsible for the activation of NADPH oxidase in neutrophils; therefore, the nonspecific immune response can be compromised in dogs with acute and chronic hyperglycemic conditions. PMID:23388121

  15. Cerebral glucose metabolism in type I alpha-N-acetylgalactosaminidase deficiency: an infantile neuroaxonal dystrophy.

    PubMed

    Rudolf, J; Grond, M; Schindler, D; Heiss, W D; Desnick, R J

    1999-08-01

    Cerebral glucose metabolism was investigated in a 4.8-year-old boy with alpha-N-acetylgalactosaminidase deficiency using 2-[18F]fluoro-2-deoxy-D-glucose and positron emission tomography (PET). In comparison to normal values for age, the overall cerebral glucose metabolism was reduced and the regional cerebral glucose metabolism was decreased in proportion to the degree of atrophy. In the supratentorial cortical regions, the hypometabolism was asymmetric. However, the level of regional cerebral glucose metabolism in all cortical regions excluded a persistent vegetative state. In the lentiform nucleus and the head of the caudate, comparatively increased regional cerebral glucose metabolism was documented, similar to findings in neurodegenerative disorders with active epilepsy. In contrast, the infratentorial structures (cerebellar hemispheres, brain stem, mesencephalon, and hypothalamus), which are predominantly affected by the atrophic process, showed distinct and symmetric hypometabolism. Thus, the 2-[18F]-fluoro-2-deoxy-D-glucose PET scans provided additional insight into and correlation of the functional and structural disturbances in type I alpha-N-acetylgalactosaminidase deficiency, in addition to documenting the hypometabolism due to brain atrophy.

  16. PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells

    PubMed Central

    Xiong, Xiaopeng; Wen, Yang-An; Mitov, Mihail I; C Oaks, Mary; Miyamoto, Shigeki; Gao, Tianyan

    2017-01-01

    Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer cells. Knockdown of PHLPP increased the rate of glucose consumption and lactate production, whereas overexpression of PHLPP had the opposite effect. Bioenergetic analysis using Seahorse Extracelluar Flux Analyzer revealed that silencing PHLPP expression induced a glycolytic shift in colon cancer cells. Mechanistically, we found that PHLPP formed a complex with Akt and hexokinase 2 (HK2) in the mitochondrial fraction of colon cancer cells and knockdown of PHLPP enhanced Akt-mediated phosphorylation and mitochondrial localization of HK2. Depletion of HK2 expression or treating cells with Akt and HK2 inhibitors reversed PHLPP loss-induced increase in glycolysis. Furthermore, PHLPP knockdown cells became addicted to glucose as a major energy source in that glucose starvation significantly decreased cancer cell survival. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our study identified PHLPP as a novel regulator of glucose metabolism by controlling HK2 activity in colon cancer cells. PMID:28179998

  17. [Metabolic control in the critically ill patient an update: hyperglycemia, glucose variability hypoglycemia and relative hypoglycemia].

    PubMed

    Pérez-Calatayud, Ángel Augusto; Guillén-Vidaña, Ariadna; Fraire-Félix, Irving Santiago; Anica-Malagón, Eduardo Daniel; Briones Garduño, Jesús Carlos; Carrillo-Esper, Raúl

    Metabolic changes of glucose in critically ill patients increase morbidity and mortality. The appropriate level of blood glucose has not been established so far and should be adjusted for different populations. However concepts such as glucose variability and relative hypoglycemia of critically ill patients are concepts that are changing management methods and achieving closer monitoring. The purpose of this review is to present new data about the management and metabolic control of patients in critical areas. Currently glucose can no longer be regarded as an innocent element in critical patients; both hyperglycemia and hypoglycemia increase morbidity and mortality of patients. Protocols and better instruments for continuous measurement are necessary to achieve the metabolic control of our patients. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

  18. High-normal fasting glucose levels are associated with increased prevalence of impaired glucose tolerance in obese children.

    PubMed

    Grandone, A; Amato, A; Luongo, C; Santoro, N; Perrone, L; del Giudice, E Miraglia

    2008-12-01

    The natural history of impaired glucose tolerance (IGT) and Type 2 diabetes among obese children is not clear. Although the cut-off for impaired fasting glucose (IFG) has recently been changed from 110 (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), it does not seem a reliable way to find all subjects with impaired glucose homeostasis. The aim of our study was to determine whether high-normal fasting glucose level could predict the occurrence of IGT and metabolic syndrome. Three hundred and twenty-three Italian obese children and adolescents were included in the study (176 females, mean age 11+/-2.9 yr; mean body mass index z-score: 3+/-0.6). Waist circumference, serum glucose, insulin, triglyceride, cholesterol HDL, blood pressure were evaluated and an oral glucose tolerance test (OGTT) was performed. The prevalence of IFG and IGT were respectively 1.5% (5 subjects) and 5% (18 patients); no diabetic patients were found. Metabolic syndrome was diagnosed in 20% of patients. Fasting glycemia values <100 mg/dl (5.6 mmol/l) have been divided in quintiles. Metabolic syndrome prevalence increased across quintiles, although not in a statistically significantly manner, but it could depend on the selected diagnostic criteria as no univocal definition exists for metabolic syndrome in youths. Interestingly high-normal fasting plasma glucose levels constitute an independent risk factor for IGT among obese children and adolescents; therefore, this very easy-to-use parameter may help to identify obese patients at increased risk of diabetes or at least could suggest in which subjects to perform an OGTT.

  19. Metabolic Effects of Glucose-Fructose Co-Ingestion Compared to Glucose Alone during Exercise in Type 1 Diabetes

    PubMed Central

    Bally, Lia; Kempf, Patrick; Zueger, Thomas; Speck, Christian; Pasi, Nicola; Ciller, Carlos; Feller, Katrin; Loher, Hannah; Rosset, Robin; Wilhelm, Matthias; Boesch, Chris; Buehler, Tania; Dokumaci, Ayse S.; Tappy, Luc; Stettler, Christoph

    2017-01-01

    This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13C-fructose and 13C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU (p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg−1·min−1, p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg−1·min−1 p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg−1·min−1, p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU (p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen. PMID:28230765

  20. Metabolic Effects of Glucose-Fructose Co-Ingestion Compared to Glucose Alone during Exercise in Type 1 Diabetes.

    PubMed

    Bally, Lia; Kempf, Patrick; Zueger, Thomas; Speck, Christian; Pasi, Nicola; Ciller, Carlos; Feller, Katrin; Loher, Hannah; Rosset, Robin; Wilhelm, Matthias; Boesch, Chris; Buehler, Tania; Dokumaci, Ayse S; Tappy, Luc; Stettler, Christoph

    2017-02-21

    This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with (13)C-fructose and (13)C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU (p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg(-1)·min(-1), p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg(-1)·min(-1)p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg(-1)·min(-1), p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU (p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.

  1. Lipocalin-2, glucose metabolism and chronic low-grade systemic inflammation in Chinese people.

    PubMed

    Huang, Ying; Yang, Zhen; Ye, Zi; Li, Qin; Wen, Jie; Tao, Xiaoming; Chen, Lili; He, Min; Wang, Xuanchun; Lu, Bin; Zhang, Zhaoyun; Zhang, Weiwei; Qu, Shen; Hu, Renming

    2012-01-31

    Lipocalin-2 is a novel adipokine with connection to insulin resistance. In this study, we aimed to investigate the association of serum lipocalin-2 with glucose metabolism and other metabolic phenotype in a large-scale Chinese population. We evaluated serum lipocalin-2 in a cross-sectional sample of 2519 Chinese aged from 50 to 82 year in a Shanghai downtown district by ELISA. Glucose, insulin, lipid profile, inflammatory markers, and adipokines were also measured. Serum lipocalin-2 was significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and newly-diagnosed type 2 diabetes than in those with normal glucose regulation. Lipocalin-2 elevation was clearly associated with a higher risk for impaired glucose regulation (OR 1.30 for each 10 ng/ml increase in serum lipocalin-2, 95% CI 1.23-1.62, p = 0.009) after adjustment of age, gender, smoking, alcohol drinking, family history of diabetes, serum CRP, serum adiponectin, serum CXCL5, HOMA-IR, BMI, and waist/hip ratio. The OR for participants with impaired glucose regulation and type 2 diabetes was 1.31 (95% CI 1.21-1.69, p < 0.001). Our findings suggest that elevated serum lipocalin-2 is closely and independently associated with impaired glucose regulation and type 2 diabetes.

  2. Daily rhythms in glucose metabolism: suprachiasmatic nucleus output to peripheral tissue.

    PubMed

    La Fleur, S E

    2003-03-01

    The body has developed several control mechanisms to maintain plasma glucose concentrations within strict boundaries. Within those physiological boundaries, a clear daily rhythm in plasma glucose concentrations is present; this rhythm depends on the biological clock, which is located in the hypothalamic suprachiasmatic nucleus (SCN), and is independent of the daily rhythm in food intake. Interestingly, there is also a daily rhythm in glucose uptake, which also depends on the SCN and follows the same pattern as the daily rhythm in plasma glucose concentrations; both rise before the onset of activity. Thus, the SCN prepares the individual for the upcoming activity period in two different ways: by increasing plasma glucose concentrations and by facilitating tissue glucose uptake. In addition to this anticipation of glucose metabolism to expected glucose demands, the SCN also influences, depending on the time of the day, the responses of pancreas and liver to abrupt glucose changes (such as a glucose rise after a meal or hypoglycaemia). This review presents the view that the SCN uses different routes to (i) maintain daily glucose balance and (ii) set the level of the endocrine response to abrupt blood glucose changes.

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

    PubMed

    Liu, Hongyun; Zhao, Ke; Liu, Jianxin

    2013-01-01

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

  4. Leptin and the CNS Control of Glucose Metabolism

    PubMed Central

    Morton, Gregory J.; Schwartz, Michael W.

    2012-01-01

    The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system (CNS) plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders. PMID:21527729

  5. Heritability of metabolic response to the intravenous glucose tolerance test in German Holstein Friesian bulls.

    PubMed

    Pieper, Laura; Staufenbiel, Rudolf; Christ, Jana; Panicke, Lothar; Müller, Uwe; Brockmann, Gudrun A

    2016-09-01

    Selection for improved health and welfare in farm animals is of increasing interest worldwide. Peripartum energy balance is a key factor for pathogenesis of diseases in dairy cows. The intravenous glucose tolerance test (ivGTT) can be used to study the metabolic response to a glucose stimulus. The aim of this study was to estimate heritability of ivGTT traits in German Holstein bulls. A total of 541 Holstein bulls aged 7 to 17 mo from 2 breeding stations were subjected to the ivGTT. Serum glucose concentrations were measured at 0, 7, 14, 21, 28, 35, 42, 49, 56, and 63 min relative to glucose infusion. The maximum increase in blood glucose concentration, glucose area equivalent, and blood glucose half-life period were calculated. Heritabilities were estimated using a univariate animal model including station-year-season and age as fixed effects, and animal additive genetic and residual as random effects. The estimated heritabilities were 0.19 for fasting glucose concentration, 0.43 for glucose area equivalent, 0.40 for glucose half-life period, 0.14 for the peak glucose concentration, and 0.12 for the maximum increase of blood glucose concentration. Correlations between ivGTT traits and breeding values for milk yield and composition were not found. The results indicate that heritability for response to glucose is high, which warrants further investigation of this trait for genetic improvement of metabolic disorders. Research is necessary to determine the target levels of ivGTT traits and potential associations between ivGTT traits in breeding bulls and periparturient diseases in their offspring. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  6. Regulation of Glucose Metabolism in Pseudomonas

    PubMed Central

    Daddaoua, Abdelali; Krell, Tino; Ramos, Juan-Luis

    2009-01-01

    In Pseudomonas putida, genes for the glucose phosphorylative pathway and the Entner-Doudoroff pathway are organized in two operons; one made up of the zwf, pgl, and eda genes and another consisting of the edd, glk, gltR2, and gltS genes. Divergently with respect to the edd gene is the gap-1 gene. Expression from Pzwf, Pedd, and Pgap is modulated by HexR in response to the availability of glucose in the medium. To study the regulatory process in greater detail we purified HexR and showed that it is a monomer in solution. Electrophoretic mobility shift assays and isothermal titration calorimetry assays were done showing that HexR recognizes the Pedd, Pzwf, and Pgap-1 promoters with affinity in the nanomolar range. DNA footprinting assays identified the binding site between +30 and +1 at Pzwf, between +16 and +41 at Pedd, and between −6 and +18 at Pgap-1. Based on DNA sequence alignment of the target sites and isothermal titration calorimetry data, two monomers of HexR bind to a pseudopalindrome with a consensus sequence of 5′-TTGTN7–8ACAA-3′. Binding of the Entner-Doudoroff pathway intermediate 2-keto-3-deoxy-6-phosphogluconate to HexR released the repressor from its target operators, whereas other chemicals such as glucose, glucose 6-phosphate, and 6-phosphogluconate did not induce complex dissociation. The phosphorylated effector is likely to be recognized by a sugar isomerase domain located at the C-terminal end of HexR, whereas the helix-turn-helix DNA binding domain of HexR exhibits high similarity to proteins of the RpiR family of regulators. PMID:19506074

  7. The role of estrogen in adipose tissue metabolism: insights into glucose homeostasis regulation.

    PubMed

    Kim, Jun Ho; Cho, Hyung Taek; Kim, Young Jun

    2014-01-01

    Adipose tissue is an organ with active endocrine function involved in the regulation of energy balance and glucose homeostasis via multiple metabolic signaling pathways targeting the brain, liver, skeletal muscle, pancreas, and other organs. There is increasing evidence demonstrating that the female sex hormone, estrogen, regulates adipose development and improves systemic glucose homeostasis in both males and females. The underlying mechanism linking estrogenic regulation in adipose tissue and systemic glucose metabolism has not been fully elucidated, but is thought to include interactions of estrogen receptor signaling events involving lipolytic and/or lipogenic enzyme activity, free fatty acid metabolism, and adipocytokine production. Thus, understanding the effects of estrogen replacement on adipose tissue biology and metabolism is important in determining the risk of developing obesity-related metabolic disorders in patients undergoing treatment for sex hormone deficiency. In this report, we review literature regarding the role of estrogens and their corresponding receptors in the control of adipose metabolism and glucose homeostasis in both rodents and humans. We also discuss the effects of selective estrogen receptor modulators on glucose metabolism.

  8. Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin.

    PubMed

    Thorn, Stephanie R; Brown, Laura D; Rozance, Paul J; Hay, William W; Friedman, Jacob E

    2013-01-01

    Intrauterine growth restriction (IUGR) increases the risk for metabolic disease and diabetes, although the developmental origins of this remain unclear. We measured glucose metabolism during basal and insulin clamp periods in a fetal sheep model of placental insufficiency and IUGR. Compared with control fetuses (CON), fetuses with IUGR had increased basal glucose production rates and hepatic PEPCK and glucose-6-phosphatase expression, which were not suppressed by insulin. In contrast, insulin significantly increased peripheral glucose utilization rates in CON and IUGR fetuses. Insulin robustly activated AKT, GSK3β, and forkhead box class O (FOXO)1 in CON and IUGR fetal livers. IUGR livers, however, had increased basal FOXO1 phosphorylation, nuclear FOXO1 expression, and Jun NH(2)-terminal kinase activation during hyperinsulinemia. Expression of peroxisome proliferator-activated receptor γ coactivator 1α and hepatocyte nuclear factor-4α were increased in IUGR livers during basal and insulin periods. Cortisol and norepinephrine concentrations were positively correlated with glucose production rates. Isolated IUGR hepatocytes maintained increased glucose production in culture. In summary, fetal sheep with IUGR have increased hepatic glucose production, which is not suppressed by insulin despite insulin sensitivity for peripheral glucose utilization. These data are consistent with a novel mechanism involving persistent transcriptional activation in the liver that seems to be unique in the fetus with IUGR.

  9. Brain glucose sensing, glucokinase and neural control of metabolism and islet function.

    PubMed

    Ogunnowo-Bada, E O; Heeley, N; Brochard, L; Evans, M L

    2014-09-01

    It is increasingly apparent that the brain plays a central role in metabolic homeostasis, including the maintenance of blood glucose. This is achieved by various efferent pathways from the brain to periphery, which help control hepatic glucose flux and perhaps insulin-stimulated insulin secretion. Also, critically important for the brain given its dependence on a constant supply of glucose as a fuel--emergency counter-regulatory responses are triggered by the brain if blood glucose starts to fall. To exert these control functions, the brain needs to detect rapidly and accurately changes in blood glucose. In this review, we summarize some of the mechanisms postulated to play a role in this and examine the potential role of the low-affinity hexokinase, glucokinase, in the brain as a key part of some of this sensing. We also discuss how these processes may become altered in diabetes and related metabolic diseases.

  10. Dietary substitution of medium-chain triglycerides improves insulin-mediated glucose metabolism in NIDDM subjects.

    PubMed

    Eckel, R H; Hanson, A S; Chen, A Y; Berman, J N; Yost, T J; Brass, E P

    1992-05-01

    Dietary medium-chain triglycerides (MCT) may improve insulin-mediated glucose metabolism. To examine this possibility, 10 non-insulin-dependent diabetes mellitus (NIDDM) patients, 4 hypertriglyceridemic, and 6 normotriglyceridemic nondiabetic control subjects were examined with a 5-day cross-over design, in which the short-term metabolic effects of a 40% fat diet containing 77.5% of fat calories as MCT were compared with an isocaloric long-chain triglyceride-containing diet. In diabetic patients, MCT failed to alter fasting serum glucose concentrations but reduced preprandial glycemic excursions by 45% (F = 7.9, P less than 0.01). On MCT, the amount of glucose needed to maintain euglycemia during an intravenous insulin infusion was increased in diabetic subjects by 30%, in hypertriglyceridemic subjects by 30%, and in normotriglyceridemic control subjects by 17%. MCT increased mean +/- SE insulin-mediated glucose disposal (4.52 +/- 0.56 vs. 2.89 +/- 0.21 mg.kg-1.min-1; n = 3, P less than 0.05) but failed to alter basal glucose metabolism or insulin-mediated suppression of hepatic glucose output. Metabolic responses to MCT were observed independent of sulfonylurea therapy or severity of fasting hyperglycemia. No change in fasting serum insulin or triglyceride concentrations were seen with MCT administration. Although MCT increased mean fasting serum beta-hydroxybutyrate levels from 0.10 +/- 0.03 to 0.26 +/- 0.06 mM (P less than 0.05) in normotriglyceridemic nondiabetic subjects, no change was seen in diabetic patients. Thus, MCT-containing diets increased insulin-mediated glucose metabolism in both diabetic patients and nondiabetic subjects. In diabetic subjects, this effect appears to be mediated by increases in insulin-mediated glucose disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Return of the glucoreceptor: Glucose activates the glucose-sensing receptor T1R3 and facilitates metabolism in pancreatic β-cells.

    PubMed

    Kojima, Itaru; Nakagawa, Yuko; Ohtsu, Yoshiaki; Hamano, Kunihisa; Medina, Johan; Nagasawa, Masahiro

    2015-05-01

    Subunits of the sweet taste receptor, namely T1R2 and T1R3, are expressed in mouse pancreatic islets. Quantitatively, the expression of messenger ribonucleic acid for T1R2 is much lower than that of T1R3, and immunoreactive T1R2 is in fact undetectable. Presumably, a homodimer of T1R3 could function as a signaling receptor. Activation of this receptor by adding an artificial sweetener, sucralose, leads to an increase in intracellular adenosine triphosphate ([ATP]c). This increase in [ATP]c is observed in the absence of ambient glucose. Sucralose also augments elevation of [ATP]c induced by methylsuccinate, a substrate for mitochondria. Consequently, activation of T1R3 promotes metabolism in mitochondria and increases [ATP]c. 3-O-Methylglucose, a non-metabolizable analog of glucose, also increases [ATP]c. Conversely, knockdown of T1R3 attenuates elevation of [ATP]c induced by glucose. Hence, glucose promotes its own metabolism by activating T1R3 and augmenting ATP production. Collectively, a homodimer of T1R3 functions as a cell surface glucose-sensing receptor and participates in the action of glucose on insulin secretion. The glucose-sensing receptor T1R3 might be the putative glucoreceptor proposed decades ago by Niki et al. The glucose-sensing receptor is involved in the action of glucose and modulates glucose metabolism in pancreatic β-cells.

  12. Carbohydrate metabolism in human platelets in a low glucose medium under aerobic conditions.

    PubMed

    Niu, X; Arthur, P; Abas, L; Whisson, M; Guppy, M

    1996-10-24

    The metabolism of human platelets has been the subject of investigation for at least three decades, at the level of basic metabolism, and because of the increasing requirement for platelet storage. Platelets are relatively active metabolically and are typical cells in terms of fuels and metabolic pathways. They contain glycogen and utilize glucose and demonstrate aerobic glycolysis and carbohydrate oxidation. Both glycolysis and carbohydrate oxidation contribute significantly to total ATP turnover, so platelets are an ideal system in which to study the partitioning of carbohydrate metabolism between the two available fuels and the two available pathways, in the presence of adequate oxygen. We have designed a system whereby we can study carbohydrate metabolism in relatively pure human platelets, under sterile conditions, over long periods. The system enables us to determine total ATP turnover and, with the aid of a mathematical model, the contribution to this turnover of glycolysis and the oxidation of glucose/glycogen and lactate. When glucose and glycogen are present, most of the glucose and glycogen utilised is converted to lactate, but lactate is being oxidised at this time. When glucose/glycogen stores are exhausted lactate oxidation continues and increases with the result that carbohydrate oxidation accounts for 41% of total ATP turnover over 48 h.

  13. Effects of pituitary hormone deficiency on growth and glucose metabolism of the sheep fetus.

    PubMed

    Fowden, A L; Forhead, A J

    2007-10-01

    Pituitary hormones are essential for normal growth and metabolic responsiveness after birth, but their role before birth remains unclear. This study examined the effects of hypophysectomizing fetal sheep on their growth and glucose metabolism during the late normal and extended periods of gestation, and on their metabolic response to maternal fasting for 48 h near term. Fetal hypophysectomy reduced crown rump length (CRL), limb lengths, and body weight but increased ponderal index relative to controls near normal term. It also lowered the daily rate of crown rump length increment uniformly from 35 d before, to 20 d after normal term. Hypophysectomized (HX) fetuses had normal weight-specific rates of umbilical uptake, utilization, and oxidation of glucose but lower rates of umbilical oxygen uptake than controls near term. All these metabolic rates were significantly less in HX fetuses during the extended period of gestation than in HX and intact fetuses near normal term. In contrast to controls, glucogenesis was negligible in HX fetuses during maternal fasting. Consequently, the rate of glucose utilization decreased significantly in fasted HX but not intact fetuses. Conversely, the rate of CO(2) production from glucose carbon decreased in fasted intact but not HX fetuses. Fetal hypophysectomy also prevented the fasting-induced increases in plasma cortisol and norepinephrine concentrations seen in controls. These findings demonstrate that the pituitary hormones are important in regulating the growth rate and adaptive responses of glucose metabolism to undernutrition in fetal sheep. They also suggest that fetal metabolism is altered when gestational length is extended.

  14. Glucose metabolic phenotype of pancreatic cancer

    PubMed Central

    Chan, Anthony KC; Bruce, Jason IE; Siriwardena, Ajith K

    2016-01-01

    AIM: To construct a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression. METHODS: A systematic review of the literature was performed using OvidSP and PubMed databases using keywords “pancreatic cancer” and individual glycolytic and mitochondrial oxidative phosphorylation (MOP) enzymes. Both human and animal studies investigating the oncological effect of enzyme expression changes and inhibitors in both an in vitro and in vivo setting were included in the review. Data reporting changes in enzyme expression and the effects on PDAC cells, such as survival and metastatic potential, were extracted to construct a metabolic phenotype. RESULTS: Seven hundred and ten papers were initially retrieved, and were screened to meet the review inclusion criteria. 107 unique articles were identified as reporting data involving glycolytic enzymes, and 28 articles involving MOP enzymes in PDAC. Data extraction followed a pre-defined protocol. There is consistent over-expression of glycolytic enzymes and lactate dehydrogenase in keeping with the Warburg effect to facilitate rapid adenosine-triphosphate production from glycolysis. Certain isoforms of these enzymes were over-expressed specifically in PDAC. Altering expression levels of HK, PGI, FBA, enolase, PK-M2 and LDA-A with metabolic inhibitors have shown a favourable effect on PDAC, thus identifying these as potential therapeutic targets. However, the Warburg effect on MOP enzymes is less clear, with different expression levels at different points in the Krebs cycle resulting in a fundamental change of metabolite levels, suggesting that other essential anabolic pathways are being stimulated. CONCLUSION: Further characterisation of the PDAC metabolic phenotype is necessary as currently there are few clinical studies and no successful clinical trials targeting metabolic enzymes. PMID:27022229

  15. Impaired glucose and lipid metabolism in ageing aryl hydrocarbon receptor deficient mice

    PubMed Central

    Biljes, Daniel; Hammerschmidt-Kamper, Christiane; Kadow, Stephanie; Diel, Patrick; Weigt, Carmen; Burkart, Volker; Esser, Charlotte

    2015-01-01

    Disturbed homeostasis of glucose and lipid metabolism are dominant features of the so-called metabolic syndrome (MetS) and can increase the risk for the development of type 2 diabetes (T2D), a severe metabolic disease. T2D prevalence increases with age. The aryl hydrocarbon receptor (AHR) is a sensor of small molecules including dietary components. AHR has been identified as potential regulator of glucose homeostasis and lipid metabolism. Epidemiologically, exposure to xenobiotic AHR ligands such as polycyclic aromatic hydrocarbons is linked to T2D. We assess here the potential role of the AHR in disturbances of glucose and lipid metabolism in young (age 2-5 months) and old (age > 1,5 years) AHR-deficient (AHR KO) mice. Fasted young wildtype (WT) and AHR-KO mice displayed similar blood glucose kinetics after challenge with intra-peritoneal glucose injection. However, old AHR-KO mice showed lower tolerance than WT to i.p. administered glucose, i.e. glucose levels rose higher and returned more slowly to normal levels. Old mice had overall higher insulin levels than young mice, and old AHR-KO had a somewhat disturbed insulin kinetic in the serum after glucose challenge. Surprisingly, young AHR-KO mice had significantly lower triglycerides, cholesterol, high density lipoprotein values than WT, i.e., a dyslipidemic profile. With ageing, AHR-KO and WT mice did not differ in these lipid levels, except for slightly reduced levels of triglycerides and cholesterol. In conclusion, our findings in AHR KO mice suggest that AHR expression is relevant for the maintenance of glucose and lipid homeostasis in old mice. PMID:26664351

  16. Overuse of paracetamol caffeine aspirin powders affects cerebral glucose metabolism in chronic migraine patients.

    PubMed

    Di, W; Shi, X; Zhu, Y; Tao, Y; Qi, W; Luo, N; Xiao, Z; Yi, C; Miao, J; Zhang, A; Zhang, X; Fang, Y

    2013-04-01

    Overuse of analgesic plays a prominent role in migraine chronification. Paracetamol caffeine aspirin (PCA) powders are commonly used in Chinese migraineurs. This study investigated the effects of the specific combination analgesic on cerebral glucose metabolism in chronic migraine (CM). 18F-FDG-PET was used to measure regional metabolism in all subjects. Brain metabolisms of CM patients with analgesic overuse (AO-CM; n=10), no analgesic overuse (NAO-CM; n=10), and no regimen (NR-CM; n=10) and 17 age- and gender-matched normal controls (NC) were compared using statistical parametric mapping. Then, all patients underwent brain MRI analysis within 7 days after PET scans, as well as MMSE and MoCA scale for cognitive function tests. Glucose metabolic changes in CM patients taking different dosage of analgesic during headache-free periods and clear distinctions in several brain regions were observed. Patients with AO-CM exhibited significant metabolic reductions in thalamus, as well as increased metabolism in middle temporal gyrus and insula relative to NR-CM and NAO-CM. However, in these regions, no difference was observed in AO-CM except for increased metabolism in the right insula relative to NC group. Overusing PCA powders affects regional brain glucose metabolism in CM. Increased metabolism in the right insula may be associated with recurrently overusing of PCA powders. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

  17. Metabolic and endocrine profiles in response to systemic infusion of fructose and glucose in rhesus macaques.

    PubMed

    Adams, Sean H; Stanhope, Kimber L; Grant, Ryan W; Cummings, Bethany P; Havel, Peter J

    2008-06-01

    Diurnal patterns of circulating leptin concentrations are attenuated after consumption of fructose-sweetened beverages compared with glucose-sweetened beverages, likely a result of limited postprandial glucose and insulin excursions after fructose. Differences in postprandial exposure of adipose tissue to peripheral circulating fructose and glucose or in adipocyte metabolism of the two sugars may also be involved. Thus, we compared plasma leptin concentrations after 6-h iv infusions of saline, glucose, or fructose (15 mg/kg.min) in overnight-fasted adult rhesus monkeys (n = 9). Despite increases of plasma fructose from undetectable levels to about 2 mm during fructose infusion, plasma leptin concentrations did not increase, and the change of insulin was only about 10% of that seen during glucose infusion. During glucose infusion, plasma leptin was significantly increased above baseline concentrations by 240 min and increased steadily until the final 480-min time point (change in leptin = +2.5 +/- 0.9 ng/ml, P < 0.001 vs. saline; percent change in leptin = +55 +/- 16%; P < 0.005 vs. saline). Substantial anaerobic metabolism of fructose was suggested by a large increase of steady-state plasma lactate (change in lactate = 1.64 +/- 0.15 mm from baseline), which was significantly greater than that during glucose (+0.53 +/- 0.14 mm) or saline (-0.51 +/- 0.14 mm) infusions (P < 0.001). Therefore, increased adipose exposure to fructose and an active whole-body anaerobic fructose metabolism are not sufficient to increase circulating leptin levels in rhesus monkeys. Thus, additional factors (i.e. limited post-fructose insulin excursions and/or hexose-specific differences in adipocyte metabolism) are likely to underlie disparate effects of fructose and glucose to increase circulating leptin concentrations.

  18. Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes.

    PubMed

    Fernández-Real, José Manuel; McClain, Donald; Manco, Melania

    2015-11-01

    The bidirectional relationship between iron metabolism and glucose homeostasis is increasingly recognized. Several pathways of iron metabolism are modified according to systemic glucose levels, whereas insulin action and secretion are influenced by changes in relative iron excess. We aimed to update the possible influence of iron on insulin action and secretion and vice versa. The mechanisms that link iron metabolism and glucose homeostasis in the main insulin-sensitive tissues and insulin-producing β-cells were revised according to their possible influence on the development of type 2 diabetes (T2D). The mechanisms leading to dysmetabolic hyperferritinemia and hepatic overload syndrome were diverse, including diet-induced alterations in iron absorption, modulation of gluconeogenesis, heme-mediated disruption of circadian glucose rhythm, impaired hepcidin secretion and action, and reduced copper availability. Glucose metabolism in adipose tissue seems to be affected by both iron deficiency and excess through interaction with adipocyte differentiation, tissue hyperplasia and hypertrophy, release of adipokines, lipid synthesis, and lipolysis. Reduced heme synthesis and dysregulated iron uptake or export could also be contributing factors affecting glucose metabolism in the senescent muscle, whereas exercise is known to affect iron and glucose status. Finally, iron also seems to modulate β-cells and insulin secretion, although this has been scarcely studied. Iron is increasingly recognized to influence glucose metabolism at multiple levels. Body iron stores should be considered as a potential target for therapy in subjects with T2D or those at risk for developing T2D. Further research is warranted. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  19. Fuel metabolism in Canada geese: effects of glucagon on glucose kinetics

    PubMed Central

    Weber, Jean-Michel

    2015-01-01

    During prolonged fasting, birds must rely on glucose mobilization to maintain normoglycemia. Glucagon is known to modulate avian energy metabolism during prolonged fasting, but the metabolic effects of this hormone on long-distance migrant birds have never been investigated. Our goal was to determine whether glucagon regulates the mobilization of the main lipid and carbohydrate fuels in migrant birds. Using the Canada goose (Branta canadensis) as a model species, we looked for evidence of fuel mobilization via changes in metabolite concentrations. No changes could be found for any lipid fraction, but glucagon elicited a strong increase in glucose concentration. Therefore, we aimed to quantify the effects of this hormone on glucose kinetics using continuous infusion of 6-[3H]-d-glucose. Glucagon was found to cause a 50% increase in glucose mobilization (from 22.2 ± 2.4 μmol·kg−1·min−1 to 33.5 ± 3.3 μmol·kg−1·min−1) and, together with an unchanged rate of carbohydrate oxidation, led to a 90% increase in plasma glucose concentration. This hormone also led to a twofold increase in plasma lactate concentration. No changes in plasma lipid concentration or composition were observed. This study is the first to demonstrate how glucagon modulates glucose kinetics in a long-distance migrant bird and to quantify its rates of glucose mobilization. PMID:26108869

  20. The infusion of glucose in ewes during the luteal phase increases the number of follicles but reduces oestradiol production and some correlates of metabolic function in the large follicles.

    PubMed

    Gallet, Claire; Dupont, Joëlle; Campbell, Bruce K; Monniaux, Danielle; Guillaume, Daniel; Scaramuzzi, Rex J

    2011-09-01

    Short-term nutritional supplementation stimulates folliculogenesis in ewes probably by insulin-mediated actions of glucose in the follicle. The aim of this study was to determine the effect of glucose on follicle number and granulosa levels of Aromatase P450 and phosphorylated Akt and AMPK. Twelve Ile-de-France ewes were allocated to two groups; one (n=7) infused with saline and the other (n=5) with glucose (10mM/h) for 72h in the luteal phase. At the end of infusion, ovaries were collected and all follicles >1mm in diameter were dissected to recover granulosa cells. Aromatase P450 and phosphorylated Akt and AMPK were analysed by Western blotting of granulosa cell lysates. Blood plasmas collected before and during the infusions were analysed for progesterone, oestradiol, LH, FSH, glucose, insulin and IGF-I. The infusion of glucose significantly increased follicle number but, significantly reduced Aromatase P450 and phosphorylated Akt and AMPK in granulosa cells. The circulating concentration of glucose rose significantly 3h after the start of the glucose infusion and remained elevated until 27h then fell; the circulating concentration of insulin rose significantly by 3h and remained elevated. The circulating concentration of oestradiol fell significantly by 32h and remained low; the circulating concentrations of LH and FSH were unaffected. These data show that short-term infusion of glucose stimulated follicular growth but decreased Aromatase P450 in granulosa cells. The reduced levels of phosphorylated Akt and AMPK suggest that the phosphatidylinositol 3-kinase pathway has been inhibited by high concentrations of glucose. These data also suggest that there may be functional cross-talk between FSH and insulin signalling in granulosa cells.

  1. Fasting glucose measurement as a potential first step screening for glucose metabolism abnormalities in women with anovulatory polycystic ovary syndrome.

    PubMed

    Veltman-Verhulst, Susanne M; Goverde, Angelique J; van Haeften, Timon W; Fauser, Bart C J M

    2013-08-01

    Is routine screening by oral glucose tolerance test (OGTT) needed for all women with polycystic ovary syndrome (PCOS)? Screening for glucose metabolism abnormalities of PCOS patients by an OGTT could potentially be limited to patients who present with a fasting glucose concentration between 6.1 and 7.0 mmol/l only. Women with PCOS are at increased risk of developing diabetes. This study proposes a stepwise screening strategy for (pre)diabetes for PCOS patients based on risk stratification by fasting plasma glucose. A cross-sectional study of 226 women diagnosed with anovulatory PCOS. A consecutive series of 226 patients, diagnosed with PCOS at the University Medical Centre Utrecht, the Netherlands, were screened for glucose metabolism abnormalities by OGTT (75 g glucose load). The majority of the 226 women (mean age: 29.6 ± 4.3 years; BMI: 27.3 ± 6.7 kg/m(2); 81% Caucasian) presented with a normal OGTT (169 women (75%)). Of the 57 (25%) women presenting with mild to moderate glucose abnormalities, 53 (93%) could be identified by fasting glucose concentrations only. Diabetes was diagnosed in a total of eight women (3.5%). In six women, the diagnosis was based on fasting glucose >7.0 mmol/l. The other two cases of diabetes initially presented with fasting glucose between 6.1 and 7.0 mmol/l and were diagnosed by OGTT assessment. No women diagnosed with diabetes presented with fasting glucose levels below 6.1 mmol/l. We therefore conclude that all diabetes patients could potentially be found by initial fasting glucose assessment followed by OGTT only in patients with fasting glucose between 6.1 and 7.0 mmol/l. Before general implementation can be advised, this screening algorithm should be validated in a prospective study of a similar or greater number of PCOS women. Our study comprised of a mostly Caucasian (81%) population, therefore generalization to other ethnic populations should be done with caution. No external finance was involved in this study. B

  2. A distinct metabolic signature predicts development of fasting plasma glucose

    PubMed Central

    2012-01-01

    Background High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. Methods We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. Results We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. Conclusions We demonstrate that metabolites identified using a high

  3. A distinct metabolic signature predicts development of fasting plasma glucose.

    PubMed

    Hische, Manuela; Larhlimi, Abdelhalim; Schwarz, Franziska; Fischer-Rosinský, Antje; Bobbert, Thomas; Assmann, Anke; Catchpole, Gareth S; Pfeiffer, Andreas Fh; Willmitzer, Lothar; Selbig, Joachim; Spranger, Joachim

    2012-02-02

    High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in

  4. AICAR administration affects glucose metabolism by upregulating the novel glucose transporter, GLUT8, in equine skeletal muscle.

    PubMed

    de Laat, M A; Robinson, M A; Gruntmeir, K J; Liu, Y; Soma, L R; Lacombe, V A

    2015-09-01

    Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Glycolysis-induced discordance between glucose metabolic rates measured with radiolabeled fluorodeoxyglucose and glucose

    SciTech Connect

    Ackermann, R.F.; Lear, J.L. )

    1989-12-01

    We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered ({sup 18}F)fluorodeoxyglucose (FDG) and ({sup 14}C)-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic (GMg) and oxidative (GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the {sup 14}C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the {sup 14}C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt. If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum.

  6. Visfatin concentrations in obese patients in relation to the presence of newly diagnosed glucose metabolism disorders.

    PubMed

    Kamińska, Anna; Kopczyńska, Ewa; Bieliński, Maciej; Borkowska, Alina; Junik, Roman

    2015-01-01

    Visfatin, protein secreted by visceral adipose tissue, exerts insulin-mimetic actions. Visfatin concentration increases in patients with longer-standing diabetes type 2 with progressive b-cell dysfunction. Data about the role of visfatin in newly diagnosed glucose metabolism abnormalities are limited. Evaluation of visfatin concentration in patients with obesity, in relation to the presence of newly diagnosed glucose metabolism disorders. The study included 68 subjects with obesity, without a previous diagnosis of abnormal glucose metabolism. In all subjects we performed an oral glucose tolerance test, and according to the results the group was divided into the subgroups: A (n = 31), with glucose metabolism disorders (impaired fasting glucose, impaired glucose tolerance and type 2 diabetes); and B (n = 37), without abnormalities. In all subjects serum lipids, uric acid, C-peptide, glycated haemoglobin (HbA1c), creatinine, and serum visfatin concentrations were measured. The control group comprised 30 lean, healthy individuals with normal glucose tolerance. We found elevated visfatin levels in obese individuals versus the control group (50.0 ± 48 vs. 26.7 ± 22.1 ng/mL; p = 0.01). Visfatin concentrations in both subgroups, A and B, did not differ (40.86 ± 27.84 vs. 57.7 ± 59.79 ng/mL; p = 0.19). In subgroup A visfatin concentration correlated significantly with triglycerides (r = 0.37, p = 0.038), HbA1c (r = -0.43, p = 0.02), C-peptide (r = -0.38,p = 0.048), and waist-hip ratio (r = -0.41, p = 0.036). The presence of newly diagnosed glucose metabolism abnormalities in obese subjects had no influence on the visfatin level, probably due to preserved endogenous insulin secretion and relatively short exposure to hyperglycaemia in patients with prediabetes or at early stage of type 2 diabetes.

  7. Glucose metabolism in different regions of the rat brain under hypokinetic stress influence

    NASA Technical Reports Server (NTRS)

    Konitzer, K.; Voigt, S.

    1980-01-01

    Glucose metabolism in rats kept under long term hypokinetic stress was studied in 7 brain regions. Determination was made of the regional levels of glucose, lactate, glutamate, glutamine, aspartate, gamma-aminobutyrate and the incorporation of C-14 from plasma glucose into these metabolites, in glycogen and protein. From the content and activity data the regional glucose flux was approximated quantitatively. Under normal conditions the activity gradient cortex and frontal pole cerebellum, thalamus and mesencephalon, hypothalamus and pons and medulla is identical with that of the regional blood supply (measured with I131 serum albumin as the blood marker). Within the first days of immobilization a functional hypoxia occurred in all brain regions and the utilization of cycle amino acids for protein synthesis was strongly diminished. After the first week of stress the capillary volumes of all regions increased, aerobic glucose metabolism was enhanced (factors 1.3 - 2.0) and the incorporation of glucose C-14 via cycle amino acids into protein was considerably potentiated. The metabolic parameters normalized between the 7th and 11th week of stress. Blood supply and metabolic rate increased most in the hypothalamus.

  8. Sex-specific effects of dehydroepiandrosterone (DHEA) on glucose metabolism in the CNS.

    PubMed

    Vieira-Marques, Claudia; Arbo, Bruno Dutra; Cozer, Aline Gonçalves; Hoefel, Ana Lúcia; Cecconello, Ana Lúcia; Zanini, Priscila; Niches, Gabriela; Kucharski, Luiz Carlos; Ribeiro, Maria Flávia M

    2017-07-01

    DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases. Copyright © 2016. Published by Elsevier Ltd.

  9. Olanzapine and aripiprazole differentially affect glucose uptake and energy metabolism in human mononuclear blood cells.

    PubMed

    Stapel, Britta; Kotsiari, Alexandra; Scherr, Michaela; Hilfiker-Kleiner, Denise; Bleich, Stefan; Frieling, Helge; Kahl, Kai G

    2017-05-01

    The use of antipsychotics carries the risk of metabolic side effects, such as weight gain and new onset type-2 diabetes mellitus. The mechanisms of the observed metabolic alterations are not fully understood. We compared the effects of two atypical antipsychotics, one known to favor weight gain (olanzapine), the other not (aripiprazole), on glucose metabolism. Primary human peripheral blood mononuclear cells (PBMC) were isolated and stimulated with olanzapine or aripiprazole for 72 h. Cellular glucose uptake was analyzed in vitro by 18F-FDG uptake. Further measurements comprised mRNA expression of glucose transporter (GLUT) 1 and 3, GLUT1 protein expression, DNA methylation of GLUT1 promoter region, and proteins involved in downstream glucometabolic processes. We observed a 2-fold increase in glucose uptake after stimulation with aripiprazole. In contrast, olanzapine stimulation decreased glucose uptake by 40%, accompanied by downregulation of the cellular energy sensor AMP activated protein kinase (AMPK). GLUT1 protein expression increased, GLUT1 mRNA expression decreased, and GLUT1 promoter was hypermethylated with both antipsychotics. Pyruvat-dehydrogenase (PDH) complex activity decreased with olanzapine only. Our findings suggest that the atypical antipsychotics olanzapine and aripiprazole differentially affect energy metabolism in PBMC. The observed decrease in glucose uptake in olanzapine stimulated PBMC, accompanied by decreased PDH point to a worsening in cellular energy metabolism not compensated by AMKP upregulation. In contrast, aripiprazole stimulation lead to increased glucose uptake, while not affecting PDH complex expression. The observed differences may be involved in the different metabolic profiles observed in aripiprazole and olanzapine treated patients.

  10. Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-hour glucose and insulin excursions

    USDA-ARS?s Scientific Manuscript database

    It has been proposed that the adverse metabolic effects of chronic consumption of sugar-sweetened beverages which contain both glucose and fructose are a consequence of increased circulating glucose and insulin excursions, i.e dietary glycemic index (GI). Objective: We determined if the greater adv...

  11. Sex Differences in Regional Brain Glucose Metabolism Following Opioid Withdrawal and Replacement.

    PubMed

    Santoro, Giovanni C; Carrion, Joseph; Patel, Krishna; Vilchez, Crystal; Veith, Jennifer; Brodie, Jonathan D; Dewey, Stephen L

    2017-08-01

    Methadone and buprenorphine are currently the most common pharmacological treatments for opioid dependence. Interestingly, the clinical response to these drugs appears to be sex specific. That is, females exhibit superior therapeutic efficacy, defined as extended periods of abstinence and longer time to relapse, compared with males. However, the underlying metabolic effects of opioid withdrawal and replacement have not been examined. Therefore, using (18)FDG and microPET, we measured differences in regional brain glucose metabolism in males and females following morphine withdrawal and subsequent methadone or buprenorphine replacement. In both males and females, spontaneous opioid withdrawal altered glucose metabolism in regions associated with reward and drug dependence. Specifically, metabolic increases in the thalamus, as well as metabolic decreases in insular cortex and the periaqueductal gray, were noted. However, compared with males, females exhibited increased metabolism in the preoptic area, primary motor cortex, and the amygdala, and decreased metabolism in the caudate/putamen and medial geniculate nucleus. Methadone and buprenorphine initially abolished these changes uniformly, but subsequently produced their own regional metabolic alterations that varied by treatment and sex. Compared with sex-matched control animals undergoing spontaneous opioid withdrawal, male animals treated with methadone exhibited increased caudate/putamen metabolism, whereas buprenorphine produced increased ventral striatum and motor cortex metabolism in females, and increased ventral striatum and somatosensory cortex metabolism in males. Notably, when treatment effects were compared between sexes, methadone-treated females showed increased cingulate cortex metabolism, whereas buprenorphine-treated females showed decreased metabolism in cingulate cortex and increased metabolism in the globus pallidus. Perhaps the initial similarities in males and females underlie early therapeutic

  12. Microbial Regulation of Glucose Metabolism and Cell-Cycle Progression in Mammalian Colonocytes

    PubMed Central

    Donohoe, Dallas R.; Wali, Aminah; Brylawski, Bruna P.; Bultman, Scott J.

    2012-01-01

    A prodigious number of microbes inhabit the human body, especially in the lumen of the gastrointestinal (GI) tract, yet our knowledge of how they regulate metabolic pathways within our cells is rather limited. To investigate the role of microbiota in host energy metabolism, we analyzed ATP levels and AMPK phosphorylation in tissues isolated from germfree and conventionally-raised C57BL/6 mice. These experiments demonstrated that microbiota are required for energy homeostasis in the proximal colon to a greater extent than other segments of the GI tract that also harbor high densities of bacteria. This tissue-specific effect is consistent with colonocytes utilizing bacterially-produced butyrate as their primary energy source, whereas most other cell types utilize glucose. However, it was surprising that glucose did not compensate for butyrate deficiency. We measured a 3.5-fold increase in glucose uptake in germfree colonocytes. However, 13C-glucose metabolic-flux experiments and biochemical assays demonstrated that they shifted their glucose metabolism away from mitochondrial oxidation/CO2 production and toward increased glycolysis/lactate production, which does not yield enough ATPs to compensate. The mechanism responsible for this metabolic shift is diminished pyruvate dehydrogenase (PDH) levels and activity. Consistent with perturbed PDH function, the addition of butyrate, but not glucose, to germfree colonocytes ex vivo stimulated oxidative metabolism. As a result of this energetic defect, germfree colonocytes exhibited a partial block in the G1-to-S-phase transition that was rescued by a butyrate-fortified diet. These data reveal a mechanism by which microbiota regulate glucose utilization to influence energy homeostasis and cell-cycle progression of mammalian host cells. PMID:23029553

  13. Role of peripheral serotonin in glucose and lipid metabolism.

    PubMed

    Watanabe, Hitoshi; Rose, Michael T; Aso, Hisashi

    2011-06-01

    Two independent serotonin systems exist, one in the brain and the other in the periphery. Serotonin is a well known monoaminergic neurotransmitter in the central nervous system and it is known to regulate feeding behavior, meal size, and body weight. On the other hand, there is much less evidence for the role of serotonin as a gastrointestinal hormone, particularly with respect to its effects on glucose and lipid metabolism. This review summarizes our current understanding of the role of peripheral serotonin on glucose and lipid metabolism and the implications of this for further research. The enterochromaffin cells of the gastrointestinal tract produce peripheral serotonin postprandially. In mice, it induces a decrease in the concentration of circulating lipids as well as hyperglycemia and hyperinsulinemia through its action on several serotonin receptors. Further, serotonin metabolites act as endogenous agonists for peroxisome proliferator-activated receptor γ and serotonin accelerates adipocyte differentiation via serotonin receptor 2A and 2C. Studies of serotonin are likely to provide new insights into the field of lipid accumulation and metabolism. Recent studies show new physiological functions of peripheral serotonin, linked to glucose and lipid metabolism. Peripheral serotonin may serve as an attractive new therapeutic target for the treatment of metabolic disorders in the near future.

  14. Education-Associated Cortical Glucose Metabolism during Sustained Attention

    PubMed Central

    Eisenberg, Daniel P.; London, Edythe D.; Matochik, John A.; Derbyshire, Stuart; Cohen, Lisa J.; Steinfeld, Matthew; Prosser, James; Galynker, Igor I.

    2007-01-01

    Despite research suggesting that education may mitigate cognitive sequelae of neural injury, little is known about interactions between education and regional brain function. We examined whether educational experience is associated with relative glucose metabolism in brain regions that are important for sustained attention and learning. Fourteen healthy adults, with twelve to eighteen years of schooling, underwent positron emission tomography (PET) scanning with 18F-fluorodeoxyglucose (FDG) during an auditory continuous discrimination task. Years of education correlated positively with relative glucose metabolism in the lingual gyri (bilaterally), left posterior cingulate gyrus, and left precuneus. Previously, these structures have shown early impairment in dementia. Further investigation should explore whether metabolic changes in these regions contribute to the possible protective effect of education on cognition. PMID:16110274

  15. Human immunodeficiency virus type 1 infection of H9 cells induces increased glucose transporter expression.

    PubMed Central

    Sorbara, L R; Maldarelli, F; Chamoun, G; Schilling, B; Chokekijcahi, S; Staudt, L; Mitsuya, H; Simpson, I A; Zeichner, S L

    1996-01-01

    A clone obtained from a differential display screen for cellular genes with altered expression during human immunodeficiency virus (HIV) infection matched the sequence for the human GLUT3 facilitative glucose transporter, a high-velocity-high-affinity facilitative transporter commonly expressed in neurons of the central nervous system. Northern (RNA) analysis showed that GLUT3 expression increased during infection. Flow cytometry showed that GLUT3 protein expression increased specifically in the HIV-infected cells; this increase correlated with increased 2-deoxyglucose transport in the HIV-infected culture. HIV infection therefore leads to increased expression of a glucose transporter normally expressed at high levels in other cell types and a corresponding increase in glucose transport activity. If HIV infection places increased metabolic demands on the host cell, changes in the expression of a cellular gene that plays an important role in cellular metabolism might provide a more favorable environment for viral replication. PMID:8794382

  16. Glucose Metabolism from Mouth to Muscle: A Student Experiment to Teach Glucose Metabolism during Exercise and Rest

    ERIC Educational Resources Information Center

    Engeroff, Tobias; Fleckenstein, Johannes; Banzer, Winfried

    2017-01-01

    We developed an experiment to help students understand basic regulation of postabsorptive and postprandial glucose metabolism and the availability of energy sources for physical activity in the fed and fasted state. Within a practical session, teams of two or three students (1 subject and 1 or 2 investigators) performed one of three different…

  17. Glucose Metabolism from Mouth to Muscle: A Student Experiment to Teach Glucose Metabolism during Exercise and Rest

    ERIC Educational Resources Information Center

    Engeroff, Tobias; Fleckenstein, Johannes; Banzer, Winfried

    2017-01-01

    We developed an experiment to help students understand basic regulation of postabsorptive and postprandial glucose metabolism and the availability of energy sources for physical activity in the fed and fasted state. Within a practical session, teams of two or three students (1 subject and 1 or 2 investigators) performed one of three different…

  18. Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis.

    PubMed

    Domínguez-Andrés, Jorge; Arts, Rob J W; Ter Horst, Rob; Gresnigt, Mark S; Smeekens, Sanne P; Ratter, Jacqueline M; Lachmandas, Ekta; Boutens, Lily; van de Veerdonk, Frank L; Joosten, Leo A B; Notebaart, Richard A; Ardavín, Carlos; Netea, Mihai G

    2017-09-01

    Monocytes are innate immune cells that play a pivotal role in antifungal immunity, but little is known regarding the cellular metabolic events that regulate their function during infection. Using complementary transcriptomic and immunological studies in human primary monocytes, we show that activation of monocytes by Candida albicans yeast and hyphae was accompanied by metabolic rewiring induced through C-type lectin-signaling pathways. We describe that the innate immune responses against Candida yeast are energy-demanding processes that lead to the mobilization of intracellular metabolite pools and require induction of glucose metabolism, oxidative phosphorylation and glutaminolysis, while responses to hyphae primarily rely on glycolysis. Experimental models of systemic candidiasis models validated a central role for glucose metabolism in anti-Candida immunity, as the impairment of glycolysis led to increased susceptibility in mice. Collectively, these data highlight the importance of understanding the complex network of metabolic responses triggered during infections, and unveil new potential targets for therapeutic approaches against fungal diseases.

  19. Yam contributes to improvement of glucose metabolism in rats.

    PubMed

    Hashimoto, Naoto; Noda, Takahiro; Kim, Sun-Ju; Sarker, Md Zaidul Islam; Yamauchi, Hiroaki; Takigawa, Shigenobu; Matsuura-Endo, Chie; Suzuki, Tatsuro; Han, Kyu-Ho; Fukushima, Michihiro

    2009-09-01

    To investigate whether yam improves glucose metabolism, yam-containing diets were given to Wistar rats. In a short-term experiment, fasted-rats were given 1.0 g of a control and 20% yam-containing diets. At 60 min after start of the feeding, glucose level in the yam diet group was lower or tended to be lower than that in the control diet. Insulin levels at 30 min and 60 min were significantly lower than those in the control group. In a long-term experiment, a normal diet (N) or 25% high fat diets with (Y) or without 15% yam powder (HF) were given to rats for 4 weeks. At 4 weeks, in an oral glucose tolerance test, the area under the curve (AUC) of plasma glucose level was higher in the HF group than that in the N group, whereas those in the Y groups did not differ from that in the N group. Glycosylated hemoglobin levels had similar tendency to the AUCs. Plasma leptin levels in the Y groups were significantly higher than that in the N group. In conclusion, yam may contribute to improvement of glucose metabolism. Additionally, we speculated that leptin level is possibly involved in the insulin-response to yam diets.

  20. Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism.

    PubMed

    Saab, Aiman S; Tzvetavona, Iva D; Trevisiol, Andrea; Baltan, Selva; Dibaj, Payam; Kusch, Kathrin; Möbius, Wiebke; Goetze, Bianka; Jahn, Hannah M; Huang, Wenhui; Steffens, Heinz; Schomburg, Eike D; Pérez-Samartín, Alberto; Pérez-Cerdá, Fernando; Bakhtiari, Davood; Matute, Carlos; Löwel, Siegrid; Griesinger, Christian; Hirrlinger, Johannes; Kirchhoff, Frank; Nave, Klaus-Armin

    2016-07-06

    Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment in vivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.

    PubMed

    Liu, T; Kishton, R J; Macintyre, A N; Gerriets, V A; Xiang, H; Liu, X; Abel, E D; Rizzieri, D; Locasale, J W; Rathmell, J C

    2014-10-16

    The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting

  2. Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis

    PubMed Central

    Liu, T; Kishton, R J; Macintyre, A N; Gerriets, V A; Xiang, H; Liu, X; Abel, E D; Rizzieri, D; Locasale, J W; Rathmell, J C

    2014-01-01

    The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting

  3. Honeybee retinal glial cells transform glucose and supply the neurons with metabolic substrate

    SciTech Connect

    Tsacopoulos, M.; Evequoz-Mercier, V.; Perrottet, P.; Buchner, E.

    1988-11-01

    The retina of the honeybee drone is a nervous tissue in which glial cells and photoreceptor cells (sensory neurons) constitute two distinct metabolic compartments. Retinal slices incubated with 2-deoxy(/sup 3/H)glucose convert this glucose analogue to 2-deoxy(/sup 3/H)glucose 6-phosphate, but this conversion is made only in the glial cells. Hence, glycolysis occurs only in glial cells. In contrast, the neurons consume O/sub 2/ and this consumption is sustained by the hydrolysis of glycogen, which is contained in large amounts in the glia. During photostimulation the increased oxidative metabolism of the neurons is sustained by a higher supply of carbohydrates from the glia. This clear case of metabolic interaction between neurons and glial cells supports Golgi's original hypothesis, proposed nearly 100 years ago, about the nutritive function of glial cells in the nervous system.

  4. Honeybee retinal glial cells transform glucose and supply the neurons with metabolic substrate.

    PubMed Central

    Tsacopoulos, M; Evêquoz-Mercier, V; Perrottet, P; Buchner, E

    1988-01-01

    The retina of the honeybee drone is a nervous tissue in which glial cells and photoreceptor cells (sensory neurons) constitute two distinct metabolic compartments. Retinal slices incubated with 2-deoxy[3H]glucose convert this glucose analogue to 2-deoxy[3H]glucose 6-phosphate, but this conversion is made only in the glial cells. Hence, glycolysis occurs only in glial cells. In contrast, the neurons consume O2 and this consumption is sustained by the hydrolysis of glycogen, which is contained in large amounts in the glia. During photostimulation the increased oxidative metabolism of the neurons is sustained by a higher supply of carbohydrates from the glia. This clear case of metabolic interaction between neurons and glial cells supports Golgi's original hypothesis, proposed nearly 100 years ago, about the nutritive function of glial cells in the nervous system. Images PMID:3186756

  5. Adrenalectomy fails to stimulate brown adipose tissue metabolism in ob/ob mice fed glucose.

    PubMed

    Kim, H K; Romsos, D R

    1988-11-01

    Adrenalectomy arrests the development of obesity in ob/ob mice fed nonpurified high-starch diets partly by stimulating the low thermogenic activity of brown adipose tissue (BAT). However, adrenalectomy fails to suppress the development of obesity in ob/ob mice fed a purified high-glucose diet. Effects of adrenalectomy on BAT metabolism in ob/ob mice fed purified high-starch or high-glucose diets were therefore examined. Adrenalectomy markedly decreased the efficiency of energy retention and increased BAT metabolism (as assessed by GDP binding to BAT mitochondria, GDP-inhibitable acetate- or chloride-induced mitochondrial swelling, and by rates of norepinephrine turnover in BAT) in ob/ob mice fed a high-starch purified diet but had only minimal effects on energy efficiency or BAT metabolism in ob/ob mice fed a high-glucose purified diet. Plasma insulin concentrations decreased and thyroxine concentrations increased in adrenalectomized ob/ob mice fed the high-starch diet; changes in these hormones were less pronounced in adrenalectomized ob/ob mice fed the high-glucose diet. Consumption of glucose mimics effects of adrenal secretions on BAT metabolism in ob/ob mice.

  6. Increased IL-1β reactivity upon a glucose challenge in patients with deliberate self-harm.

    PubMed

    Westling, S; Ahrén, B; Träskman-Bendz, L; Brundin, L

    2011-10-01

    A disturbed glucose metabolism has been observed in patients with aggressive behaviour. Interleukin (IL)-1β is a pro-inflammatory cytokine that can induce hypoglycaemia, but has also been suggested to be involved in the generation of hostility and aggression. Our group has previously shown an altered glucose metabolism in patients with self-inflicted aggressive behaviour. We investigated the hypothesis that the levels of IL-1β would be increased in these patients, because this might explain the aberrant glucose metabolism and add further knowledge to the aetiology of self-inflicted aggressive behaviour. We investigated plasma cytokine changes in 13 patients with borderline personality disorder and 13 healthy controls during a 5-h glucose challenge. Plasma samples were analysed for cytokines IL-1β, TNF-α and IL-6 using high-sensitivity multiplex ELISA. Psychiatric symptoms were rated using the Aggression Questionnaire Revised Swedish Version. Basal plasma levels of the three cytokines did not differ between patients and controls. All three cytokines reacted significantly upon the glucose challenge. The increase in IL-1β levels in response to glucose was significantly greater in patients than in controls. Furthermore, IL-1β reactivity was associated with symptoms of hostility. An increased reactivity of IL-1β might be part of a pathogenetic mechanism in patients with deliberate self-harm. © 2011 John Wiley & Sons A/S.

  7. Changes induced by sucrose administration on glucose metabolism in pancreatic islets in normal hamsters.

    PubMed

    Massa, M L; Borelli, M I; Del Zotto, H; Gagliardino, J J

    2001-12-01

    measured at 1 and 100 mM (hexokinase/glucokinase ratio) was significantly higher in S5 (0.26+/-0.02) than in C5 animals (0.11+/-0.01, P<0.005), and it was attributable to an increase in the hexokinase activity in S5 animals. In conclusion, sucrose administration increased the hexokinase/glucokinase activity ratio in the islets, which would condition the increase in glucose metabolism by beta-cells, and in beta-cell sensitivity and responsiveness to glucose. These results support the concept that increased hexokinase rather than glucokinase activity causes the beta-cell hypersensitivity to glucose, hexokinase being metabolically more active than glucokinase to up-regulate beta-cell function.

  8. Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae.

    PubMed

    Vemuri, G N; Eiteman, M A; McEwen, J E; Olsson, L; Nielsen, J

    2007-02-13

    Respiratory metabolism plays an important role in energy production in the form of ATP in all aerobically growing cells. However, a limitation in respiratory capacity results in overflow metabolism, leading to the formation of byproducts, a phenomenon known as "overflow metabolism" or "the Crabtree effect." The yeast Saccharomyces cerevisiae has served as an important model organism for studying the Crabtree effect. When subjected to increasing glycolytic fluxes under aerobic conditions, there is a threshold value of the glucose uptake rate at which the metabolism shifts from purely respiratory to mixed respiratory and fermentative. It is well known that glucose repression of respiratory pathways occurs at high glycolytic fluxes, resulting in a decrease in respiratory capacity. Despite many years of detailed studies on this subject, it is not known whether the onset of the Crabtree effect is due to limited respiratory capacity or is caused by glucose-mediated repression of respiration. When respiration in S. cerevisiae was increased by introducing a heterologous alternative oxidase, we observed reduced aerobic ethanol formation. In contrast, increasing nonrespiratory NADH oxidation by overexpression of a water-forming NADH oxidase reduced aerobic glycerol formation. The metabolic response to elevated alternative oxidase occurred predominantly in the mitochondria, whereas NADH oxidase affected genes that catalyze cytosolic reactions. Moreover, NADH oxidase restored the deficiency of cytosolic NADH dehydrogenases in S. cerevisiae. These results indicate that NADH oxidase localizes in the cytosol, whereas alternative oxidase is directed to the mitochondria.

  9. Metabolic fate of glucose and candidate signaling and excess-fuel detoxification pathways in pancreatic β-cells.

    PubMed

    Mugabo, Yves; Zhao, Shangang; Lamontagne, Julien; Al-Mass, Anfal; Peyot, Marie-Line; Corkey, Barbara E; Joly, Erik; Madiraju, S R Murthy; Prentki, Marc

    2017-05-05

    Glucose metabolism promotes insulin secretion in β-cells via metabolic coupling factors that are incompletely defined. Moreover, chronically elevated glucose causes β-cell dysfunction, but little is known about how cells handle excess fuels to avoid toxicity. Here we sought to determine which among the candidate pathways and coupling factors best correlates with glucose-stimulated insulin secretion (GSIS), define the fate of glucose in the β-cell, and identify pathways possibly involved in excess-fuel detoxification. We exposed isolated rat islets for 1 h to increasing glucose concentrations and measured various pathways and metabolites. Glucose oxidation, oxygen consumption, and ATP production correlated well with GSIS and saturated at 16 mm glucose. However, glucose utilization, glycerol release, triglyceride and glycogen contents, free fatty acid (FFA) content and release, and cholesterol and cholesterol esters increased linearly up to 25 mm glucose. Besides being oxidized, glucose was mainly metabolized via glycerol production and release and lipid synthesis (particularly FFA, triglycerides, and cholesterol), whereas glycogen production was comparatively low. Using targeted metabolomics in INS-1(832/13) cells, we found that several metabolites correlated well with GSIS, in particular some Krebs cycle intermediates, malonyl-CoA, and lower ADP levels. Glucose dose-dependently increased the dihydroxyacetone phosphate/glycerol 3-phosphate ratio in INS-1(832/13) cells, indicating a more oxidized state of NAD in the cytosol upon glucose stimulation. Overall, the data support a role for accelerated oxidative mitochondrial metabolism, anaplerosis, and malonyl-CoA/lipid signaling in β-cell metabolic signaling and suggest that a decrease in ADP levels is important in GSIS. The results also suggest that excess-fuel detoxification pathways in β-cells possibly comprise glycerol and FFA formation and release extracellularly and the diversion of glucose carbons to

  10. Comparison of Glucose and Lipid Metabolic Gene Expressions between Fat and Lean Lines of Rainbow Trout after a Glucose Load

    PubMed Central

    Jin, Junyan; Médale, Françoise; Kamalam, Biju Sam; Aguirre, Peyo; Véron, Vincent; Panserat, Stéphane

    2014-01-01

    Two experimental rainbow trout lines developed through divergent selection for low (Lean ‘L’ line) or high (Fat ‘F’ line) muscle fat content were used as models to study the genetic determinism of fat depots. Previous nutritional studies suggested that the F line had a better capability to use glucose than the L line during feeding trials. Based on that, we put forward the hypothesis that F line has a greater metabolic ability to clear a glucose load effectively, compared to L line. In order to test this hypothesis, 250 mg/kg glucose was intraperitoneally injected to the two rainbow trout lines fasted for 48 h. Hyperglycemia was observed after glucose treatment in both lines without affecting the phosphorylation of AMPK (cellular energy sensor) and Akt-TOR (insulin signaling) components. Liver glucokinase and glucose-6-phosphate dehydrogenase expression levels were increased by glucose, whereas mRNA levels of β-oxidation enzymes (CPT1a, CPT1b, HOAD and ACO) were down-regulated in the white skeletal muscle of both lines. Regarding the genotype effect, concordant with normoglycemia at 12 h after glucose treatment, higher muscle glycogen was found in F line compared to L line which exhibited hyperglycemia. Moreover, mRNA levels of hepatic glycolytic enzymes (GK, 6PFK and PK), gluconeogenic enzyme PEPCK and muscle fatty acid oxidation enzymes (CPT1a, CPT1b and HOAD) were concurrently higher in the F line. Overall, these findings suggest that F line may have a better ability to maintain glucose homeostasis than L line. PMID:25141351

  11. Alterations of hippocampal glucose metabolism by even versus uneven medium chain triglycerides

    PubMed Central

    McDonald, Tanya S; Tan, Kah Ni; Hodson, Mark P; Borges, Karin

    2014-01-01

    Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of β-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain. PMID:24169853

  12. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

    PubMed Central

    Fu, Xianghui; Dong, Bingning; Tian, Yan; Lefebvre, Philippe; Meng, Zhipeng; Wang, Xichun; Pattou, François; Han, Weidong; Wang, Xiaoqiong; Lou, Fang; Jove, Richard; Staels, Bart; Moore, David D.; Huang, Wendong

    2015-01-01

    Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet–fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D. PMID:25961460

  13. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids.

    PubMed

    Fu, Xianghui; Dong, Bingning; Tian, Yan; Lefebvre, Philippe; Meng, Zhipeng; Wang, Xichun; Pattou, François; Han, Weidong; Wang, Xiaoqiong; Lou, Fang; Jove, Richard; Staels, Bart; Moore, David D; Huang, Wendong

    2015-06-01

    Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

  14. Glucose metabolism of lactic acid bacteria changed by quinone-mediated extracellular electron transfer.

    PubMed

    Yamazaki, Shin-ichi; Kaneko, Tsutomu; Taketomo, Naoki; Kano, Kenji; Ikeda, Tokuji

    2002-10-01

    It can be expected that extracellular electron transfer to regenerate NAD+ changes the glucose metabolism of the homofermentative lactic acid bacteria. In this work, the glucose metabolism of Lactobacillusplantarum and Lactococcus lactis was examined in resting cells with 2-amino-3-carboxy-1,4-naphthoquinone (ACNQ) as the electron transfer mediator and ferricyanide (Fe(CN)6(3-)) as the extracellular electron acceptor. NADH in the cells was oxidized by ACNQ with the aid of diaphorase, and the reduced ACNQ was reoxidized with Fe(CN)6(3-). The extracellular electron transfer system promoted the generation of pyruvate, acetate, and acetoin from glucose, and restricted lactate production. Diaphorase activity increased when cultivation was aerobic, and this increased the concentrations of pyruvate, acetate, and acetoin relative to the concentration of lactate to increase in the presence of ACNQ and Fe(CN)6(3-)

  15. Implications of Resveratrol on Glucose Uptake and Metabolism.

    PubMed

    León, David; Uribe, Elena; Zambrano, Angara; Salas, Mónica

    2017-03-07

    Resveratrol-a polyphenol of natural origin-has been the object of massive research in the past decade because of its potential use in cancer therapy. However, resveratrol has shown an extensive range of cellular targets and effects, which hinders the use of the molecule for medical applications including cancer and type 2 diabetes. Here, we review the latest advances in understanding how resveratrol modulates glucose uptake, regulates cellular metabolism, and how this may be useful to improve current therapies. We discuss challenges and findings regarding the inhibition of glucose uptake by resveratrol and other polyphenols of similar chemical structure. We review alternatives that can be exploited to improve cancer therapies, including the use of other polyphenols, or the combination of resveratrol with other molecules and their impact on glucose homeostasis in cancer and diabetes.

  16. Glucose metabolism from mouth to muscle: a student experiment to teach glucose metabolism during exercise and rest.

    PubMed

    Engeroff, Tobias; Fleckenstein, Johannes; Banzer, Winfried

    2017-03-01

    We developed an experiment to help students understand basic regulation of postabsorptive and postprandial glucose metabolism and the availability of energy sources for physical activity in the fed and fasted state. Within a practical session, teams of two or three students (1 subject and 1 or 2 investigators) performed one of three different trials: 1) inactive, in which subjects ingested a glucose solution (75 g in 300 ml of water) and rested in the seated position until the end of the trial; 2) prior activity, in which the subject performed 15 min of walking before glucose ingestion and a subsequent resting phase; and 3) postactivity, in which the subject ingested glucose solution, walked (15 min), and rested afterwards. Glucose levels were drawn before trials (fasting value), immediately after glucose ingestion (0 min), and 5, 10, 15, 20, 25, 30, 40, 50, and 60 min thereafter. Students analyzed glucose values and worked on 12 tasks. Students evaluated the usefulness of the experiment; 54.2% of students found the experiment useful to enable them to gain a further understanding of the learning objectives and to clarify items, and 44.1% indicated that the experiment was necessary to enable them to understand the learning objectives. For 6.8% the experiment was not necessary but helpful to check what they had learned, and 3.4% found that the experiment was not necessary. The present article shows the great value of experiments within practical courses to help students gain knowledge of energy metabolism. Using an active learning strategy, students outworked complex physiological tasks and improved beneficial communication and interaction between students with different skill sets and problem-solving strategies. Copyright © 2017 the American Physiological Society.

  17. Cerebral energy metabolism, glucose transport and blood flow: changes with maturation and adaptation to hypoglycaemia.

    PubMed

    Nehlig, A

    1997-02-01

    Brain maturation is characterized by a peak of cerebral energy metabolism and blood flow occurring between 3 and 8 years of age in humans and around 14-17 days of postnatal life in rats. This high activity coincides with the period of active brain growth. The human brain is dependent on glucose alone during that period, whereas rat brain uses both glucose and ketone bodies to cover its energetic and biosynthetic needs. The maturation of the density of glucose transporter sites-GLUT1 located at the blood-brain barrier and GLUT3 at the neuronal membrane-parallels the development of cerebral glucose utilization. During moderate acute hypoglycaemia, there are no changes in cerebral functional activity; cerebral glucose utilization decreases and blood flow increases only when hypoglycaemia is severe (lower than 2 mumol/ml). During chronic hypoglycaemia, the brain adapts to the low circulating levels of glucose: the number of glucose transporter sites is increased, and cerebral glucose utilization and function are maintained at normal levels while cerebral blood flow is more moderately increased than during acute hypoglycaemia. Neuronal damage consecutive to severe and prolonged hypoglycaemia occurs mainly in the cerebral cortex, hippocampus and caudate-putamen as a result of active release of excitatory amino acids.

  18. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

    NASA Astrophysics Data System (ADS)

    Birsoy, Kıvanç; Possemato, Richard; Lorbeer, Franziska K.; Bayraktar, Erol C.; Thiru, Prathapan; Yucel, Burcu; Wang, Tim; Chen, Walter W.; Clish, Clary B.; Sabatini, David M.

    2014-04-01

    As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

  19. In vitro metabolic engineering of bioelectricity generation by the complete oxidation of glucose.

    PubMed

    Zhu, Zhiguang; Zhang, Y-H Percival

    2017-01-01

    The direct generation of electricity from the most abundant renewable sugar, glucose, is an appealing alternative to the production of liquid biofuels and biohydrogen. However, enzyme-catalyzed bioelectricity generation from glucose suffers from low yields due to the incomplete oxidation of the six-carbon compound glucose via one or few enzymes. Here, we demonstrate a synthetic ATP- and CoA-free 12-enzyme pathway to implement the complete oxidation of glucose in vitro. This pathway is comprised of glucose phosphorylation via polyphosphate glucokinase, NADH generation catalyzed by glucose 6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH), electron transfer from NADH to the anode, and glucose 6-phosphate regeneration via the non-oxidative pentose phosphate pathway and gluconeogenesis. The faraday efficiency from glucose to electrons via this pathway was as high as 98.8%, suggesting the generation of nearly 24 electrons per molecule of glucose. The generated current density was greatly increased from 2.8 to 6.9mAcm(-2) by replacing a low-activity G6PDH with a high-activity G6PDH and introducing a new enzyme, 6-phosphogluconolactonase, between G6PDH and 6PGDH. These results suggest the great potential of high-yield bioelectricity generation through in vitro metabolic engineering.

  20. Glucose metabolism in gastric cancer: The cutting-edge

    PubMed Central

    Yuan, Lian-Wen; Yamashita, Hiroharu; Seto, Yasuyuki

    2016-01-01

    Glucose metabolism in gastric cancer cells differs from that of normal epithelial cells. Upregulated aerobic glycolysis (Warburg effect) in gastric cancer meeting the demands of cell proliferation is associated with genetic mutations, epigenetic modification and proteomic alteration. Understanding the mechanisms of aerobic glycolysis may contribute to our knowledge of gastric carcinogenesis. Metabolomic studies offer novel, convenient and practical tools in the search for new biomarkers for early detection, diagnosis, prognosis, and chemosensitivity prediction of gastric cancer. Interfering with the process of glycolysis in cancer cells may provide a new and promising therapeutic strategy for gastric cancer. In this article, we present a brief review of recent studies of glucose metabolism in gastric cancer, with primary focus on the clinical applications of new biomarkers and their potential therapeutic role in gastric cancer. PMID:26877609

  1. Cerebral metabolism of glucose in benign hereditary chorea

    SciTech Connect

    Suchowersky, O.; Hayden, M.R.; Martin, W.R.; Stoessl, A.J.; Hildebrand, A.M.; Pate, B.D.

    1986-01-01

    Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by chorea of early onset with little or no progression. There is marked clinical variability in this disease with some subjects having onset in infancy and others with onset in early adulthood. In contrast to Huntington's disease (HD), there is no dementia. Computed tomography is normal in all subjects with no evidence of caudate nucleus atrophy. We present the results of positron emission tomography using YF-2-fluorodeoxyglucose on three patients with this disorder from two families. Cerebral glucose metabolism in one patient was decreased in the caudate nucleus, as previously reported in HD. The other two persons from a second family showed a relative decrease in metabolic rates of glucose in the caudate when compared with the thalamus. It appears that caudate hypometabolism is not specific for HD. These findings suggest that the caudate nucleus may play a significant role in the pathophysiology of some persons with BHC.

  2. Bone and Glucose Metabolism: A Two-Way Street

    PubMed Central

    Motyl, Katherine J.; McCabe, Laura R.; Schwartz, Ann V.

    2010-01-01

    Evidence from rodent models indicates that undercarboxylated osteocalcin (ucOC), a product of osteoblasts, is a hormone affecting insulin production by the pancreas and insulin sensitivity in peripheral tissues, at least in part through enhanced secretion of adiponectin from adipocytes. Clinical research to test whether this relationship is found in humans is just beginning to emerge. Cross-sectional studies confirm associations between total osteocalcin (OC), ucOC and glucose metabolism but cannot distinguish causality. To date, longitudinal studies have not provided a consistent picture of the effects of ucOC or OC on fasting glucose and insulin sensitivity. Further exploration into the physiological and mechanistic effects of ucOC and OC, in rodent models and clinical studies, is necessary to determine to what extent the skeleton regulates energy metabolism in humans. PMID:20682281

  3. Quantifying the contribution of the liver to glucose homeostasis: a detailed kinetic model of human hepatic glucose metabolism.

    PubMed

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.

  4. Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

    PubMed Central

    König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

    2012-01-01

    Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. PMID:22761565

  5. [Gut microbiota may have influence on glucose and lipid metabolism].

    PubMed

    Hallundbæk Mikkelsen, Kristian; Nielsen, Morten Frost; Tvede, Michael; Hansen, Torben; Pedersen, Oluf Borbye; Holst, Jens Juul; Vilsbøll, Tina; Knop, Filip Krag

    2013-11-11

    New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism.

  6. Red blood cell glucose metabolism in human chronic fluoride toxicity

    SciTech Connect

    Saralakumari, D.; Rao, P.R. )

    1991-12-01

    Fluoride is a well known inhibitor of many enzyme systems in vitro. The most widely studied classic example of fluoride inhibition is its potent inhibition of glycolysis, specifically its action on the enzyme enolase. Despite the plethora of in vitro studies on the effects of fluoride on the enzyme activity, there is a paucity of information concerning the in vivo metabolic lesions caused by the chronic toxic doses of fluoride in humans. The present study has been undertaken with a view to assess the changes in glucose metabolism and related enzymes in erythrocytes of humans consuming toxic doses of fluoride for prolonged periods.

  7. Effects of Mangifera indica (Careless) on Microcirculation and Glucose Metabolism in Healthy Volunteers.

    PubMed

    Buchwald-Werner, Sybille; Schön, Christiane; Frank, Sonja; Reule, Claudia

    2017-02-10

    A commercial Mangifera indica fruit powder (Careless) showed beneficial acute effects on microcirculation in a randomized, double-blind, crossover pilot study. Here, long-term effects on microcirculation and glucose metabolism were investigated in a double-blind, randomized, placebo-controlled, 3-arm parallel-design study in healthy individuals. A daily dose of 100 mg or 300 mg of the fruit powder was compared to placebo after supplementation for 4 weeks. Microcirculation and endothelial function were assessed by the Oxygen-to-see System and pulse amplitude tonometry, respectively. Glucose metabolism was assessed under fasting and postprandial conditions by capillary glucose and HbA1c values.Microcirculatory reactive hyperemia flow increased, especially in the 100 mg group (p = 0.025). The 300 mg of the M. indica fruit preparation reduced postprandial glucose levels by trend if compared to placebo (p = 0.0535) accompanied by significantly lower HbA1c values compared to baseline. Furthermore, 300 mg intake significantly improved postprandial endothelial function in individuals with decreased endothelial function after high-dose glucose intake (p = 0.0408; n = 11).In conclusion, the study suggests moderate beneficial effects of M. indica fruit preparation on microcirculation, endothelial function, and glucose metabolism.

  8. Metabolic Networks and Metabolites Underlie Associations Between Maternal Glucose During Pregnancy and Newborn Size at Birth

    PubMed Central

    Bain, James R.; Reisetter, Anna C.; Muehlbauer, Michael J.; Nodzenski, Michael; Stevens, Robert D.; Ilkayeva, Olga; Lowe, Lynn P.; Metzger, Boyd E.; Newgard, Christopher B.; Lowe, William L.

    2016-01-01

    Maternal metabolites and metabolic networks underlying associations between maternal glucose during pregnancy and newborn birth weight and adiposity demand fuller characterization. We performed targeted and nontargeted gas chromatography/mass spectrometry metabolomics on maternal serum collected at fasting and 1 h following glucose beverage consumption during an oral glucose tolerance test (OGTT) for 400 northern European mothers at ∼28 weeks' gestation in the Hyperglycemia and Adverse Pregnancy Outcome Study. Amino acids, fatty acids, acylcarnitines, and products of lipid metabolism decreased and triglycerides increased during the OGTT. Analyses of individual metabolites indicated limited maternal glucose associations at fasting, but broader associations, including amino acids, fatty acids, carbohydrates, and lipids, were found at 1 h. Network analyses modeling metabolite correlations provided context for individual metabolite associations and elucidated collective associations of multiple classes of metabolic fuels with newborn size and adiposity, including acylcarnitines, fatty acids, carbohydrates, and organic acids. Random forest analyses indicated an improved ability to predict newborn size outcomes by using maternal metabolomics data beyond traditional risk factors, including maternal glucose. Broad-scale association of fuel metabolites with maternal glucose is evident during pregnancy, with unique maternal metabolites potentially contributing specifically to newborn birth weight and adiposity. PMID:27207545

  9. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death

    PubMed Central

    Graham, Nicholas A; Tahmasian, Martik; Kohli, Bitika; Komisopoulou, Evangelia; Zhu, Maggie; Vivanco, Igor; Teitell, Michael A; Wu, Hong; Ribas, Antoni; Lo, Roger S; Mellinghoff, Ingo K; Mischel, Paul S; Graeber, Thomas G

    2012-01-01

    The altered metabolism of cancer can render cells dependent on the availability of metabolic substrates for viability. Investigating the signaling mechanisms underlying cell death in cells dependent upon glucose for survival, we demonstrate that glucose withdrawal rapidly induces supra-physiological levels of phospho-tyrosine signaling, even in cells expressing constitutively active tyrosine kinases. Using unbiased mass spectrometry-based phospho-proteomics, we show that glucose withdrawal initiates a unique signature of phospho-tyrosine activation that is associated with focal adhesions. Building upon this observation, we demonstrate that glucose withdrawal activates a positive feedback loop involving generation of reactive oxygen species (ROS) by NADPH oxidase and mitochondria, inhibition of protein tyrosine phosphatases by oxidation, and increased tyrosine kinase signaling. In cells dependent on glucose for survival, glucose withdrawal-induced ROS generation and tyrosine kinase signaling synergize to amplify ROS levels, ultimately resulting in ROS-mediated cell death. Taken together, these findings illustrate the systems-level cross-talk between metabolism and signaling in the maintenance of cancer cell homeostasis. PMID:22735335

  10. Glucose metabolic flux distribution of Lactobacillus amylophilus during lactic acid production using kitchen waste saccharified solution.

    PubMed

    Liu, Jianguo; Wang, Qunhui; Zou, Hui; Liu, Yingying; Wang, Juan; Gan, Kemin; Xiang, Juan

    2013-11-01

    The (13) C isotope tracer method was used to investigate the glucose metabolic flux distribution and regulation in Lactobacillus amylophilus to improve lactic acid production using kitchen waste saccharified solution (KWSS). The results demonstrate that L. amylophilus is a homofermentative bacterium. In synthetic medium, 60.6% of the glucose entered the Embden-Meyerhof-Parnas (EMP) to produce lactic acid, whereas 36.4% of the glucose entered the pentose phosphate metabolic pathway (HMP). After solid-liquid separation of the KWSS, the addition of Fe(3+) during fermentation enhanced the NADPH production efficiency and increased the NADH content. The flux to the EMP was also effectively increased. Compared with the control (60.6% flux to EMP without Fe(3+) addition), the flux to the EMP with the addition of Fe(3+) (74.3%) increased by 23.8%. In the subsequent pyruvate metabolism, Fe(3+) also increased lactate dehydrogenase activity, and inhibited alcohol dehydrogenase, pyruvate dehydrogenase and pyruvate carboxylase, thereby increasing the lactic acid production to 9.03 g l(-1) , an increase of 8% compared with the control. All other organic acid by-products were lower than in the control. However, the addition of Zn(2+) showed an opposite effect, decreasing the lactic acid production. In conclusion it is feasible and effective means using GC-MS, isotope experiment and MATLAB software to integrate research the metabolic flux distribution of lactic acid bacteria, and the results provide the theoretical foundation for similar metabolic flux distribution.

  11. Glucose metabolic flux distribution of Lactobacillus amylophilus during lactic acid production using kitchen waste saccharified solution

    PubMed Central

    Liu, Jianguo; Wang, Qunhui; Zou, Hui; Liu, Yingying; Wang, Juan; Gan, Kemin; Xiang, Juan

    2013-01-01

    The 13C isotope tracer method was used to investigate the glucose metabolic flux distribution and regulation in Lactobacillus amylophilus to improve lactic acid production using kitchen waste saccharified solution (KWSS). The results demonstrate that L. amylophilus is a homofermentative bacterium. In synthetic medium, 60.6% of the glucose entered the Embden–Meyerhof–Parnas (EMP) to produce lactic acid, whereas 36.4% of the glucose entered the pentose phosphate metabolic pathway (HMP). After solid–liquid separation of the KWSS, the addition of Fe3+ during fermentation enhanced the NADPH production efficiency and increased the NADH content. The flux to the EMP was also effectively increased. Compared with the control (60.6% flux to EMP without Fe3+ addition), the flux to the EMP with the addition of Fe3+ (74.3%) increased by 23.8%. In the subsequent pyruvate metabolism, Fe3+ also increased lactate dehydrogenase activity, and inhibited alcohol dehydrogenase, pyruvate dehydrogenase and pyruvate carboxylase, thereby increasing the lactic acid production to 9.03 g l−1, an increase of 8% compared with the control. All other organic acid by-products were lower than in the control. However, the addition of Zn2+ showed an opposite effect, decreasing the lactic acid production. In conclusion it is feasible and effective means using GC-MS, isotope experiment and MATLAB software to integrate research the metabolic flux distribution of lactic acid bacteria, and the results provide the theoretical foundation for similar metabolic flux distribution. PMID:23489617

  12. Systemic glucose and brain energy metabolism after subarachnoid hemorrhage.

    PubMed

    Helbok, Raimund; Schmidt, J Michael; Kurtz, Pedro; Hanafy, Khalid A; Fernandez, Luis; Stuart, R Morgan; Presciutti, Mary; Ostapkovich, Noeleen D; Connolly, E Sander; Lee, Kiwon; Badjatia, Neeraj; Mayer, Stephan A; Claassen, Jan

    2010-06-01

    Brain energy metabolic crisis (MC) and lactate-pyruvate ratio (LPR) elevations have been linked to poor outcome in comatose patients. We sought to determine if MC and LPR elevations after subarachnoid hemorrhage (SAH) are associated with acute reductions in serum glucose. Twenty-eight consecutive comatose SAH patients that underwent multimodality monitoring with intracranial pressure and microdialysis were studied. MC was defined as lactate/pyruvate ratio (LPR) > or = 40 and brain glucose < 0.7 mmol/l. Time-series data were analyzed using a multivariable general linear model with a logistic link function for dichotomized outcomes. Multimodality monitoring included 3,178 h of observation (mean 114 +/- 65 h per patient). In exploratory analysis, serum glucose significantly decreased from 8.2 +/- 1.8 mmol/l (148 mg/dl) 2 h before to 6.9 +/- 1.9 mmol/l (124 mg/dl) at the onset of MC (P < 0.001). Reductions in serum glucose of 25% or more were significantly associated with new onset MC (adjusted odds ratio [OR] 3.6, 95% confidence interval [CI] 2.2-6.0). Acute reductions in serum glucose of 25% or more were also significantly associated with an LPR rise of 25% or more (adjusted OR 1.6, 95% CI 1.1-2.4). All analyses were adjusted for significant covariates including Glasgow Coma Scale and cerebral perfusion pressure. Acute reductions in serum glucose, even to levels within the normal range, may be associated with brain energy metabolic crisis and LPR elevation in poor-grade SAH patients.

  13. Serum uromodulin is associated with impaired glucose metabolism

    PubMed Central

    Leiherer, Andreas; Muendlein, Axel; Saely, Christoph H.; Kinz, Elena; Brandtner, Eva M.; Fraunberger, Peter; Drexel, Heinz

    2017-01-01

    Abstract Uromodulin is the most abundant urine protein under physiological conditions. It has recently been described as a serum and plasma marker for kidney disease. Whether uromodulin is associated with impaired glucose metabolism is unknown. We therefore measured serum uromodulin and glucose traits in a cohort of 529 consecutively recruited patients. Serum uromodulin was significantly and inversely correlated with fasting plasma glucose (r = −0.161; P < 0.001), with plasma glucose 2 hours after an oral 75 g glucose challenge (r = −0.158; P = 0.001), and with HbA1c (r = −0.103; P = 0.018). A total of 146 (27.6%) of our patients had type 2 diabetes mellitus (T2DM). Analysis of covariance confirmed that T2DM was an independent determinant of serum uromodulin (F = 5.5, P = 0.020) after multivariate adjustment including hypertension and glomerular filtration rate. Prospectively, uromodulin was lowest in patients with T2DM at baseline, higher in initially nondiabetic subjects who developed diabetes during follow-up (FU) and highest among nondiabetic patients (147.7 ± 69.9 vs 164 ± 67 vs 179.9 ± 82.2 ng/mL, Ptrend < 0.001). Similar results were seen with respect to prediabetes (168.0 ± 81.2 vs 172.8 ± 66.3 vs 188.2 ± 74.0 ng/mL, P = 0.011). We conclude that serum uromodulin is significantly associated with impaired glucose metabolism and the development of prediabetes and diabetes. PMID:28151855

  14. Sex-specific effects of prenatal stress on glucose homoeostasis and peripheral metabolism in rats.

    PubMed

    Brunton, Paula J; Sullivan, Katie M; Kerrigan, David; Russell, John A; Seckl, Jonathan R; Drake, Amanda J

    2013-05-01

    Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically relevant maternal stress is less clear, yet of physiological importance. Here, we investigated in rats the short- and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose-insulin homoeostasis and peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action. Prenatal stress (PNS) was associated with reduced birth weight in female, but not male, offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months; however, at 6 months, PNS females were hyperinsulinaemic following an oral glucose load. In PNS males, plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor α (Pparα (Ppara)) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1α (Ppargc1a)) and Pparγ (Pparg) expression, whereas only Pgc1α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11βhsd1), phosphoenolpyruvate carboxykinase (Pepck (Pck1)), adipose triglyceride lipase (Atgl) and diglyceride acyltransferase 2 (Dgat2) in females, but only Pepck mRNA expression was reduced in PNS males. Thus, prenatal social stress differentially programmes glucose homoeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.

  15. Changes in cerebral glucose metabolism during early abstinence from chronic methamphetamine abuse.

    PubMed

    Berman, S M; Voytek, B; Mandelkern, M A; Hassid, B D; Isaacson, A; Monterosso, J; Miotto, K; Ling, W; London, E D

    2008-09-01

    Changes in brain function during the initial weeks of abstinence from chronic methamphetamine abuse may substantially affect clinical outcome, but are not well understood. We used positron emission tomography with [F-18]fluorodeoxyglucose (FDG) to quantify regional cerebral glucose metabolism, an index of brain function, during performance of a vigilance task. A total of 10 methamphetamine-dependent subjects were tested after 5-9 days of abstinence, and after 4 additional weeks of supervised abstinence. A total of 12 healthy control subjects were tested at corresponding times. Global glucose metabolism increased between tests (P=0.01), more in methamphetamine-dependent (10.9%, P=0.02) than control subjects (1.9%, NS). Glucose metabolism did not change in subcortical regions of methamphetamine-dependent subjects, but increased in neocortex, with maximal increase (>20%) in parietal regions. Changes in reaction time and self-reports of negative affect varied more in methamphetamine-dependent than in control subjects, and correlated both with the increase in parietal glucose metabolism, and decrease in relative activity (after scaling to the global mean) in some regions. A robust relationship between change in self-reports of depressive symptoms and relative activity in the ventral striatum may have great relevance to treatment success because of the role of this region in drug abuse-related behaviors. Shifts in cortical-subcortical metabolic balance either reflect new processes that occur during early abstinence, or the unmasking of effects of chronic methamphetamine abuse that are obscured by suppression of cortical glucose metabolism that continues for at least 5-9 days after cessation of methamphetamine self-administration.

  16. The Lin28/let-7 axis regulates glucose metabolism

    PubMed Central

    Zhu, Hao; Shyh-Chang, Ng; Segrè, Ayellet V.; Shinoda, Gen; Shah, Samar P.; Einhorn, William S.; Takeuchi, Ayumu; Engreitz, Jesse M.; Hagan, John P.; Kharas, Michael G; Urbach, Achia; Thornton, James E.; Triboulet, Robinson; Gregory, Richard I.; Altshuler, David; Daley, George Q.

    2012-01-01

    SUMMARY The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by blocking let-7 biogenesis. In studies of the Lin28/let-7 pathway, we discovered unexpected roles in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promoted an insulin-sensitized state that resisted high fat diet-induced diabetes, whereas muscle-specific loss of Lin28a and overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance. These phenomena occurred in part through let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. The mTOR inhibitor rapamycin abrogated the enhanced glucose uptake and insulin-sensitivity conferred by Lin28a in vitro and in vivo. In addition, we found that let-7 targets were enriched for genes that contain SNPs associated with type 2 diabetes and fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. PMID:21962509

  17. The Lin28/let-7 axis regulates glucose metabolism.

    PubMed

    Zhu, Hao; Shyh-Chang, Ng; Segrè, Ayellet V; Shinoda, Gen; Shah, Samar P; Einhorn, William S; Takeuchi, Ayumu; Engreitz, Jesse M; Hagan, John P; Kharas, Michael G; Urbach, Achia; Thornton, James E; Triboulet, Robinson; Gregory, Richard I; Altshuler, David; Daley, George Q

    2011-09-30

    The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion.

    PubMed

    Christopher, Michael; Rantzau, Christian; Chen, Zhi-Ping; Snow, Rodney; Kemp, Bruce; Alford, Frank P

    2006-11-01

    AMPK plays a central role in influencing fuel usage and selection. The aim of this study was to analyze the impact of low-dose AMP analog 5-aminoimidazole-4-carboxamide-1-beta-d-ribosyl monophosphate (ZMP) on whole body glucose turnover and skeletal muscle (SkM) glucose metabolism. Dogs were restudied after prior 48-h fatty acid oxidation (FA(OX)) blockade by methylpalmoxirate (MP; 5 x 12 hourly 10 mg/kg doses). During the basal equilibrium period (0-150 min), fasting dogs (n = 8) were infused with [3-(3)H]glucose followed by either 2-h saline or AICAR (1.5-2.0 mg x kg(-1) x min(-1)) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FA(OX) blockade. The AICAR and AICAR + MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (R(d tissue)), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCR(g)) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACC approximately pSer(221)) increased by 50%. In the AICAR + MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and R(d tissue) responses were markedly attenuated, but MCR(g) and GF increased significantly. SkM substrates were unchanged, but ACC approximately pSer(221) rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FA(ox) blockade.

  19. Polydatin improves glucose and lipid metabolism in experimental diabetes through activating the Akt signaling pathway.

    PubMed

    Hao, Jie; Chen, Cheng; Huang, Kaipeng; Huang, Junying; Li, Jie; Liu, Peiqing; Huang, Heqing

    2014-12-15

    Recently, the effect of polydatin on lipid regulation has gained considerable attention. And previous study has demonstrated that polydatin has hypoglycemic effect on experimental diabetic rats. Repressed Akt pathway contributes to glucose and lipid disorders in diabetes. Thus, whether polydatin regulates glucose and lipid metabolism in experimental diabetic models through the Akt pathway arouses interest. The purpose was to explore the regulatory mechanism of polydain on glucose and lipid through Akt pathway. We used a diabetic rat model induced by high-fat and -sugar diet with low-dose of streptozocin and an insulin resistant HepG2 cell model induced by palmitic acid to clarify the role of polydatin on glucose and lipid metabolism. Here, we found that polydatin significantly attenuated fasting blood–glucose, glycosylated hemoglobin, glycosylated serum protein, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in diabetic rats. Furthermore, polydatin significantly increased glucose uptake and consumption and decreased lipid accumulation in insulin resistant HepG2 cells. Polydatin markedly increased serum insulin levels in diabetic rats, and obviously activated the Akt signaling pathway in diabetic rat livers and insulin resistant HepG2 cells. Polydatin markedly increased phosphorylated GSK-3β, decreased the protein levels of G6Pase and SREBP-1c, and increased protein levels of GCK, LDLR, and phosphorylated IRS in livers and HepG2 cells. Overall, the results indicate that polydatin regulates glucose and lipid metabolism in experimental diabetic models, the underlying mechanism is probably associated with regulating the Akt pathway. The effect of polydatin on increased Akt phosphorylation is independent of prompting insulin secretion, but dependent of increasing IRS phosphorylation.

  20. Metabolism and acetylation contribute to leucine-mediated inhibition of cardiac glucose uptake.

    PubMed

    Renguet, Edith; Ginion, Audrey; Gélinas, Roselle; Bultot, Laurent; Auquier, Julien; Robillard Frayne, Isabelle; Daneault, Caroline; Vanoverschelde, Jean-Louis; Des Rosiers, Christine; Hue, Louis; Horman, Sandrine; Beauloye, Christophe; Bertrand, Luc

    2017-08-01

    High plasma leucine levels strongly correlate with type 2 diabetes. Studies of muscle cells have suggested that leucine alters the insulin response for glucose transport by activating an insulin-negative feedback loop driven by the mammalian target of rapamycin/p70 ribosomal S6 kinase (mTOR/p70S6K) pathway. Here, we examined the molecular mechanism involved in leucine's action on cardiac glucose uptake. Leucine was indeed able to curb glucose uptake after insulin stimulation in both cultured cardiomyocytes and perfused hearts. Although leucine activated mTOR/p70S6K, the mTOR inhibitor rapamycin did not prevent leucine's inhibitory action on glucose uptake, ruling out the contribution of the insulin-negative feedback loop. α-Ketoisocaproate, the first metabolite of leucine catabolism, mimicked leucine's effect on glucose uptake. Incubation of cardiomyocytes with [(13)C]leucine ascertained its metabolism to ketone bodies (KBs), which had a similar negative impact on insulin-stimulated glucose transport. Both leucine and KBs reduced glucose uptake by affecting translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Finally, we found that leucine elevated the global protein acetylation level. Pharmacological inhibition of lysine acetyltransferases counteracted this increase in protein acetylation and prevented leucine's inhibitory action on both glucose uptake and GLUT4 translocation. Taken together, these results indicate that leucine metabolism into KBs contributes to inhibition of cardiac glucose uptake by hampering the translocation of GLUT4-containing vesicles via acetylation. They offer new insights into the establishment of insulin resistance in the heart.NEW & NOTEWORTHY Catabolism of the branched-chain amino acid leucine into ketone bodies efficiently inhibits cardiac glucose uptake through decreased translocation of glucose transporter 4 to the plasma membrane. Leucine increases protein acetylation. Pharmacological inhibition of acetylation

  1. Effects of berberine on glucose metabolism in vitro.

    PubMed

    Yin, Jun; Hu, Renming; Chen, Mingdao; Tang, Jinfeng; Li, Fengying; Yang, Ying; Chen, Jialun

    2002-11-01

    The action of berberine was compared with metformin and troglitazone (TZD) with regard to the glucose-lowering action in vitro. HepG2 cell line, phenotypically similar to human hepatocytes, was used for glucose consumption (GC) studies. Cell proliferation was measured by methylthiotetrazole (MTT) assay. In moderate high glucose concentration (11.1 mmol/L), GC of HepG2 cells was increased by 32% to 60% (P <.001 to P <.0001) with 5 x 10(-6) mol/L to 1 x 10(-4) mol/L berberine, which was comparable to that with 1 x 10(-3) mol/L metformin. The glucose-lowering effect of berberine decreased as the glucose concentration increased. The maximal potency was reached in the presence of 5.5 mmol/L glucose, and it was abolished when the glucose concentration increased to 22.2 mmol/L. The effect was not dependent on insulin concentration, which was similar to that of metformin and was different from that of TZD, whose glucose-lowering effect is insulin dependent. TZD had a better antihyperglycemic potency than metformin when insulin was added (P <.001). In the meantime, a significant toxicity of the drug to HepG2 cells was also observed. The betaTC3 cell line was used for insulin release testing, and no secretogogue effect of berberine was observed. These observations suggest that berberine is able to exert a glucose-lowering effect in hepatocytes, which is insulin independent and similar to that of metformin, but has no effect on insulin secretion.

  2. Regional cerebral glucose metabolic rate in human sleep assessed by positron emission tomography

    SciTech Connect

    Buchsbaum, M.S.; Wu, J.; Hazlett, E.; Sicotte, N.; Bunney, W.E. Jr. ); Gillin, J.C. )

    1989-01-01

    The cerebral metabolic rate of glucose was measured during nighttime sleep in 36 normal volunteers using positron emission tomography and fluorine-18-labeled 2-deoxyglucose (FDG). In comparison to waking controls, subjects given FDG during non-rapid eye movement (NREM) sleep showed about a 23% reduction in metabolic rate across the entire brain. This decrease was greater for the frontal than temporal or occipital lobes, and greater for basal ganglia and thalamus than cortex. Subjects in rapid eye movement (REM) sleep tended to have higher cortical metabolic rates than walking subjects. The cingulate gyrus was the only cortical structure to show a significant increase in glucose metabolic rate in REM sleep in comparison to waking. The basal ganglia were relatively more active on the right in REM sleep and symmetrical in NREM sleep.

  3. Effects of poor and short sleep on glucose metabolism and obesity risk.

    PubMed

    Spiegel, Karine; Tasali, Esra; Leproult, Rachel; Van Cauter, Eve

    2009-05-01

    The importance of sleep to hormones and glucose metabolism was first documented more than four decades ago. Since then, sleep curtailment has become an endemic behavior in modern society. In addition, the prevalence of sleep disorders, particularly obstructive sleep apnea (OSA), has increased. OSA is very common in endocrine and metabolic disorders, but often remains undiagnosed. This Review summarizes the laboratory and epidemiologic evidence that suggests how sleep loss, either behavioral or disease-related, and poor quality of sleep might promote the development of obesity and diabetes mellitus, and exacerbate existing endocrine conditions. Treatment of sleep disorders has the potential to improve glucose metabolism and energy balance. Screening for habitual sleep patterns and OSA might be critically important for patients with endocrine and metabolic disorders.

  4. Effects of poor and short sleep on glucose metabolism and obesity risk

    PubMed Central

    Spiegel, Karine; Tasali, Esra; Leproult, Rachel; Van Cauter, Eve

    2015-01-01

    The importance of sleep to hormones and glucose metabolism was first documented more than four decades ago. Since then, sleep curtailment has become an endemic behavior in modern society. In addition, the prevalence of sleep disorders, particularly obstructive sleep apnea (OSA), has increased. OSA is very common in endocrine and metabolic disorders, but often remains undiagnosed. This Review summarizes the laboratory and epidemiologic evidence that suggests how sleep loss, either behavioral or disease-related, and poor quality of sleep might promote the development of obesity and diabetes mellitus, and exacerbate existing endocrine conditions. Treatment of sleep disorders has the potential to improve glucose metabolism and energy balance. Screening for habitual sleep patterns and OSA might be critically important for patients with endocrine and metabolic disorders. PMID:19444258

  5. Metabolically engineered glucose-utilizing Shewanella strains under anaerobic conditions.

    PubMed

    Choi, Donggeon; Lee, Sae Bom; Kim, Sohyun; Min, Byoungnam; Choi, In-Geol; Chang, In Seop

    2014-02-01

    Comparative genome analysis of Shewanella strains predicted that the strains metabolize preferably two- and three-carbon carbohydrates as carbon/electron source because many Shewanella genomes are deficient of the key enzymes in glycolysis (e.g., glucokinase). In addition, all Shewanella genomes are known to have only one set of genes associated with the phosphotransferase system required to uptake sugars. To engineer Shewanella strains that can utilize five- and six-carbon carbohydrates, we constructed glucose-utilizing Shewanella oneidensis MR-1 by introducing the glucose facilitator (glf; ZMO0366) and glucokinase (glk; ZMO0369) genes of Zymomonas mobilis. The engineered MR-1 strain was able to grow on glucose as a sole carbon/electron source under anaerobic conditions. The glucose affinity (Ks) and glucokinase activity in the engineered MR-1 strain were 299.46 mM and 0.259 ± 0.034 U/g proteins. The engineered strain was successfully applied to a microbial fuel cell system and exhibited current generation using glucose as the electron source. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Accumulation of d-Glucose from Pentoses by Metabolically Engineered Escherichia coli

    PubMed Central

    Xia, Tian; Han, Qi; Costanzo, William V.; Zhu, Yixuan; Urbauer, Jeffrey L.

    2015-01-01

    Escherichia coli that is unable to metabolize d-glucose (with knockouts in ptsG, manZ, and glk) accumulates a small amount of d-glucose (yield of about 0.01 g/g) during growth on the pentoses d-xylose or l-arabinose as a sole carbon source. Additional knockouts in the zwf and pfkA genes, encoding, respectively, d-glucose-6-phosphate 1-dehydrogenase and 6-phosphofructokinase I (E. coli MEC143), increased accumulation to greater than 1 g/liter d-glucose and 100 mg/liter d-mannose from 5 g/liter d-xylose or l-arabinose. Knockouts of other genes associated with interconversions of d-glucose-phosphates demonstrate that d-glucose is formed primarily by the dephosphorylation of d-glucose-6-phosphate. Under controlled batch conditions with 20 g/liter d-xylose, MEC143 generated 4.4 g/liter d-glucose and 0.6 g/liter d-mannose. The results establish a direct link between pentoses and hexoses and provide a novel strategy to increase carbon backbone length from five to six carbons by directing flux through the pentose phosphate pathway. PMID:25746993

  7. Metabolic effects of fructose and the worldwide increase in obesity.

    PubMed

    Tappy, Luc; Lê, Kim-Anne

    2010-01-01

    While virtually absent in our diet a few hundred years ago, fructose has now become a major constituent of our modern diet. Our main sources of fructose are sucrose from beet or cane, high fructose corn syrup, fruits, and honey. Fructose has the same chemical formula as glucose (C(6)H(12)O(6)), but its metabolism differs markedly from that of glucose due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. Fructose was initially thought to be advisable for patients with diabetes due to its low glycemic index. However, chronically high consumption of fructose in rodents leads to hepatic and extrahepatic insulin resistance, obesity, type 2 diabetes mellitus, and high blood pressure. The evidence is less compelling in humans, but high fructose intake has indeed been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Hepatic de novo lipogenesis and lipotoxicity, oxidative stress, and hyperuricemia have all been proposed as mechanisms responsible for these adverse metabolic effects of fructose. Although there is compelling evidence that very high fructose intake can have deleterious metabolic effects in humans as in rodents, the role of fructose in the development of the current epidemic of metabolic disorders remains controversial. Epidemiological studies show growing evidence that consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose) is associated with a high energy intake, increased body weight, and the occurrence of metabolic and cardiovascular disorders. There is, however, no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects. There has also been much concern that consumption of free fructose, as provided in high fructose corn syrup, may cause more adverse effects than consumption of fructose consumed with sucrose. There is, however, no direct evidence for more serious metabolic

  8. Effects of intermittent fasting on glucose and lipid metabolism.

    PubMed

    Antoni, Rona; Johnston, Kelly L; Collins, Adam L; Robertson, M Denise

    2017-08-01

    Two intermittent fasting variants, intermittent energy restriction (IER) and time-restricted feeding (TRF), have received considerable interest as strategies for weight-management and/or improving metabolic health. With these strategies, the pattern of energy restriction and/or timing of food intake are altered so that individuals undergo frequently repeated periods of fasting. This review provides a commentary on the rodent and human literature, specifically focusing on the effects of IER and TRF on glucose and lipid metabolism. For IER, there is a growing evidence demonstrating its benefits on glucose and lipid homeostasis in the short-to-medium term; however, more long-term safety studies are required. Whilst the metabolic benefits of TRF appear quite profound in rodents, findings from the few human studies have been mixed. There is some suggestion that the metabolic changes elicited by these approaches can occur in the absence of energy restriction, and in the context of IER, may be distinct from those observed following similar weight-loss achieved via modest continuous energy restriction. Mechanistically, the frequently repeated prolonged fasting intervals may favour preferential reduction of ectopic fat, beneficially modulate aspects of adipose tissue physiology/morphology, and may also impinge on circadian clock regulation. However, mechanistic evidence is largely limited to findings from rodent studies, thus necessitating focused human studies, which also incorporate more dynamic assessments of glucose and lipid metabolism. Ultimately, much remains to be learned about intermittent fasting (in its various forms); however, the findings to date serve to highlight promising avenues for future research.

  9. Viral affects on metabolism: changes in glucose and glutamine utilization during human cytomegalovirus infection

    PubMed Central

    Yu, Yongjun; Clippinger, Amy J.; Alwine, James C.

    2011-01-01

    Human cytomegalovirus (HCMV) infection causes dramatic alterations of intermediary metabolism, similar to those found in tumor cells. In infected cells, glucose carbon is not completely broken down by the tricarboxylic acid (TCA) cycle for energy; instead it is used biosynthetically. This process requires increased glucose uptake, increased glycolysis and the diversion of glucose carbon, in the form of citrate, from the TCA cycle for use in HCMV-induced fatty acid biosynthesis. The diversion of citrate from the TCA cycle (cataplerosis) requires induction of enzymes to promote glutaminolysis, the conversion of glutamine to -ketoglutarate in order to maintain the TCA cycle (anaplerosis) and ATP production. Such changes could result in heretofore uncharacterized pathogenesis, potentially implicating HCMV as a subtle co-factor in many maladies, including oncogenesis. Recognition of the effects of HCMV, and other viruses, on host cell metabolism will provide new understanding of viral pathogenesis and novel avenues for antiviral therapy. PMID:21570293

  10. Effects of extracellular modulation through hypoxia on the glucose metabolism of human breast cancer stem cells

    NASA Astrophysics Data System (ADS)

    Yustisia, I.; Jusman, S. W. A.; Wanandi, S. I.

    2017-08-01

    Cancer stem cells have been reported to maintain stemness under certain extracellular changes. This study aimed to analyze the effect of extracellular O2 level modulation on the glucose metabolism of human CD24-/CD44+ breast cancer stem cells (BCSCs). The primary BCSCs (CD24-/CD44+ cells) were cultured under hypoxia (1% O2) for 0.5, 4, 6, 24 and 48 hours. After each incubation period, HIF1α, GLUT1 and CA9 expressions, as well as glucose metabolism status, including glucose consumption, lactate production, O2 consumption and extracellular pH (pHe) were analyzed using qRT-PCR, colorimetry, fluorometry, and enzymatic reactions, respectively. Hypoxia caused an increase in HIF1α mRNA expressions and protein levels and shifted the metabolic states to anaerobic glycolysis, as demonstrated by increased glucose consumption and lactate production, as well as decreased O2 consumption and pHe. Furthermore, we demonstrated that GLUT1 and CA9 mRNA expressions simultaneously increased, in line with HIF1α expression. In conclusion, modulation of the extracellular environment of human BCSCs through hypoxia shifedt the metabolic state of BCSCs to anaerobic glycolysis, which might be associated with GLUT1 and CA9 expressions regulated by HIFlα transcription factor.

  11. Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One–Carbon Cycle Energy Producing Pathway

    PubMed Central

    Varma, Vijayalakshmi; Boros, László G.; Nolen, Greg T.; Chang, Ching-Wei; Wabitsch, Martin; Beger, Richard D.; Kaput, Jim

    2015-01-01

    Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes. PMID:26087138

  12. Fructose Alters Intermediary Metabolism of Glucose in Human Adipocytes and Diverts Glucose to Serine Oxidation in the One-Carbon Cycle Energy Producing Pathway.

    PubMed

    Varma, Vijayalakshmi; Boros, László G; Nolen, Greg T; Chang, Ching-Wei; Wabitsch, Martin; Beger, Richard D; Kaput, Jim

    2015-06-16

    Increased consumption of sugar and fructose as sweeteners has resulted in the utilization of fructose as an alternative metabolic fuel that may compete with glucose and alter its metabolism. To explore this, human Simpson-Golabi-Behmel Syndrome (SGBS) preadipocytes were differentiated to adipocytes in the presence of 0, 1, 2.5, 5 or 10 mM of fructose added to a medium containing 5 mM of glucose representing the normal blood glucose concentration. Targeted tracer [1,2-13C2]-d-glucose fate association approach was employed to examine the influence of fructose on the intermediary metabolism of glucose. Increasing concentrations of fructose robustly increased the oxidation of [1,2-13C2]-d-glucose to 13CO2 (p < 0.000001). However, glucose-derived 13CO2 negatively correlated with 13C labeled glutamate, 13C palmitate, and M+1 labeled lactate. These are strong markers of limited tricarboxylic acid (TCA) cycle, fatty acid synthesis, pentose cycle fluxes, substrate turnover and NAD+/NADP+ or ATP production from glucose via complete oxidation, indicating diminished mitochondrial energy metabolism. Contrarily, a positive correlation was observed between glucose-derived 13CO2 formed and 13C oleate and doses of fructose which indicate the elongation and desaturation of palmitate to oleate for storage. Collectively, these results suggest that fructose preferentially drives glucose through serine oxidation glycine cleavage (SOGC pathway) one-carbon cycle for NAD+/NADP+ production that is utilized in fructose-induced lipogenesis and storage in adipocytes.

  13. Retinoblastoma Protein Knockdown Favors Oxidative Metabolism and Glucose and Fatty Acid Disposal in Muscle Cells.

    PubMed

    Petrov, Petar D; Ribot, Joan; López-Mejía, Isabel C; Fajas, Lluís; Palou, Andreu; Bonet, M Luisa

    2016-03-01

    Deficiency in the retinoblastoma protein (Rb) favors leanness and a healthy metabolic profile in mice largely attributed to activation of oxidative metabolism in white and brown adipose tissues. Less is known about Rb modulation of skeletal muscle metabolism. This was studied here by transiently knocking down Rb expression in differentiated C2C12 myotubes using small interfering RNAs. Compared with control cells transfected with non-targeting RNAs, myotubes silenced for Rb (by 80-90%) had increased expression of genes related to fatty acid uptake and oxidation such as Cd36 and Cpt1b (by 61% and 42%, respectively), increased Mitofusin 2 protein content (∼2.5-fold increase), increased mitochondrial to nuclear DNA ratio (by 48%), increased oxygen consumption (by 65%) and decreased intracellular lipid accumulation. Rb silenced myotubes also displayed up-regulated levels of glucose transporter type 4 expression (∼5-fold increase), increased basal glucose uptake, and enhanced insulin-induced Akt phosphorylation. Interestingly, exercise in mice led to increased Rb phosphorylation (inactivation) in skeletal muscle as evidenced by immunohistochemistry analysis. In conclusion, the silencing of Rb enhances mitochondrial oxidative metabolism and fatty acid and glucose disposal in skeletal myotubes, and changes in Rb status may contribute to muscle physiological adaptation to exercise. © 2015 Wiley Periodicals, Inc.

  14. UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets

    SciTech Connect

    Dalgaard, Louise T.

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer UCP2 mRNA levels are decreased in islets of Langerhans from glucokinase deficient mice. Black-Right-Pointing-Pointer UCP2 mRNA up-regulation by glucose is dependent on glucokinase. Black-Right-Pointing-Pointer Absence of UCP2 increases GSIS of glucokinase heterozygous pancreatic islets. Black-Right-Pointing-Pointer This may protect glucokinase deficient mice from hyperglycemic damages. -- Abstract: Uncoupling Protein 2 (UCP2) is expressed in the pancreatic {beta}-cell, where it partially uncouples the mitochondrial proton gradient, decreasing both ATP-production and glucose-stimulated insulin secretion (GSIS). Increased glucose levels up-regulate UCP2 mRNA and protein levels, but the mechanism for UCP2 up-regulation in response to increased glucose is unknown. The aim was to examine the effects of glucokinase (GK) deficiency on UCP2 mRNA levels and to characterize the interaction between UCP2 and GK with regard to glucose-stimulated insulin secretion in pancreatic islets. UCP2 mRNA expression was reduced in GK+/- islets and GK heterozygosity prevented glucose-induced up-regulation of islet UCP2 mRNA. In contrast to UCP2 protein function UCP2 mRNA regulation was not dependent on superoxide generation, but rather on products of glucose metabolism, because MnTBAP, a superoxide dismutase mimetic, did not prevent the glucose-induced up-regulation of UCP2. Glucose-stimulated insulin secretion was increased in UCP2-/- and GK+/- islets compared with GK+/- islets and UCP2 deficiency improved glucose tolerance of GK+/- mice. Accordingly, UCP2 deficiency increased ATP-levels of GK+/- mice. Thus, the compensatory down-regulation of UCP2 is involved in preserving the insulin secretory capacity of GK mutant mice and might also be implicated in limiting disease progression in MODY2 patients.

  15. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance.

    PubMed

    Yoshino, Jun; Conte, Caterina; Fontana, Luigi; Mittendorfer, Bettina; Imai, Shin-ichiro; Schechtman, Kenneth B; Gu, Charles; Kunz, Iris; Rossi Fanelli, Filippo; Patterson, Bruce W; Klein, Samuel

    2012-11-07

    Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo-controlled trial to evaluate the metabolic effects of 12 weeks of resveratrol supplementation (75 mg/day) in nonobese, postmenopausal women with normal glucose tolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of in vivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have beneficial metabolic effects in nonobese, postmenopausal women with normal glucose tolerance. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Germ band retraction as a landmark in glucose metabolism during Aedes aegypti embryogenesis

    PubMed Central

    2010-01-01

    Background The mosquito A. aegypti is vector of dengue and other viruses. New methods of vector control are needed and can be achieved by a better understanding of the life cycle of this insect. Embryogenesis is a part of A. aegypty life cycle that is poorly understood. In insects in general and in mosquitoes in particular energetic metabolism is well studied during oogenesis, when the oocyte exhibits fast growth, accumulating carbohydrates, lipids and proteins that will meet the regulatory and metabolic needs of the developing embryo. On the other hand, events related with energetic metabolism during A. aegypti embryogenesis are unknown. Results Glucose metabolism was investigated throughout Aedes aegypti (Diptera) embryonic development. Both cellular blastoderm formation (CBf, 5 h after egg laying - HAE) and germ band retraction (GBr, 24 HAE) may be considered landmarks regarding glucose 6-phosphate (G6P) destination. We observed high levels of glucose 6-phosphate dehydrogenase (G6PDH) activity at the very beginning of embryogenesis, which nevertheless decreased up to 5 HAE. This activity is correlated with the need for nucleotide precursors generated by the pentose phosphate pathway (PPP), of which G6PDH is the key enzyme. We suggest the synchronism of egg metabolism with carbohydrate distribution based on the decreasing levels of phosphoenolpyruvate carboxykinase (PEPCK) activity and on the elevation observed in protein content up to 24 HAE. Concomitantly, increasing levels of hexokinase (HK) and pyruvate kinase (PK) activity were observed, and PEPCK reached a peak around 48 HAE. Glycogen synthase kinase (GSK3) activity was also monitored and shown to be inversely correlated with glycogen distribution during embryogenesis. Conclusions The results herein support the hypothesis that glucose metabolic fate changes according to developmental embryonic stages. Germ band retraction is a moment that was characterized as a landmark in glucose metabolism during Aedes

  17. Dietary patterns in men and women are simultaneously determinants of altered glucose metabolism and bone metabolism.

    PubMed

    Langsetmo, Lisa; Barr, Susan I; Dasgupta, Kaberi; Berger, Claudie; Kovacs, Christopher S; Josse, Robert G; Adachi, Jonathan D; Hanley, David A; Prior, Jerilynn C; Brown, Jacques P; Morin, Suzanne N; Davison, Kenneth S; Goltzman, David; Kreiger, Nancy

    2016-04-01

    We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Protein Kinase N2 Regulates AMP-Kinase Signaling and Insulin Responsiveness of Glucose Metabolism in Skeletal Muscle.

    PubMed

    Ruby, Maxwell A; Riedl, Isabelle; Massart, Julie; Åhlin, Marcus; Zierath, Juleen R

    2017-07-18

    Insulin resistance is central to the development of type 2 diabetes and related metabolic disorders. As skeletal muscle is responsible for the majority of whole body insulin-stimulated glucose uptake, regulation of glucose metabolism in this tissue is of particular importance. While Rho GTPases and many of their affecters influence skeletal muscle metabolism, there is a paucity of information on the protein kinase N (PKN) family of serine/threonine protein kinases. We investigated the impact of PKN2 on insulin signaling and glucose metabolism in primary human skeletal muscle cells in vitro and mouse tibialis anterior muscle in vivo. PKN2 knockdown in vitro decreased insulin-stimulated glucose uptake, incorporation into glycogen, and oxidation. PKN2 siRNA increased 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, while stimulating fatty acid oxidation and incorporation into triglycerides, and decreasing protein synthesis. At the transcriptional level, PKN2 knockdown increased expression of PGC1α and SREBP1c and their target genes. In mature skeletal muscle, in vivo PKN2 knockdown decreased glucose uptake and increased AMPK phosphorylation. Thus, PKN2 alters key signaling pathways and transcriptional networks to regulate glucose and lipid metabolism. Identification of PKN2 as a novel regulator of insulin and AMPK signaling may provide an avenue for manipulation of skeletal muscle metabolism. Copyright © 2017, American Journal of Physiology-Endocrinology and Metabolism.

  19. Metabolic Impact of Increased NADH Availability in Saccharomyces cerevisiae▿

    PubMed Central

    Hou, Jin; Scalcinati, Gionata; Oldiges, Marco; Vemuri, Goutham N.

    2010-01-01

    Engineering the level of metabolic cofactors to manipulate metabolic flux is emerging as an attractive strategy for bioprocess applications. We present the metabolic consequences of increasing NADH in the cytosol and the mitochondria of Saccharomyces cerevisiae. In a strain that was disabled in formate metabolism, we either overexpressed the native NAD+-dependent formate dehydrogenase in the cytosol or directed it into the mitochondria by fusing it with the mitochondrial signal sequence encoded by the CYB2 gene. Upon exposure to formate, the mutant strains readily consumed formate and induced fermentative metabolism even under conditions of glucose derepression. Cytosolic overexpression of formate dehydrogenase resulted in the production of glycerol, while when this enzyme was directed into the mitochondria, we observed glycerol and ethanol production. Clearly, these results point toward different patterns of compartmental regulation of redox homeostasis. When pulsed with formate, S. cerevisiae cells growing in a steady state on glucose immediately consumed formate. However, formate consumption ceased after 20 min. Our analysis revealed that metabolites at key branch points of metabolic pathways were affected the most by the genetic perturbations and that the intracellular concentrations of sugar phosphates were specifically affected by time. In conclusion, the results have implications for the design of metabolic networks in yeast for industrial applications. PMID:20023106

  20. Metabolic reconfiguration of the central glucose metabolism: a crucial strategy of Leishmania donovani for its survival during oxidative stress.

    PubMed

    Ghosh, Ayan K; Sardar, Abul H; Mandal, Abhishek; Saini, Savita; Abhishek, Kumar; Kumar, Ashish; Purkait, Bidyut; Singh, Ruby; Das, Sushmita; Mukhopadhyay, Rupkatha; Roy, Syamal; Das, Pradeep

    2015-05-01

    Understanding the mechanism that allows the intracellular protozoan parasite Leishmania donovani (Ld) to respond to reactive oxygen species (ROS) is of increasing therapeutic importance because of the continuing resistance toward antileishmanial drugs and for determining the illusive survival strategy of these parasites. A shift in primary carbon metabolism is the fastest response to oxidative stress. A (14)CO2 evolution study, expression of glucose transporters together with consumption assays, indicated a shift in metabolic flux of the parasites from glycolysis toward pentose phosphate pathway (PPP) when exposed to different oxidants in vitro/ex vivo. Changes in gene expression, protein levels, and enzyme activities all pointed to a metabolic reconfiguration of the central glucose metabolism in response to oxidants. Generation of glucose-6-phosphate dehydrogenase (G6PDH) (∼5-fold) and transaldolase (TAL) (∼4.2-fold) overexpressing Ld cells reaffirmed that lethal doses of ROS were counterbalanced by effective manipulation of NADPH:NADP(+) ratio and stringent maintenance of reduced thiol content. The extent of protein carbonylation and accumulation of lipid peroxidized products were also found to be less in overexpressed cell lines. Interestingly, the LD50 of sodium antimony gluconate (SAG), amphotericin-B (AmB), and miltefosine were significantly high toward overexpressing parasites. Consequently, this study illustrates that Ld strategizes a metabolic reconfiguration for replenishment of NADPH pool to encounter oxidative challenges. © FASEB.

  1. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

    PubMed Central

    Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, Atalanta; Vaccaro, Nicole; Farrell, Kristin; Rothenberg, Paul; Henry, Robert R.

    2013-01-01

    OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. PMID:23412078

  2. Nuclear factor E2-related factor 2 knockdown enhances glucose uptake and alters glucose metabolism in AML12 hepatocytes.

    PubMed

    Yuan, Xiaoyang; Huang, Huijing; Huang, Yi; Wang, Jinli; Yan, Jinhua; Ding, Ling; Zhang, Cuntai; Zhang, Le

    2017-05-01

    Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce the expression of a variety of antioxidant and detoxification genes. Recently, increasing evidence has revealed roles for Nrf2 in glucose, lipid, and energy metabolism; however, the exact functions of Nrf2 in hepatocyte biology are largely unclear. In the current study, the transient knockdown of Nrf2 via siRNA transfection enhanced the glucose uptake of fasting AML12 hepatocytes to 325.3 ± 11.1% ( P < 0.05) of that of untransfected control cells. The impacts of Nrf2 knockdown (NK) on the antioxidant system, inflammatory response, and glucose metabolism were then examined in AML12 cells under both high-glucose (33 mmol/L) and low-glucose (4.5 mmol/L) conditions. NK lowered the gene and protein expression of the anti-oxidases heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 and increased p-eukaryotic initiation factor-2α(S51), p-nuclear factor-κB p65(S276), and its downstream proinflammatory factors, including interleukin-1 beta, tumor necrosis factor-α, matrix metalloproteinase 2, and matrix metalloproteinase 9, at the protein level. NK also altered the protein expression of fibroblast growth factor 21, glucose transporter type 4, insulin-like growth factor 1, forkhead box protein O1, p-AKT(S473), and p-GSK3α/β(Y279/Y216), which are involved in glucose uptake, glycogenesis, and gluconeogenesis in AML12 cells. Our results provide a comprehensive understanding of the central role of Nrf2 in the regulation of glucose metabolism in AML12 hepatocytes, in addition to its classical roles in the regulation of redox signaling, endoplasmic reticulum stress and proinflammatory responses, and support the potential of Nrf2 as a therapeutic target for the prevention and treatment of obesity and other associated metabolic syndromes. Impact statement Increasing evidence supports the complexity of Nrf2 functions beyond the antioxidant and detoxification response. Previous in

  3. Metabolic ketoacidosis with normal blood glucose: A rare complication of sodium–glucose cotransporter 2 inhibitors

    PubMed Central

    Ullah, Saad; Khan, Noman; Zeb, Hassan; Tahir, Hassan

    2016-01-01

    Ketoacidosis is a significant and often a life-threatening complication of diabetes mellitus seen mostly in type 1 diabetes mellitus as well as occasionally in type 2 diabetes mellitus. Diabetic ketoacidosis usually manifests with high blood glucose more than 250 mg/dL, but euglycemic diabetic ketoacidosis is defined as ketoacidosis associated with blood glucose level less than 250 mg/dL. Normal blood glucose in such patients results in significant delay in diagnosis and management of diabetic ketoacidosis, thus increasing mortality and morbidity. We present a case of euglycemic diabetic ketoacidosis secondary to canagliflozin in a type 2 diabetic patient. PMID:27928503

  4. Glucose Metabolism in the Progression of Prostate Cancer

    PubMed Central

    Cutruzzolà, Francesca; Giardina, Giorgio; Marani, Marina; Macone, Alberto; Paiardini, Alessandro; Rinaldo, Serena; Paone, Alessio

    2017-01-01

    Prostate cancer is one of the most common types of cancer in western country males but the mechanisms involved in the transformation processes have not been clearly elucidated. Alteration in cellular metabolism in cancer cells is recognized as a hallmark of malignant transformation, although it is becoming clear that the biological features of metabolic reprogramming not only differ in different cancers, but also among different cells in a type of cancer. Normal prostate epithelial cells have a peculiar and very inefficient energy metabolism as they use glucose to synthesize citrate that is secreted as part of the seminal liquid. During the transformation process, prostate cancer cells modify their energy metabolism from inefficient to highly efficient, often taking advantage of the interaction with other cell types in the tumor microenvironment that are corrupted to produce and secrete metabolic intermediates used by cancer cells in catabolic and anabolic processes. We recapitulate the metabolic transformations occurring in the prostate from the normal cell to the metastasis, highlighting the role of the microenvironment and summarizing what is known on the molecular mechanisms involved in the process. PMID:28270771

  5. Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse.

    PubMed

    Béland-Millar, Alexandria; Larcher, Jeremy; Courtemanche, Justine; Yuan, Tina; Messier, Claude

    2017-01-01

    Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved.

  6. Effects of Systemic Metabolic Fuels on Glucose and Lactate Levels in the Brain Extracellular Compartment of the Mouse

    PubMed Central

    Béland-Millar, Alexandria; Larcher, Jeremy; Courtemanche, Justine; Yuan, Tina; Messier, Claude

    2017-01-01

    Classic neuroenergetic research has emphasized the role of glucose, its transport and its metabolism in sustaining normal neural function leading to the textbook statement that it is the necessary and sole metabolic fuel of the mammalian brain. New evidence, including the Astrocyte-to-Neuron Lactate Shuttle hypothesis, suggests that the brain can use other metabolic substrates. To further study that possibility, we examined the effect of intraperitoneally administered metabolic fuels (glucose, fructose, lactate, pyruvate, ß-hydroxybutyrate, and galactose), and insulin, on blood, and extracellular brain levels of glucose and lactate in the adult male CD1 mouse. Primary motor cortex extracellular levels of glucose and lactate were monitored in freely moving mice with the use of electrochemical electrodes. Blood concentration of these same metabolites were obtained by tail vein sampling and measured with glucose and lactate meters. Blood and extracellular fluctuations of glucose and lactate were monitored for a 2-h period. We found that the systemic injections of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate increased blood lactate levels. Apart for a small transitory rise in brain extracellular lactate levels, the main effect of the systemic injection of glucose, fructose, lactate, pyruvate, and ß-hydroxybutyrate was an increase in brain extracellular glucose levels. Systemic galactose injections produced a small rise in blood glucose and lactate but almost no change in brain extracellular lactate and glucose. Systemic insulin injections led to a decrease in blood glucose and a small rise in blood lactate; however brain extracellular glucose and lactate monotonically decreased at the same rate. Our results support the concept that the brain is able to use alternative fuels and the current experiments suggest some of the mechanisms involved. PMID:28154523

  7. Seasonal Temperature Changes Do Not Affect Cardiac Glucose Metabolism

    PubMed Central

    Schildt, Jukka; Loimaala, Antti; Hippeläinen, Eero; Nikkinen, Päivi; Ahonen, Aapo

    2015-01-01

    FDG-PET/CT is widely used to diagnose cardiac inflammation such as cardiac sarcoidosis. Physiological myocardial FDG uptake often creates a problem when assessing the possible pathological glucose metabolism of the heart. Several factors, such as fasting, blood glucose, and hormone levels, influence normal myocardial glucose metabolism. The effect of outdoor temperature on myocardial FDG uptake has not been reported before. We retrospectively reviewed 29 cancer patients who underwent PET scans in warm summer months and again in cold winter months. We obtained myocardial, liver, and mediastinal standardized uptake values (SUVs) as well as quantitative cardiac heterogeneity and the myocardial FDG uptake pattern. We also compared age and body mass index to other variables. The mean myocardial FDG uptake showed no significant difference between summer and winter months. Average outdoor temperature did not correlate significantly with myocardial SUVmax in either summer or winter. The heterogeneity of myocardial FDG uptake did not differ significantly between seasons. Outdoor temperature seems to have no significant effect on myocardial FDG uptake or heterogeneity. Therefore, warming the patients prior to attending cardiac PET studies in order to reduce physiological myocardial FDG uptake seems to be unnecessary. PMID:26858844

  8. Fetuin B Is a Secreted Hepatocyte Factor Linking Steatosis to Impaired Glucose Metabolism.

    PubMed

    Meex, Ruth C; Hoy, Andrew J; Morris, Alexander; Brown, Russell D; Lo, Jennifer C Y; Burke, Melissa; Goode, Robert J A; Kingwell, Bronwyn A; Kraakman, Michael J; Febbraio, Mark A; Greve, Jan Willem; Rensen, Sander S; Molloy, Mark P; Lancaster, Graeme I; Bruce, Clinton R; Watt, Matthew J

    2015-12-01

    Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. The Role of Glucose Metabolism and Glucose-Associated Signalling in Cancer

    PubMed Central

    Wittig, Rainer; Coy, Johannes F.

    2007-01-01

    Aggressive carcinomas ferment glucose to lactate even in the presence of oxygen. This particular metabolism, termed aerobic glycolysis, the glycolytic phenotype, or the Warburg effect, was discovered by Nobel laureate Otto Warburg in the 1920s. Since these times, controversial discussions about the relevance of the fermentation of glucose by tumours took place; however, a majority of cancer researchers considered the Warburg effect as a non-causative epiphenomenon. Recent research demonstrated, that several common oncogenic events favour the expression of the glycolytic phenotype. Moreover, a suppression of the phenotypic features by either substrate limitation, pharmacological intervention, or genetic manipulation was found to mediate potent tumour-suppressive effects. The discovery of the transketolase-like 1 (TKTL1) enzyme in aggressive cancers may deliver a missing link in the interpretation of the Warburg effect. TKTL1-activity could be the basis for a rapid fermentation of glucose in aggressive carcinoma cells via the pentose phosphate pathway, which leads to matrix acidification, invasive growth, and ultimately metastasis. TKTL1 expression in certain non-cancerous tissues correlates with aerobic formation of lactate and rapid fermentation of glucose, which may be required for the prevention of advanced glycation end products and the suppression of reactive oxygen species. There is evidence, that the activity of this enzyme and the Warburg effect can be both protective or destructive for the organism. These results place glucose metabolism to the centre of pathogenesis of several civilisation related diseases and raise concerns about the high glycaemic index of various food components commonly consumed in western diets. PMID:19812737

  10. Effects of air pollution exposure on glucose metabolism in Los Angeles minority children.

    PubMed

    Toledo-Corral, C M; Alderete, T L; Habre, R; Berhane, K; Lurmann, F W; Weigensberg, M J; Goran, M I; Gilliland, F D

    2016-12-06

    Growing evidence indicates that ambient (AAP: NO2 , PM2.5 and O3 ) and traffic-related air pollutants (TRAP) contribute to metabolic disease risk in adults; however, few studies have examined these relationships in children. Metabolic profiling was performed in 429 overweight and obese African-American and Latino youth living in urban Los Angeles, California. This cross-sectional study estimated individual residential air pollution exposure and used linear regression to examine relationships between air pollution and metabolic outcomes. AAP and TRAP exposure were associated with adverse effects on glucose metabolism independent of body fat percent. PM2.5 was associated with 25.0% higher fasting insulin (p < 0.001), 8.3% lower insulin sensitivity (p < 0.001), 14.7% higher acute insulin response to glucose (p = 0.001) and 1.7% higher fasting glucose (p < 0.001). Similar associations were observed for increased NO2 exposure. TRAP from non-freeway roads was associated with 12.1% higher insulin (p < 0.001), 6.9% lower insulin sensitivity (p = 0.02), 10.8% higher acute insulin response to glucose (p = 0.003) and 0.7% higher fasting glucose (p = 0.047). Elevated air pollution exposure was associated with a metabolic profile that is characteristic of increased risk for type 2 diabetes. These results indicate that increased prior year exposure to air pollution may adversely affect type 2 diabetes-related pathophysiology in overweight and obese minority children. © 2016 World Obesity Federation.

  11. Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus.

    PubMed

    Bally, Lia; Laimer, Markus; Stettler, Christoph

    2015-07-01

    The primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM. Recent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM. Exercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise-associated glucose levels in these patients.

  12. Glucose metabolism and astrocyte-neuron interactions in the neonatal brain.

    PubMed

    Brekke, Eva; Morken, Tora Sund; Sonnewald, Ursula

    2015-03-01

    Glucose is essentially the sole fuel for the adult brain and the mapping of its metabolism has been extensive in the adult but not in the neonatal brain, which is believed to rely mainly on ketone bodies for energy supply. However, glucose is absolutely indispensable for normal development and recent studies have shed light on glycolysis, the pentose phosphate pathway and metabolic interactions between astrocytes and neurons in the 7-day-old rat brain. Appropriately (13)C labeled glucose was used to distinguish between glycolysis and the pentose phosphate pathway during development. Experiments using (13)C labeled acetate provided insight into the GABA-glutamate-glutamine cycle between astrocytes and neurons. It could be shown that in the neonatal brain the part of this cycle that transfers glutamine from astrocytes to neurons is operating efficiently while, in contrast, little glutamate is shuttled from neurons to astrocytes. This lack of glutamate for glutamine synthesis is compensated for by anaplerosis via increased pyruvate carboxylation relative to that in the adult brain. Furthermore, compared to adults, relatively more glucose is prioritized to the pentose phosphate pathway than glycolysis and pyruvate dehydrogenase activity. The reported developmental differences in glucose metabolism and neurotransmitter synthesis may determine the ability of the brain at various ages to resist excitotoxic insults such as hypoxia-ischemia.

  13. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy?

    PubMed Central

    Hay, Nissim

    2017-01-01

    In recent years there has been a growing interest among cancer biologists in cancer metabolism. This Review summarizes past and recent advances in our understanding of the reprogramming of glucose metabolism in cancer cells, which is mediated by oncogenic drivers and by the undifferentiated character of cancer cells. The reprogrammed glucose metabolism in cancer cells is required to fulfil anabolic demands. This Review discusses the possibility of exploiting the reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells. PMID:27634447

  14. Ozone induces glucose intolerance and systemic metabolic effects in young and aged brown Norway rats

    SciTech Connect

    Bass, V.; Gordon, C.J.; Jarema, K.A.; MacPhail, R.C.; Cascio, W.E.; Phillips, P.M.; Ledbetter, A.D.; Schladweiler, M.C.; Andrews, D.; Miller, D.; Doerfler, D.L.; Kodavanti, U.P.

    2013-12-15

    Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α{sub 2}-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2 > 1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation. - Highlights: • Air pollutants have been associated with increased diabetes in humans. • Acute ozone exposure produces profound metabolic alterations in rats. • Age influences metabolic risk factors in aging BN rats. • Acute metabolic effects are reversible and repeated exposure reduces these effects. • Ozone

  15. Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors

    PubMed Central

    Song, Zhilin; Levin, Barry E.; Stevens, Wanida

    2014-01-01

    Neurons in the supraoptic nuclei (SON) produce oxytocin and vasopressin and express insulin receptors (InsR) and glucokinase. Since oxytocin is an anorexigenic agent and glucokinase and InsR are hallmarks of cells that function as glucose and/or metabolic sensors, we evaluated the effect of glucose, insulin, and their downstream effector ATP-sensitive potassium (KATP) channels on calcium signaling in SON neurons and on oxytocin and vasopressin release from explants of the rat hypothalamo-neurohypophyseal system. We also evaluated the effect of blocking glucokinase and phosphatidylinositol 3 kinase (PI3K; mediates insulin-induced mobilization of glucose transporter, GLUT4) on responses to glucose and insulin. Glucose and insulin increased intracellular calcium ([Ca2+]i). The responses were glucokinase and PI3K dependent, respectively. Insulin and glucose alone increased vasopressin release (P < 0.002). Oxytocin release was increased by glucose in the presence of insulin. The oxytocin (OT) and vasopressin (VP) responses to insulin+glucose were blocked by the glucokinase inhibitor alloxan (4 mM; P ≤ 0.002) and the PI3K inhibitor wortmannin (50 nM; OT: P = 0.03; VP: P ≤ 0.002). Inactivating KATP channels with 200 nM glibenclamide increased oxytocin and vasopressin release (OT: P < 0.003; VP: P < 0.05). These results suggest that insulin activation of PI3K increases glucokinase-mediated ATP production inducing closure of KATP channels, opening of voltage-sensitive calcium channels, and stimulation of oxytocin and vasopressin release. The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and “metabolic” sensors to participate in appetite regulation. PMID:24477542

  16. Psychosocial stress predicts abnormal glucose metabolism: the Australian Diabetes, Obesity and Lifestyle (AusDiab) study.

    PubMed

    Williams, Emily D; Magliano, Dianna J; Tapp, Robyn J; Oldenburg, Brian F; Shaw, Jonathan E

    2013-08-01

    The evidence supporting a relationship between stress and diabetes has been inconsistent. This study examined the effects of stress on abnormal glucose metabolism, using a population-based sample of 3,759, with normoglycemia at baseline, from the Australian Diabetes, Obesity and Lifestyle study. Perceived stress and stressful life events were measured at baseline, with health behavior and anthropometric information also collected. Oral glucose tolerance tests were undertaken at baseline and 5-year follow-up. The primary outcome was the development of abnormal glucose metabolism (impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes), according to WHO 1999 criteria. Perceived stress predicted incident abnormal glucose metabolism in women but not men, after multivariate adjustment. Life events showed an inconsistent relationship with abnormal glucose metabolism. Perceived stress predicted abnormal glucose metabolism in women. Healthcare professionals should consider psychosocial adversity when assessing risk factor profiles for the development of diabetes.

  17. Chronic unpredictable stress regulates visceral adipocyte‐mediated glucose metabolism and inflammatory circuits in male rats

    PubMed Central

    Karagiannides, Iordanes; Golovatscka, Viktoriya; Bakirtzi, Kyriaki; Sideri, Aristea; Salas, Martha; Stavrakis, Dimitris; Polytarchou, Christos; Iliopoulos, Dimitrios; Pothoulakis, Charalabos; Bradesi, Sylvie

    2014-01-01

    Abstract Chronic psychological stress is a prominent risk factor involved in the pathogenesis of many complex diseases, including major depression, obesity, and type II diabetes. Visceral adipose tissue is a key endocrine organ involved in the regulation of insulin action and an important component in the development of insulin resistance. Here, we examined for the first time the changes on visceral adipose tissue physiology and on adipocyte‐associated insulin sensitivity and function after chronic unpredictable stress in rats. Male rats were subjected to chronic unpredictable stress for 35 days. Total body and visceral fat was measured. Cytokines and activated intracellular kinase levels were determined using high‐throughput multiplex assays. Adipocyte function was assessed via tritiated glucose uptake assay. Stressed rats showed no weight gain, and their fat/lean mass ratio increased dramatically compared to control animals. Stressed rats had significantly higher mesenteric fat content and epididymal fat pad weight and demonstrated reduced serum glucose clearing capacity following glucose challenge. Alterations in fat depot size were mainly due to changes in adipocyte numbers and not size. High‐throughput molecular screening in adipocytes isolated from stressed rats revealed activation of intracellular inflammatory, glucose metabolism, and MAPK networks compared to controls, as well as significantly reduced glucose uptake capacity in response to insulin stimulation. Our study identifies the adipocyte as a key regulator of the effects of chronic stress on insulin resistance, and glucose metabolism, with important ramifications in the pathophysiology of several stress‐related disease states. PMID:24819750

  18. A new application of electrical impedance spectroscopy for measuring glucose metabolism: a phantom study

    NASA Astrophysics Data System (ADS)

    Dhurjaty, Sreeram; Qiu, Yuchen; Tan, Maxine; Liu, Hong; Zheng, Bin

    2015-03-01

    Glucose metabolism relates to biochemical processes in living organisms and plays an important role in diabetes and cancer-metastasis. Although many methods are available for measuring glucose metabolism-activities, from simple blood tests to positron emission tomography, currently there is no robust and affordable device that enables monitoring of glucose levels in real-time. In this study we tested feasibility of applying a unique resonance-frequency based electronic impedance spectroscopy (REIS) device that has been, recently developed to measure and monitor glucose metabolism levels using a phantom study. In this new testing model, a multi-frequency electrical signal sequence is applied and scanned through the subject. When the positive reactance of an inductor inside the device cancels out the negative reactance of the capacitance of the subject, the electrical impedance reaches a minimum value and this frequency is defined as the resonance frequency. The REIS system has a 24-bit analog-to-digital signal convertor and a frequency-resolution of 100Hz. In the experiment, two probes are placed inside a 100cc container initially filled with distilled water. As we gradually added liquid-glucose in increments of 1cc (250mg), we measured resonance frequencies and minimum electrical signal values (where A/D was normalized to a full scale of 1V). The results showed that resonance frequencies monotonously decreased from 243kHz to 178kHz, while the minimum voltages increased from 405mV to 793mV as the added amount of glucose increased from 0 to 5cc. The study demonstrated the feasibility of applying this new REIS technology to measure and/or monitor glucose levels in real-time in future.

  19. Low Glucose but Not Galactose Enhances Oxidative Mitochondrial Metabolism in C2C12 Myoblasts and Myotubes

    PubMed Central

    Elkalaf, Moustafa; Anděl, Michal; Trnka, Jan

    2013-01-01

    Background Substituting galactose for glucose in cell culture media has been suggested to enhance mitochondrial metabolism in a variety of cell lines. We studied the effects of carbohydrate availability on growth, differentiation and metabolism of C2C12 myoblasts and myotubes. Methodology/Principal Findings We measured growth rates, ability to differentiate, citrate synthase and respiratory chain activities and several parameters of mitochondrial respiration in C2C12 cells grown in media with varying carbohydrate availability (5 g/l glucose, 1 g/l glucose, 1 g/l galactose, and no added carbohydrates). C2C12 myoblasts grow more slowly without glucose irrespective of the presence of galactose, which is not consumed by the cells, and they fail to differentiate without glucose in the medium. Cells grown in a no-glucose medium (with or without galactose) have lower maximal respiration and spare respiratory capacity than cells grown in the presence of glucose. However, increasing glucose concentration above physiological levels decreases the achievable maximal respiration. C2C12 myotubes differentiated at a high glucose concentration showed higher dependency on oxidative respiration under basal conditions but had lower maximal and spare respiratory capacity when compared to cells differentiated under low glucose condition. Citrate synthase activity or mitochondrial yield were not significantly affected by changes in the available substrate concentration but a trend towards a higher respiratory chain activity was observed at reduced glucose levels. Conclusions/Significance Our results show that using galactose to increase oxidative metabolism may not be applicable to every cell line, and the changes in mitochondrial respiratory parameters associated with treating cells with galactose are mainly due to glucose deprivation. Moderate concentrations of glucose (1 g/l) in a growth medium are optimal for mitochondrial respiration in C2C12 cell line while supraphysiological

  20. Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats.

    PubMed

    Bass, V; Gordon, C J; Jarema, K A; MacPhail, R C; Cascio, W E; Phillips, P M; Ledbetter, A D; Schladweiler, M C; Andrews, D; Miller, D; Doerfler, D L; Kodavanti, U P

    2013-12-15

    Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.

  1. Effects of Cell Phone Radiofrequency Signal Exposure on Brain Glucose Metabolism

    PubMed Central

    Volkow, Nora D.; Tomasi, Dardo; Wang, Gene-Jack; Vaska, Paul; Fowler, Joanna S.; Telang, Frank; Alexoff, Dave; Logan, Jean; Wong, Christopher

    2011-01-01

    Context The dramatic increase in use of cellular telephones has generated concern about possible negative effects of radiofrequency signals delivered to the brain. However, whether acute cell phone exposure affects the human brain is unclear. Objective To evaluate if acute cell phone exposure affects brain glucose metabolism, a marker of brain activity. Design, Setting, and Participants Randomized crossover study conducted between January 1 and December 31, 2009, at a single US laboratory among 47 healthy participants recruited from the community. Cell phones were placed on the left and right ears and positron emission tomography with (18F)fluorodeoxyglucose injection was used to measure brain glucose metabolism twice, once with the right cell phone activated (sound muted) for 50 minutes (“on” condition) and once with both cell phones deactivated (“off” condition). Statistical parametric mapping was used to compare metabolism between on and off conditions using paired t tests, and Pearson linear correlations were used to verify the association of metabolism and estimated amplitude of radiofrequency-modulated electromagnetic waves emitted by the cell phone. Clusters with at least 1000 voxels (volume >8 cm3) and P < .05 (corrected for multiple comparisons) were considered significant. Main Outcome Measure Brain glucose metabolism computed as absolute metabolism (µmol/100 g per minute) and as normalized metabolism (region/whole brain). Results Whole-brain metabolism did not differ between on and off conditions. In contrast, metabolism in the region closest to the antenna (orbitofrontal cortex and temporal pole) was significantly higher for on than off conditions (35.7 vs 33.3 µmol/100 g per minute; mean difference, 2.4 [95% confidence interval, 0.67–4.2]; P = .004). The increases were significantly correlated with the estimated electromagnetic field amplitudes both for absolute metabolism (R = 0.95, P < .001) and normalized metabolism (R = 0.89; P < .001

  2. Dual roles of glucose in the freeze-tolerant earthworm Dendrobaena octaedra: cryoprotection and fuel for metabolism.

    PubMed

    Calderon, Sofia; Holmstrup, Martin; Westh, Peter; Overgaard, Johannes

    2009-03-01

    Ectothermic animals inhabiting the subarctic and temperate regions have evolved strategies to deal with periods of continuous frost during winter. The earthworm Dendrobaena octaedra is freeze tolerant and accumulates large concentrations of glucose upon freezing. The present study investigates the roles of glucose accumulation for long-term freeze tolerance in worms kept frozen at -2 degrees C for 47 days. During this period, worms were sampled periodically for determination of survival and for measurements of glucose, glycogen, lactate, alanine and succinate. In addition we performed calorimetric measurements to assess metabolic rate of frozen and unfrozen worms. Long-term freezing was associated with a gradual depletion of glucose and worms that succumbed during this period were always characterised by low glucose and glycogen levels. The anaerobic waste products lactate and alanine increased slightly whereas succinate levels remained constant. However, it is argued that other waste products (particularly propionate) could be the primary end product of a continued anaerobic metabolism. Calorimetric measures of the metabolic rate of frozen worms were in accord with values calculated from the reduction in glucose assuming that most ( approximately 90%) glucose was metabolised anaerobically. Both estimates of metabolic rate demonstrated a 10-fold metabolic depression associated with freezing. Thus, in addition to the suspected role of glucose as cryoprotectant, the present study demonstrates that glucose accumulation is vital to ensure substrate for long-term anaerobic metabolism in frozen worms. On the basis of the estimated metabolite levels, we calculate that the combined effect of metabolic depression and large glucose stores enables a projected 3 months survival of freezing at -2 degrees C of the ;average' D. octaedra. Such conditions are very likely to occur in the northern distribution ranges of this stress-tolerant earthworm.

  3. Deletion of Cyclophilin D Impairs β-Oxidation and Promotes Glucose Metabolism

    PubMed Central

    Tavecchio, Michele; Lisanti, Sofia; Bennett, Michael J.; Languino, Lucia R.; Altieri, Dario C.

    2015-01-01

    Cyclophilin D (CypD) is a mitochondrial matrix protein implicated in cell death, but a potential role in bioenergetics is not understood. Here, we show that loss or depletion of CypD in cell lines and mice induces defects in mitochondrial bioenergetics due to impaired fatty acid β-oxidation. In turn, CypD loss triggers a global compensatory shift towards glycolysis, with transcriptional upregulation of effectors of glucose metabolism, increased glucose consumption and higher ATP production. In vivo, the glycolytic shift secondary to CypD deletion is associated with expansion of insulin-producing β-cells, mild hyperinsulinemia, improved glucose tolerance, and resistance to high fat diet-induced liver damage and weight gain. Therefore, CypD is a novel regulator of mitochondrial bioenergetics, and unexpectedly controls glucose homeostasis, in vivo. PMID:26515038

  4. GSM mobile phone radiation suppresses brain glucose metabolism

    PubMed Central

    Kwon, Myoung Soo; Vorobyev, Victor; Kännälä, Sami; Laine, Matti; Rinne, Juha O; Toivonen, Tommi; Johansson, Jarkko; Teräs, Mika; Lindholm, Harri; Alanko, Tommi; Hämäläinen, Heikki

    2011-01-01

    We investigated the effects of mobile phone radiation on cerebral glucose metabolism using high-resolution positron emission tomography (PET) with the 18F-deoxyglucose (FDG) tracer. A long half-life (109 minutes) of the 18F isotope allowed a long, natural exposure condition outside the PET scanner. Thirteen young right-handed male subjects were exposed to a pulse-modulated 902.4 MHz Global System for Mobile Communications signal for 33 minutes, while performing a simple visual vigilance task. Temperature was also measured in the head region (forehead, eyes, cheeks, ear canals) during exposure. 18F-deoxyglucose PET images acquired after the exposure showed that relative cerebral metabolic rate of glucose was significantly reduced in the temporoparietal junction and anterior temporal lobe of the right hemisphere ipsilateral to the exposure. Temperature rise was also observed on the exposed side of the head, but the magnitude was very small. The exposure did not affect task performance (reaction time, error rate). Our results show that short-term mobile phone exposure can locally suppress brain energy metabolism in humans. PMID:21915135

  5. The Relationship of Pregnancy, Vaginal Candidiasis and Glucose Metabolism

    PubMed Central

    Robinson, S. C.; Nicholas, W. C.; Lee, D. T.; Wanklin, J. M.; Zwicker, Betty

    1967-01-01

    In 72 pregnant women with culture-proved vaginal candidiasis, and an equal number of controls matched for parity, size, stage of gestation and age, the intravenous glucose tolerance curves were compared using Silverstone's method. The results in both study and control groups did not differ and resembled closely those in Silverstone's series. Half the study group were treated using nystatin alone, while the other half also received tolbutamide. The cure rate was equal in the two groups. Candidiasis in pregnancy does not appear to be related to altered glucose metabolism nor does the addition of this hypoglycemic drug (tolbutamide) improve results. No ill effects, fetal or maternal, were apparent following the use of tolbutamide. PMID:6020207

  6. Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

    PubMed Central

    Sugiura, Yuki; Honda, Kurara; Kondo, Koki; Miura, Masayuki

    2017-01-01

    Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development. PMID:28049690

  7. Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching.

    PubMed

    Miyazawa, Hidenobu; Yamaguchi, Yoshifumi; Sugiura, Yuki; Honda, Kurara; Kondo, Koki; Matsuda, Fumio; Yamamoto, Takehiro; Suematsu, Makoto; Miura, Masayuki

    2017-01-01

    Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development. © 2017. Published by The Company of Biologists Ltd.

  8. Differential expression of genes related to glucose metabolism in domesticated pigs and wild boar.

    PubMed

    He, Dafang; Ma, Jideng; Long, Keren; Wang, Xun; Li, Xuewei; Jiang, Anan; Li, Mingzhou

    2017-08-01

    Glucose metabolism is a basic biological process that shows substantial variation within and between species. Using pig as a model organism, we investigated differences in glucose metabolic genes in seven tissues from domesticated pigs (Rongchang pig and Tibetan pig, meanwhile, the Tibetan pig just as a special case of the domesticated pig under plateau condition) and wild boar. We found large differences in the expression of genes involved in multiple aspects of glucose metabolism, including genes associated with glucose transport, gluconeogenesis, and glycolysis. In addition, we identified microRNAs (miRNAs) that may be involved in the divergence of glucose metabolism in pig. A combined analysis of mRNA and miRNA expression indicated that some miRNA:mRNA pairs showed ab facto function in it. Our results provide a valuable resource for further determination of miRNA regulatory roles in pig glucose metabolism and reveal the divergence of glucose metabolism in pigs under domestication.

  9. Fractional uptake value as a good indicator for glucose metabolism

    SciTech Connect

    Nishizawa, S.; Yonekura, Y.; Mukai, T. |

    1995-05-01

    In a previous paper, we demonstrated that hyperglycemia enhanced brain tumor detection in FDG-PET studies. However, the autoradiographic method underestimated cerebral glucose metabolism (CMRglc) in hyperglycemia, while dynamic PET scans are often not feasible due to patient`s condition. For such situations, we propose the use of the fractional uptake value (FUV) which is given by Ci(t)/{integral}Ca(t)dt where Ci(t) and Ca(t) are radio-activities in brain and plasma. In this study, we tested FUV as an indicator of the net clearance coefficient of FDG (K*) over a side range of plasma glucose levels. Seven patients with brain tumor underwent FDG-PET studies in normoglycemia (mean: 5.2 mM) and hyperglycemia (mean: 14.6 mM) on separate days. Dynamic PET scan was performed for 40 min with arterial sampling after an i.v. injection of 160-370 MBq of FDG. Data analysis was carried out on cortices contralateral of the tumor. The rate constants (K1*,k2*,k3*, and k4*) and cerebral blood volume of a 3 compartment model were estimated by non-linear least squared optimization. K* was defined as K*=K1*,k3*/(k2*+k3*). FUV was calculated using 4-min scan data from 36 to 40 min of the dynamic scan. The FUV demonstrated a good relationship with K value over a wide range of plasma glucose level (K*=2.0 10{sup -3} +1.02 FUV r=0.99), and proved to be a good indicator for cerebral glucose metabolism.

  10. Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer's disease.

    PubMed

    Cisternas, Pedro; Inestrosa, Nibaldo C

    2017-06-15

    The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer's disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer's disease. Copyright © 2017. Published by Elsevier Ltd.

  11. Metabolic syndrome or glucose challenge in first episode of psychosis?

    PubMed

    Garcia-Rizo, C; Fernandez-Egea, E; Oliveira, C; Meseguer, A; Cabrera, B; Mezquida, G; Bioque, M; Penades, R; Parellada, E; Bernardo, M; Kirkpatrick, B

    2017-03-01

    Patients with schizophrenia exhibit a reduced life expectancy. Although unhealthy lifestyle or suicide risk plays a role, the main causes are diverse medical conditions such as cardiovascular diseases, type 2 diabetes mellitus and metabolic syndrome. Albeit pharmacological secondary side effects might also trigger previous conditions, studies in naïve patients reflect diverse anomalies at the onset. Patients with a first episode of psychosis, display a wide scope of metabolic abnormalities, ranging from normality till pathological values depending on the parameters studied. We attempted to evaluate the metabolic syndrome and glycemic homeostasis in a subset of antipsychotic-naïve patients with a first episode of non-affective psychosis. Patients (n=84) showed a similar prevalence of metabolic syndrome compared with a matched control sample (n=98) (6% vs 4%, P=0.562), while glucose homeostasis values differed significantly (14% vs. 5%, P=0.034). Our results suggest that metabolic syndrome is not a useful clinical condition to be evaluated in patients before pharmacological treatment. Abnormal glycemic homeostasis at the onset of the disease requires specific diagnostic tools and preventive measures in order to avoid future cardiovascular events. New strategies must be implemented in order to evaluate the cardiovascular risk and subsequent morbidity in patients at the onset of the disease.

  12. Response of C2C12 myoblasts to hypoxia: the relative roles of glucose and oxygen in adaptive cellular metabolism.

    PubMed

    Li, Wei; Hu, Zhen-Fu; Chen, Bin; Ni, Guo-Xin

    2013-01-01

    Oxygen and glucose are two important nutrients for mammalian cell function. In this study, the effect of glucose and oxygen concentrations on C2C12 cellular metabolism was characterized with an emphasis on detecting whether cells show oxygen conformance (OC) in response to hypoxia. After C2C12 cells being cultured in the levels of glucose at 0.6 mM (LG), 5.6 mM (MG), or 23.3 mM(HG) under normoxic or hypoxic (1% oxygen) condition, cellular oxygen consumption, glucose consumption, lactate production, and metabolic status were determined. Short-term oxygen consumption was measured with a novel oxygen biosensor technique. Longer-term measurements were performed with standard glucose, lactate, and cell metabolism assays. It was found that oxygen depletion in normoxia is dependent on the glucose concentration in the medium. Cellular glucose uptake and lactate production increased significantly in hypoxia than those in normoxia. In hypoxia the cellular response to the level of glucose was different to that in normoxia. The metabolic activities decreased while glucose concentration increased in normoxia, while in hypoxia, metabolic activity was reduced in LG and MG, but unchanged in HG condition. The OC phenomenon was not observed in the present study. Our findings suggested that a combination of low oxygen and low glucose damages the viability of C2C12 cells more seriously than low oxygen alone. In addition, when there is sufficient glucose, C2C12 cells will respond to hypoxia by upregulating anaerobic respiration, as shown by lactate production.

  13. Deoxyglucose method for the estimation of local myocardial glucose metabolism with positron computed tomography

    SciTech Connect

    Ratib, O.; Phelps, M.E.; Huang, S.C.; Henze, E.; Selin, C.E.; Schelbert, H.R.

    1981-01-01

    The deoxyglucose method originally developed for measurements of the local cerebral metabolic rate for glucose has been investigated in terms of its application to studies of the heart with positron computed tomography (PCT) and FDG. Studies were performed in dogs to measure the tissue kinetics of FDG with PCT and by direct arterial-venous sampling. The operational equation developed in our laboratory as an extension of the Sokoloff model was used to analyze the data. The FDG method accurately predicted the true MMRGlc even when the glucose metabolic rate was normal but myocardial blood flow (MBF) was elevated 5 times the control value or when metabolism was reduced to 10% of normal and MBF increased 5 times normal. Improvements in PCT resolution are required to improve the accuracy of the estimates of the rate constants and the MMRGlc.

  14. Insulin signalling and the regulation of glucose and lipid metabolism.

    PubMed

    Saltiel, A R; Kahn, C R

    2001-12-13

    The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

  15. Insulin signalling and the regulation of glucose and lipid metabolism

    NASA Astrophysics Data System (ADS)

    Saltiel, Alan R.; Kahn, C. Ronald

    2001-12-01

    The epidemic of type 2 diabetes and impaired glucose tolerance is one of the main causes of morbidity and mortality worldwide. In both disorders, tissues such as muscle, fat and liver become less responsive or resistant to insulin. This state is also linked to other common health problems, such as obesity, polycystic ovarian disease, hyperlipidaemia, hypertension and atherosclerosis. The pathophysiology of insulin resistance involves a complex network of signalling pathways, activated by the insulin receptor, which regulates intermediary metabolism and its organization in cells. But recent studies have shown that numerous other hormones and signalling events attenuate insulin action, and are important in type 2 diabetes.

  16. Postprandial gut hormone responses and glucose metabolism in cholecystectomized patients.

    PubMed

    Sonne, David P; Hare, Kristine J; Martens, Pernille; Rehfeld, Jens F; Holst, Jens J; Vilsbøll, Tina; Knop, Filip K

    2013-02-15

    Preclinical studies suggest that gallbladder emptying, via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells, may play a significant role in the secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and, hence, postprandial glucose homeostasis. We examined the secretion of gut hormones in cholecystectomized subjects to test the hypothesis that gallbladder emptying potentiates postprandial release of GLP-1. Ten cholecystectomized subjects and 10 healthy, age-, gender-, and body mass index-matched control subjects received a standardized fat-rich liquid meal (2,200 kJ). Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), cholecystokinin (CCK), and gastrin were measured. Furthermore, gastric emptying and duodenal and serum bile acids were measured. We found similar basal glucose concentrations in the two groups, whereas cholecystectomized subjects had elevated postprandial glucose excursions. Cholecystectomized subjects had reduced postprandial concentrations of duodenal bile acids, but preserved postprandial plasma GLP-1 responses, compared with control subjects. Also, cholecystectomized patients exhibited augmented fasting glucagon. Basal plasma CCK concentrations were lower and peak concentrations were higher in cholecystectomized patients. The concentrations of GIP, GLP-2, and gastrin were similar in the two groups. In conclusion, cholecystectomized subjects had preserved postprandial GLP-1 responses in spite of decreased duodenal bile delivery, suggesting that gallbladder emptying is not a prerequisite for GLP-1 release. Cholecystectomized patients demonstrated a slight deterioration of postprandial glycemic control, probably because of metabolic changes unrelated to incretin secretion.

  17. Analysis of kinetic, stoichiometry and regulation of glucose and glutamine metabolism in hybridoma batch cultures using logistic equations

    PubMed Central

    Acosta, María Lourdes; Sánchez, Asterio; García, Francisco; Molina, Emilio

    2007-01-01

    Batch cultures were carried out to study the kinetic, stoichiometry, and regulation of glucose and glutamine metabolism of a murine hybridoma line. Asymmetric logistic equations (ALEs) were used to fit total and viable cell density, and nutrient and metabolite/product concentrations. Since these equations were analytically differentiable, specific rates and yield coefficients were readily calculated. Asymmetric logistic equations described satisfactorily uncontrolled batch cultures, including death phase. Specific growth rate showed a Monod-type dependence on initial glucose and glutamine concentrations. Yield coefficients of cell and lactate from glucose, and cell and ammonium from glutamine were all found to change dramatically at low residual glucose and glutamine concentrations. Under stoichiometric glucose limitation, the glucose-to-cell yield increased and glucose-to-lactate yield decreased, indicating a metabolic shift. Under stoichiometric glutamine limitation the glutamine-to-cell and glutamine-to-ammonium yields increased, but also glucose-to-cell yield increased and the glucose-to-lactate yield decreased. Monoclonal antibody production was mainly non-growth associated, independently of glucose and glutamine levels. PMID:19003011

  18. A mechanistic study to increase understanding of titanium dioxide nanoparticles-increased plasma glucose in mice.

    PubMed

    Hu, Hailong; Li, Li; Guo, Qian; Jin, Sanli; Zhou, Ying; Oh, Yuri; Feng, Yujie; Wu, Qiong; Gu, Ning

    2016-09-01

    Titanium dioxide nanoparticle (TiO2 NP) is an authorized food additive. Previous studies determined oral administration of TiO2 NPs increases plasma glucose in mice via inducing insulin resistance. An increase in reactive oxygen species (ROS) has been considered the possible mechanism of increasing plasma glucose. However, persistently high plasma glucose is also a mechanism of increasing ROS. This study aims to explore whether TiO2 NPs increase plasma glucose via ROS. We found after oral administration of TiO2 NPs, an increase in ROS preceded an increase in plasma glucose. Subsequently, mice were treated with two antioxidants (resveratrol and vitamin E) at the same time as oral administration of TiO2 NPs. Results showed resveratrol and vitamin E reduced TiO2 NPs-increased ROS. An increase in plasma glucose was also inhibited. Further research showed resveratrol and vitamin E inhibited the secretion of TNF-α and IL-6, and the phosphorylation of JNK and p38 MAPK, resulting in improved insulin resistance. These results suggest TiO2 NPs increased ROS levels, and then ROS activated inflammatory cytokines and phosphokinases, and thus induced insulin resistance, resulting in an increase in plasma glucose. Resveratrol and vitamin E can reduce TiO2 NPs-increased ROS and thereby inhibit an increase in plasma glucose in mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. The influence of high glucose on the aerobic metabolism of endothelial EA.hy926 cells.

    PubMed

    Koziel, Agnieszka; Woyda-Ploszczyca, Andrzej; Kicinska, Anna; Jarmuszkiewicz, Wieslawa

    2012-12-01

    The endothelium is considered to be relatively independent of the mitochondrial energy supply. The goals of this study were to examine mitochondrial respiratory functions in endothelial cells and isolated mitochondria and to assess the influence of chronic high glucose exposure on the aerobic metabolism of these cells. A procedure to isolate of bioenergetically active endothelial mitochondria was elaborated. Human umbilical vein endothelial cells (EA.hy926 line) were grown in medium containing either 5.5 or 25 mM glucose. The respiratory response to elevated glucose was observed in cells grown in 25 mM glucose for at least 6 days or longer. In EA.hy926 cells, growth in high glucose induced considerably lower mitochondrial respiration with glycolytic fuels, less pronounced with glutamine, and higher respiration with palmitate. The Crabtree effect was observed in both types of cells. High glucose conditions produced elevated levels of cellular Q10, increased ROS generation, increased hexokinase I, lactate dehydrogenase, acyl-CoA dehydrogenase, uncoupling protein 2 (UCP2), and superoxide dismutase 2 expression, and decreased E3-binding protein of pyruvate dehydrogenase expression. In isolated mitochondria, hyperglycaemia induced an increase in the oxidation of palmitoylcarnitine and glycerol-3-phosphate (lipid-derived fuels) and a decrease in the oxidation of pyruvate (a mitochondrial fuel); in addition, increased UCP2 activity was observed. Our results demonstrate that primarily glycolytic endothelial cells possess highly active mitochondria with a functioning energy-dissipating pathway (UCP2). High-glucose exposure induces a shift of the endothelial aerobic metabolism towards the oxidation of lipids and amino acids.

  20. Short-term glucose metabolism and gut hormone modulations after Billroth II gastrojejunostomy in nonobese gastric cancer patients with type 2 diabetes mellitus, impaired glucose tolerance and normal glucose tolerance.

    PubMed

    Zhang, Xiao-juan; Xiao, Zhu; Yu, Hong-ling; Zhang, Xiang-xun; Cheng, Zhong; Tian, Hao-ming

    2013-08-01

    Roux-en-Y gastric bypass (RYGB) is effective in controlling blood glucose in obese patients with type 2 diabetes (T2DM). The alterations of gut hormones involving in glucose metabolism may play an important role. Our aim was to explore the short-term effects of Billroth II gastrojejunostomy (a similar type of RYGB) on glucose metabolism and gut hormone modulations in nonobese patients with different levels of blood glucose tolerance. Twenty one nonobese gastric cancer patients with different levels of blood glucose tolerance were submitted to Billroth II gastrojejunostomy. Among them, seven had T2DM, seven with impaired glucose tolerance (IGT) and the other seven had normal glucose tolerance (NGT). Body weight, glucose parameters, responses of plasma glucagon-like peptide-1 (GLP-1), peptide YY (PYY) and gastric inhibitory polypeptide (GIP) to 75 g glucose were measured at baseline and 3 months after surgery. Similar weight losses were observed in all groups. Blood glucose was reduced in T2DM and IGT patients. Fasting and 30-min plasma glucose were increased significantly in NGT. GLP-1 showed insignificant alterations in all groups. PYY was evaluated in T2DM and IGT but remained unchanged in the NGT group. Decreased fasting and AUC GIP were observed in patients with T2DM; however, fasting and 30-min GIP were increased in NGT patients. Billroth II gastrojejunostomy is effective in reducing blood glucose in nonobese patients with T2DM and IGT but could deteriorate early blood glucose in nonobese NGT in a 3-month time period. Variations of glucose and gut hormone changes in the three groups suggest a role of proximal intestine in the pathophysiology of T2DM. Copyright © 2013 IMSS. Published by Elsevier Inc. All rights reserved.

  1. Metabolic phenotyping guidelines: assessing glucose homeostasis in rodent models.

    PubMed

    Bowe, James E; Franklin, Zara J; Hauge-Evans, Astrid C; King, Aileen J; Persaud, Shanta J; Jones, Peter M

    2014-09-01

    The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasis in vivo has become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designing in vivo experiments for the measurement of glucose homeostasis are also discussed.

  2. Experimental type II diabetes and related models of impaired glucose metabolism differentially regulate glucose transporters at the proximal tubule brush border membrane.

    PubMed

    Chichger, Havovi; Cleasby, Mark E; Srai, Surjit K; Unwin, Robert J; Debnam, Edward S; Marks, Joanne

    2016-06-01

    What is the central question of this study? Although SGLT2 inhibitors represent a promising treatment for patients suffering from diabetic nephropathy, the influence of metabolic disruption on the expression and function of glucose transporters is largely unknown. What is the main finding and its importance? In vivo models of metabolic disruption (Goto-Kakizaki type II diabetic rat and junk-food diet) demonstrate increased expression of SGLT1, SGLT2 and GLUT2 in the proximal tubule brush border. In the type II diabetic model, this is accompanied by increased SGLT- and GLUT-mediated glucose uptake. A fasted model of metabolic disruption (high-fat diet) demonstrated increased GLUT2 expression only. The differential alterations of glucose transporters in response to varying metabolic stress offer insight into the therapeutic value of inhibitors. SGLT2 inhibitors are now in clinical use to reduce hyperglycaemia in type II diabetes. However, renal glucose reabsorption across the brush border membrane (BBM) is not completely understood in diabetes. Increased consumption of a Western diet is strongly linked to type II diabetes. This study aimed to investigate the adaptations that occur in renal glucose transporters in response to experimental models of diet-induced insulin resistance. The study used Goto-Kakizaki type II diabetic rats and normal rats rendered insulin resistant using junk-food or high-fat diets. Levels of protein kinase C-βI (PKC-βI), GLUT2, SGLT1 and SGLT2 were determined by Western blotting of purified renal BBM. GLUT- and SGLT-mediated d-[(3) H]glucose uptake by BBM vesicles was measured in the presence and absence of the SGLT inhibitor phlorizin. GLUT- and SGLT-mediated glucose transport was elevated in type II diabetic rats, accompanied by increased expression of GLUT2, its upstream regulator PKC-βI and SGLT1 protein. Junk-food and high-fat diet feeding also caused higher membrane expression of GLUT2 and its upstream regulator PKC

  3. Regulation of Lipid and Glucose Metabolism by Phosphatidylcholine Transfer Protein

    PubMed Central

    Kang, Hye Won; Wei, Jie; Cohen, David E.

    2010-01-01

    Phosphatidylcholine transfer protein (PC-TP, a.k.a. StARD2) binds phosphatidylcholines and catalyzes their intermembrane transfer and exchange in vitro. The structure of PC-TP comprises a hydrophobic pocket and a well-defined head-group binding site, and its gene expression is regulated by peroxisome proliferator activated receptor α. Recent studies have revealed key regulatory roles for PC-TP in lipid and glucose metabolism. Notably, Pctp−/− mice are sensitized to insulin action and exhibit more efficient brown fat-mediated thermogenesis. PC-TP appears to limit access of fatty acids to mitochondria by stimulating the activity of thioesterase superfamily member 2, a newly characterized long-chain fatty acyl-CoA thioesterase. Because PC-TP discriminates among phosphatidylcholines within lipid bilayers, it may function as a sensor that links metabolic regulation to membrane composition. PMID:20338778

  4. Resistin: regulation of food intake, glucose homeostasis and lipid metabolism.

    PubMed

    Nogueiras, Ruben; Novelle, Marta G; Vazquez, María Jesús; Lopez, Miguel; Dieguez, Carlos

    2010-01-01

    Resistin has been identified as a hormone secreted by adipocytes that is under hormonal and nutritional control. This hormone has been suggested to be the link between obesity and type 2 diabetes. In rodents, resistin is mainly located and secreted from adipocytes, even though its expression was also found in several other tissues. However, in humans resistin is expressed primarily by macrophages and seems to be involved in the recruitment of other immune cells and the secretion of pro-inflammatory factors, although its role in insulin resistance cannot be ruled out. In addition to its role in glucose metabolism, resistin has been also involved in the control of hypothalamic and peripheral lipid metabolism and in the regulation of food intake. In this short review, we will summarize the most relevant findings of this hormone in rodents. Copyright 2010 S. Karger AG, Basel.

  5. Energetic limits to metabolic flexibility: responses of Saccharomyces cerevisiae to glucose-galactose transitions.

    PubMed

    van den Brink, J; Akeroyd, M; van der Hoeven, R; Pronk, J T; de Winde, J H; Daran-Lapujade, P

    2009-04-01

    Glucose is the favoured carbon source for Saccharomyces cerevisiae, and the Leloir pathway for galactose utilization is only induced in the presence of galactose during glucose-derepressed conditions. The goal of this study was to investigate the dynamics of glucose-galactose transitions. To this end, well-controlled, glucose-limited chemostat cultures were switched to galactose-excess conditions. Surprisingly, galactose was not consumed upon a switch to galactose excess under anaerobic conditions. However, the transcripts of the Leloir pathway were highly increased upon galactose excess under both aerobic and anaerobic conditions. Protein and enzyme-activity assays showed that impaired galactose consumption under anaerobiosis coincided with the absence of the Leloir-pathway proteins. Further results showed that absence of protein synthesis was not caused by glucose-mediated translation inhibition. Analysis of adenosine nucleotide pools revealed a fast decrease of the energy charge after the switch from glucose to galactose under anaerobic conditions. Similar results were obtained when glucose-galactose transitions were analysed under aerobic conditions with a respiratory-deficient strain. It is concluded that under fermentative conditions, the energy charge was too low to allow synthesis of the Leloir proteins. Hence, this study conclusively shows that the intracellular energy status is an important factor in the metabolic flexibility of S. cerevisiae upon changes in its environment.

  6. Effects of insulin infusion on glucose homeostasis and glucose metabolism in rainbow trout fed a high-carbohydrate diet.

    PubMed

    Polakof, S; Moon, T W; Aguirre, P; Skiba-Cassy, S; Panserat, S

    2010-12-15

    The origin for the poor glucose utilization in carnivorous fish species fed high carbohydrate diets remains under debate. In the present study, we have fed rainbow trout a diet containing 30% carbohydrate for 1 or 5 days. In both cases, fish were implanted with mini-osmotic pumps releasing 0.7 i.u. kg(-1) day(-1) bovine insulin, and mRNA transcripts and the protein phosphorylation status of proteins controlling glycemia and glucose-related metabolism were studied in fish killed 6 h after the last meal. We demonstrate that when the exposure occurs over a short term (30 h), insulin exerts beneficial actions on trout glucose homeostasis, including a lowered glycemia and increased hepatic lipogenic and glycogenic potentials. However, when trout were fed for 5 days, these beneficial actions of insulin infusion were no longer observed. Thus, the increased lipogenic potential observed after one single meal was not present, and this together with the increased glycogenesis and the decreased glucose exported to the blood from the liver explains the lack of hypoglycemic action of insulin. The fact that insulin improved glucose homeostasis when administrated over a short time period implies that endogenous insulin secretion is inadequate in trout to deal with this amount of dietary carbohydrates. Moreover, the fact that a longer exposure to insulin resulted in a reduced response indicates that the rainbow trout is sensitive to insulin, re-enforcing the hypothesis that the hyperglycemia observed following a high carbohydrate meal is an insulin secretion issue rather an insulin action issue.

  7. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition.

    PubMed

    Rajeev, S P; Cuthbertson, D J; Wilding, J P H

    2016-02-01

    Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines. © 2015 John Wiley & Sons Ltd.

  8. Effect of modified atmosphere composition on the metabolism of glucose by Brochothrix thermosphacta.

    PubMed

    Pin, Carmen; García de Fernando, Gonzalo D; Ordóñez, Juan A

    2002-09-01

    The influence of atmosphere composition on the metabolism of Brochothrix thermosphacta was studied by analyzing the consumption of glucose and the production of ethanol, acetic and lactic acids, acetaldehyde, and diacetyl-acetoin under atmospheres containing different combinations of carbon dioxide and oxygen. When glucose was metabolized under oxygen-free atmospheres, lactic acid was one of the main end products, while under atmospheres rich in oxygen mainly acetoin-diacetyl was produced. The proportions of the total consumed glucose used for the production of acetoin (aerobic metabolism) and lactic acid (anaerobic metabolism) were used to decide whether aerobic or anaerobic metabolism predominated at a given atmosphere composition. The boundary conditions between dominantly anaerobic and aerobic metabolisms were determined by logistic regression. The metabolism of glucose by B. thermosphacta was influenced not only by the oxygen content of the atmosphere but also by the carbon dioxide content. At high CO(2) percentages, glucose metabolism remained anaerobic under greater oxygen contents.

  9. Effect of Modified Atmosphere Composition on the Metabolism of Glucose by Brochothrix thermosphacta

    PubMed Central

    Pin, Carmen; García de Fernando, Gonzalo D.; Ordóñez, Juan A.

    2002-01-01

    The influence of atmosphere composition on the metabolism of Brochothrix thermosphacta was studied by analyzing the consumption of glucose and the production of ethanol, acetic and lactic acids, acetaldehyde, and diacetyl-acetoin under atmospheres containing different combinations of carbon dioxide and oxygen. When glucose was metabolized under oxygen-free atmospheres, lactic acid was one of the main end products, while under atmospheres rich in oxygen mainly acetoin-diacetyl was produced. The proportions of the total consumed glucose used for the production of acetoin (aerobic metabolism) and lactic acid (anaerobic metabolism) were used to decide whether aerobic or anaerobic metabolism predominated at a given atmosphere composition. The boundary conditions between dominantly anaerobic and aerobic metabolisms were determined by logistic regression. The metabolism of glucose by B. thermosphacta was influenced not only by the oxygen content of the atmosphere but also by the carbon dioxide content. At high CO2 percentages, glucose metabolism remained anaerobic under greater oxygen contents. PMID:12200298

  10. Molybdate and tungstate act like vanadate on glucose metabolism in isolated hepatocytes.

    PubMed Central

    Fillat, C; Rodríguez-Gil, J E; Guinovart, J J

    1992-01-01

    In rat hepatocytes, molybdate and tungstate inactivate glycogen synthase by a mechanism independent of Ca2+ and activate glycogen phosphorylase by a Ca(2+)-dependent mechanism. On the other hand, both molybdate and tungstate increase fructose 2,6-bisphosphate levels and counteract the decrease in this metabolite induced by glucagon. These effectors do not directly modify 6-phosphofructo-2-kinase activity, even though they partially counteract the inactivation of this enzyme induced by glucagon. These effects are related to an increase on the glycolytic flux, as indicated by the increase in L-lactate and CO2 production and the decrease in glucose 6-phosphate levels in the presence of glucose. All these effects are similar to those previously reported for vanadate, although molybdate and tungstate are less effective than vanadate. These results could indicate that molybdate, tungstate and vanadate act on glucose metabolism in isolated hepatocytes by a similar mechanism of action. PMID:1313228

  11. CC3/TIP30 regulates metabolic adaptation of tumor cells to glucose limitation

    PubMed Central

    Chen, Vivian

    2010-01-01

    CC3/TIP30 is a metastasis and tumor suppressor, with reduced or absent expression in a variety of aggressive tumors. Overexpression of CC3 in tumor cells predisposes them to apoptosis in response to different death signals. We found that silencing of CC3 expression does not increase apoptotic resistance of cells. However, it strongly improves survival of tumor cells in response to glucose limitation. HeLa cells with silenced CC3 survive long-term in low glucose, and in comparison to control HeLa cells, show superior metabolic adaptation to glucose limitation. First, unlike the parental HeLa cells, HeLa with silenced CC3 activate and maintain high levels of mitochondrial respiration that is critical for their ability to thrive in low glucose. Second, silencing of CC3 leads to higher expression levels of mitochondrial proteins in respiration complexes when cells are continuously cultured in limiting glucose. Third, HeLa cells with silenced CC3 maintain higher levels of c-MYC and the M2 isoform of pyruvate kinase in low glucose, contributing to more efficient glycolysis. Fourth, HeLa cells with silenced CC3 fail to fully activate AMPK in response to glucose limitation. Inhibition of AMPK, either pharmacologic or via siRNA, protects control HeLa cells from death in low glucose. The metabolic flexibility acquired by cells after silencing of CC3 could be directly relevant to the development of metastatic and aggressive human tumors that frequently have low or absent expression of CC3. PMID:21150275

  12. Effect of pyruvate kinase overproduction on glucose metabolism of Lactococcus lactis.

    PubMed

    Ramos, Ana; Neves, Ana Rute; Ventura, Rita; Maycock, Christopher; López, Paloma; Santos, Helena

    2004-04-01

    Lactococcus lactis strain NZ9000(pNZpyk), which overproduces pyruvate kinase (PK), was constructed. The pNZpyk plasmid carries the P(nisA)-pyk transcriptional fusion, and the overexpression of its pyk gene was accomplished by using the nisin-inducible expression system of the NZ9000 strain. In vivo (13)C- and (31)P-NMR spectroscopy was used to evaluate the effect of this modification on the metabolism of glucose in non-growing cells. A detailed description of the kinetics of glucose, end products, glycolytic intermediates, NAD(+) and NADH was obtained. A 15-fold increase in the level of PK did not increase the overall glycolytic flux, which, on the contrary, was slightly reduced. Significant differences were observed in (i) the level of 3-phosphoglycerate (3-PGA) and phosphoenolpyruvate (PEP), metabolites associated with starvation; (ii) the rate of fructose 1,6-bisphosphate (FBP) depletion upon glucose exhaustion; and (iii) the NAD(+)/NADH ratio during glucose catabolism. In the mutant, the rate of FBP consumption after glucose depletion was notably accelerated under anaerobic conditions, whereas 3-PGA and PEP decreased to undetectable levels. Furthermore, the level of NAD(+) decreased steadily during the utilization of glucose, probably due to the unanticipated reduction in the lactate dehydrogenase activity in comparison with the control strain, NZ9000(pNZ8020). The results show that PK is an important bottleneck to carbon flux only when glucose becomes limiting; in the overproducer this constriction was no longer present, as evidenced by the faster FBP consumption and lack of accumulation of 3-PGA and PEP in anaerobic as well as aerobic conditions. Despite these clear changes, the PK-overproducing strain showed typical homolactic metabolism under anaerobic conditions, as did the strain harbouring the vector plasmid without the pyk insert. However, under an oxygen atmosphere, there was increased channelling of carbon to the production of acetate and acetoin, to

  13. Glycogen storage disease type Ia (GSDIa) but not Glycogen storage disease type Ib (GSDIb) is associated to an increased risk of metabolic syndrome: possible role of microsomal glucose 6-phosphate accumulation.

    PubMed

    Melis, Daniela; Rossi, Alessandro; Pivonello, Rosario; Salerno, Mariacarolina; Balivo, Francesca; Spadarella, Simona; Muscogiuri, Giovanna; Casa, Roberto Della; Formisano, Pietro; Andria, Generoso; Colao, Annamaria; Parenti, Giancarlo

    2015-07-29

    In GSDIa, glucose 6-phosphate (G6P) accumulates in the endoplasmic reticulum (ER); in GSDIb, G6P levels are reduced in ER. G6P availability directly modulates the activity of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), an ER-bound enzyme playing a key role in the development of the metabolic syndrome (MS). To evaluate the prevalence of MS and Insulin Resistance (IR) in GSDIa and GSDIb patients. This was a prospective study. All the enrolled patients were followed at the Department of Pediatrics "Federico II" University of Naples for 10 years. Clinical and biochemical parameters of MS and the presence of IR were recorded. The results were correlated with the biochemical parameters of GSDI-related metabolic control. 10 GSDIa patient (median age 12.10 ± 1.50), 7 GSDIb patients (median age 14.90 ± 2.20 were enrolled in the study. They were compared to 20 and 14 age and sex matched controls, respectively. 10 GSDIa patients (median age 24.60 ± 1.50) and 6 GSDIb patients (median age 25.10 ± 2.00) completed the 10-year-follow-up. At the end of the study the patients' data were compared to 10 and 6 age and sex matched controls, respectively. At study entry, 20 % GSDIa patients had MS and 80 % showed 2 criteria for MS. GSDIa patients showed higher HOMA-IR than controls and GSDIb patients (p < 0.001, p < 0.05), respectively. Baseline ISI was lower in GSDIa than controls (p < 0.001). QUICKI was significantly lower in GSDIa than in controls (p < 0.001). At the end of the study 70 % of GSDIa patients had MS and 30 % showed 2 criteria for MS. HOMA-IR was higher in GSDIa than controls (p < 0.01). Baseline ISI was higher in GSDIb than controls (p < 0.005) and GSD1a (p < 0.05). QUICKI was lower in GSD1a patients than in controls (p < 0.03). VAI was higher in GSDIa patients than controls (p < 0.001) and GSDIb patients (p = 0.002). Our data showed high prevalence of IR and MS in GSDIa patients. We speculate a

  14. Obesity and associated lifestyles modify the effect of glucose metabolism-related genetic variants on impaired glucose homeostasis among postmenopausal women.

    PubMed

    Jung, Su Yon; Sobel, Eric M; Papp, Jeanette C; Crandall, Carolyn J; Fu, Alan N; Zhang, Zuo-Feng

    2016-09-01

    Impaired glucose metabolism-related genetic variants likely interact with obesity-modifiable factors in response to glucose intolerance, yet their interconnected pathways have not been fully characterized. With data from 1,027 postmenopausal participants of the Genomics and Randomized Trials Network study and 15 single-nucleotide polymorphisms (SNPs) associated with glucose homeostasis, we assessed whether obesity, physical activity, and high dietary fat intake interact with the SNP-glucose variations. We used regression analysis plus stratification and graphic approaches. Across carriers of the 15 SNPs, fasting levels of glucose, insulin, and homeostatic model assessment-insulin resistance (HOMA-IR) were higher in obese, inactive, and high fat-diet women than in their respective counterparts. Carriers within subgroups differently demonstrated the direction and/or magnitude of the variants' effect on glucose-relevant traits. Variants in GCKR, GCK, DGKB/TMEM195 (P for interactions = 0.02, 0.02, and 0.01), especially, showed interactions with obesity: obese, inactive, and high fat-diet women had greater increases in fasting glucose, insulin, and HOMA-IR levels. Obese carriers at TCF7L2 variant had greater increases in fasting glucose levels than nonobese carriers (P for interaction = 0.04), whereas active women had greater decreases in insulin and HOMA-IR levels than inactive women (P for interaction = 0.02 in both levels). Our data support the important role of obesity in modifying glucose homeostasis in response to glucose metabolism-relevant variants. These findings may inform research on the role of glucose homeostasis in the etiology of chronic disease and the development of intervention strategies to reduce risk in postmenopausal women. © 2016 WILEY PERIODICALS, INC.

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

    PubMed

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

    2015-04-01

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

  16. [Study of regional cerebral glucose metabolism, in man, while awake or asleep, by positron emission tomography].

    PubMed

    Franck, G; Salmon, E; Poirrier, R; Sadzot, B; Franco, G

    1987-03-01

    Measurements of regional cerebral glucose uptake by the 18F-fluorodeoxyglucose technique (18FDG) and positron emission tomography (PET) along with polygraph recordings were made serially during relaxed wakefulness and different stages of nocturnal sleep in two right-handed normal volunteers. During stage III-IV sleep, values declined diffusely in both hemispheric regions (-31%), thalamus (-33%), cerebellum (-33%) and brain stem (-25%). During paradoxical sleep regional values increased diffusely compared with slow wave sleep. Compared to wakefulness, regional metabolic values seemed to increase but the results were more variable from one volunteer to the other. These preliminary data indicate important regional alterations in cerebral metabolism between sleep states.

  17. The low affinity glucose transporter HxtB is also involved in glucose signalling and metabolism in Aspergillus nidulans

    PubMed Central

    dos Reis, Thaila Fernanda; Nitsche, Benjamin M.; de Lima, Pollyne Borborema Almeida; de Assis, Leandro José; Mellado, Laura; Harris, Steven D.; Meyer, Vera; dos Santos, Renato A. Corrêa; Riaño-Pachón, Diego M.; Ries, Laure Nicolas Annick; Goldman, Gustavo H.

    2017-01-01

    One of the drawbacks during second-generation biofuel production from plant lignocellulosic biomass is the accumulation of glucose, the preferred carbon source of microorganisms, which causes the repression of hydrolytic enzyme secretion by industrially relevant filamentous fungi. Glucose sensing, subsequent transport and cellular signalling pathways have been barely elucidated in these organisms. This study therefore characterized the transcriptional response of the filamentous fungus Aspergillus nidulans to the presence of high and low glucose concentrations under continuous chemostat cultivation with the aim to identify novel factors involved in glucose sensing and signalling. Several transcription factor- and transporter-encoding genes were identified as being differentially regulated, including the previously characterized glucose and xylose transporter HxtB. HxtB was confirmed to be a low affinity glucose transporter, localizing to the plasma membrane under low- and high-glucose conditions. Furthermore, HxtB was shown to be involved in conidiation-related processes and may play a role in downstream glucose signalling. A gene predicted to encode the protein kinase PskA was also identified as being important for glucose metabolism. This study identified several proteins with predicted roles in glucose metabolic processes and provides a foundation for further investigation into the response of biotechnologically important filamentous fungi to glucose. PMID:28361917

  18. The low affinity glucose transporter HxtB is also involved in glucose signalling and metabolism in Aspergillus nidulans.

    PubMed

    Dos Reis, Thaila Fernanda; Nitsche, Benjamin M; de Lima, Pollyne Borborema Almeida; de Assis, Leandro José; Mellado, Laura; Harris, Steven D; Meyer, Vera; Dos Santos, Renato A Corrêa; Riaño-Pachón, Diego M; Ries, Laure Nicolas Annick; Goldman, Gustavo H

    2017-03-31

    One of the drawbacks during second-generation biofuel production from plant lignocellulosic biomass is the accumulation of glucose, the preferred carbon source of microorganisms, which causes the repression of hydrolytic enzyme secretion by industrially relevant filamentous fungi. Glucose sensing, subsequent transport and cellular signalling pathways have been barely elucidated in these organisms. This study therefore characterized the transcriptional response of the filamentous fungus Aspergillus nidulans to the presence of high and low glucose concentrations under continuous chemostat cultivation with the aim to identify novel factors involved in glucose sensing and signalling. Several transcription factor- and transporter-encoding genes were identified as being differentially regulated, including the previously characterized glucose and xylose transporter HxtB. HxtB was confirmed to be a low affinity glucose transporter, localizing to the plasma membrane under low- and high-glucose conditions. Furthermore, HxtB was shown to be involved in conidiation-related processes and may play a role in downstream glucose signalling. A gene predicted to encode the protein kinase PskA was also identified as being important for glucose metabolism. This study identified several proteins with predicted roles in glucose metabolic processes and provides a foundation for further investigation into the response of biotechnologically important filamentous fungi to glucose.

  19. Effects of D-allulose on glucose metabolism after the administration of sugar or food in healthy dogs

    PubMed Central

    NISHII, Naohito; NOMIZO, Toru; TAKASHIMA, Satoshi; MATSUBARA, Tatsuya; TOKUDA, Masaaki; KITAGAWA, Hitoshi

    2016-01-01

    D-allulose is a C-3 epimer of D-fructose and has recently been investigated for its hypoglycemic effects. In the present study, the effects of D-allulose on glucose metabolism were evaluated in healthy dogs administrated sugar or food. The oral administrations of D-allulose decreased plasma glucose concentrations after oral glucose or maltose administration, with a diminished plasma insulin rise. The glucose suppressive effect of D-allulose was also observed after intravenous glucose administrations without increase in plasma insulin concentration. In contrast, D-allulose showed no effect on plasma glucose and insulin concentrations after feeding. The present results suggest that D-allulose administration may be beneficial in dogs with impaired glucose tolerance. Further studies investigating the therapeutic efficacy of D-allulose in diabetic dogs are required. PMID:27452736

  20. Effects of D-allulose on glucose metabolism after the administration of sugar or food in healthy dogs.

    PubMed

    Nishii, Naohito; Nomizo, Toru; Takashima, Satoshi; Matsubara, Tatsuya; Tokuda, Masaaki; Kitagawa, Hitoshi

    2016-12-01

    D-allulose is a C-3 epimer of D-fructose and has recently been investigated for its hypoglycemic effects. In the present study, the effects of D-allulose on glucose metabolism were evaluated in healthy dogs administrated sugar or food. The oral administrations of D-allulose decreased plasma glucose concentrations after oral glucose or maltose administration, with a diminished plasma insulin rise. The glucose suppressive effect of D-allulose was also observed after intravenous glucose administrations without increase in plasma insulin concentration. In contrast, D-allulose showed no effect on plasma glucose and insulin concentrations after feeding. The present results suggest that D-allulose administration may be beneficial in dogs with impaired glucose tolerance. Further studies investigating the therapeutic efficacy of D-allulose in diabetic dogs are required.

  1. Apelin targets gut contraction to control glucose metabolism via the brain

    PubMed Central

    Fournel, Audren; Drougard, Anne; Duparc, Thibaut; Marlin, Alysson; Brierley, Stuart M; Castro, Joel; Le-Gonidec, Sophie; Masri, Bernard; Colom, André; Lucas, Alexandre; Rousset, Perrine; Cenac, Nicolas; Vergnolle, Nathalie; Valet, Philippe; Cani, Patrice D; Knauf, Claude

    2017-01-01

    Objective The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. Design We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. Results In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Conclusions Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders. PMID:26565000

  2. Apelin targets gut contraction to control glucose metabolism via the brain.

    PubMed

    Fournel, Audren; Drougard, Anne; Duparc, Thibaut; Marlin, Alysson; Brierley, Stuart M; Castro, Joel; Le-Gonidec, Sophie; Masri, Bernard; Colom, André; Lucas, Alexandre; Rousset, Perrine; Cenac, Nicolas; Vergnolle, Nathalie; Valet, Philippe; Cani, Patrice D; Knauf, Claude

    2017-02-01

    The gut-brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus. We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose. In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle. Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  3. Influence of oxygen therapy on glucose-lactate metabolism after diffuse brain injury.

    PubMed

    Reinert, Michael; Schaller, Benoit; Widmer, Hans Rudolf; Seiler, Rolf; Bullock, Ross

    2004-08-01

    Severe traumatic brain injury (TBI) imposes a huge metabolic load on brain tissue, which can be summarized initially as a state of hypermetabolism and hyperglycolysis. In experiments O2 consumption has been shown to increase early after trauma, especially in the presence of high lactate levels and forced O2 availability. In recent clinical studies the effect of increasing O2 availability on brain metabolism has been analyzed. By their nature, however, clinical trauma models suffer from a heterogeneous injury distribution. The aim of this study was to analyze, in a standardized diffuse brain injury model, the effect of increasing the fraction of inspired O2 on brain glucose and lactate levels, and to compare this effect with the metabolism of the noninjured sham-operated brain. A diffuse severe TBI model developed by Foda and Maramarou, et al., in which a 420-g weight is dropped from a height of 2 m was used in this study. Forty-one male Wistar rats each weighing approximately 300 g were included. Anesthesized rats were monitored by placing a femoral arterial line for blood pressure and blood was drawn for a blood gas analysis. Two time periods were defined: Period A was defined as preinjury and Period B as postinjury. During Period B two levels of fraction of inspired oxygen (FiO2) were studied: air (FiO2 0.21) and oxygen (FiO2 1). Four groups were studied including sham-operated animals: air-air-sham (AAS); air-O2-sham (AOS); air-air-trauma (AAT); and air-O2-trauma (AOT). In six rats the effect of increasing the FiO2 on serum glucose and lactate was analyzed. During Period B lactate values in the brain determined using microdialysis were significantly lower (p < 0.05) in the AOT group than in the AAT group and glucose values in the brain determined using microdialysis were significantly higher (p < 0.04). No differences were demonstrated in the other groups. Increasing the FiO2 had no significant effect on the serum levels of glucose and lactate. Increasing the Fi

  4. Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions123

    PubMed Central

    Stanhope, Kimber L; Griffen, Steven C; Bremer, Andrew A; Vink, Roel G; Schaefer, Ernst J; Nakajima, Katsuyuki; Schwarz, Jean-Marc; Beysen, Carine; Berglund, Lars; Keim, Nancy L; Havel, Peter J

    2011-01-01

    Background: Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). Objective: We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. Design: The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. Results: Consumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. Conclusion: The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853. PMID:21613559

  5. Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions.

    PubMed

    Stanhope, Kimber L; Griffen, Steven C; Bremer, Andrew A; Vink, Roel G; Schaefer, Ernst J; Nakajima, Katsuyuki; Schwarz, Jean-Marc; Beysen, Carine; Berglund, Lars; Keim, Nancy L; Havel, Peter J

    2011-07-01

    Consumption of sugar-sweetened beverages has been shown to be associated with dyslipidemia, insulin resistance, fatty liver, diabetes, and cardiovascular disease. It has been proposed that adverse metabolic effects of chronic consumption of sugar-sweetened beverages are a consequence of increased circulating glucose and insulin excursions, ie, dietary glycemic index (GI). We determined whether the greater adverse effects of fructose than of glucose consumption were associated with glucose and insulin exposures. The subjects were studied in a metabolic facility and consumed energy-balanced diets containing 55% of energy as complex carbohydrate for 2 wk (GI = 64). The subjects then consumed 25% of energy requirements as fructose- or glucose-sweetened beverages along with their usual ad libitum diets for 8 wk at home and then as part of energy-balanced diets for 2 wk at the metabolic facility (fructose GI = 38, glucose GI = 83). The 24-h glucose and insulin profiles and fasting plasma glycated albumin and fructosamine concentrations were measured 0, 2, 8, and 10 wk after beverage consumption. Consumption of fructose-sweetened beverages lowered glucose and insulin postmeal peaks and the 23-h area under the curve compared with the baseline diet and with the consumption of glucose-sweetened beverages (all P < 0.001, effect of sugar). Plasma glycated albumin concentrations were lower 10 wk after fructose than after glucose consumption (P < 0.01, effect of sugar), whereas fructosamine concentrations did not differ between groups. The results suggest that the specific effects of fructose, but not of glucose and insulin excursions, contribute to the adverse effects of consuming sugar-sweetened beverages on lipids and insulin sensitivity. This study is registered at clinicaltrials.gov as NCT01165853.

  6. Diminished brain glucose metabolism is a significant determinant for falling rates of systemic glucose utilization during sleep in normal humans.

    PubMed Central

    Boyle, P J; Scott, J C; Krentz, A J; Nagy, R J; Comstock, E; Hoffman, C

    1994-01-01

    Systemic glucose utilization declines during sleep in man. We tested the hypothesis that this decline in utilization is largely accounted for by reduced brain glucose metabolism. 10 normal subjects underwent internal jugular and radial artery cannulation to determine cerebral blood flow by N2O equilibrium technique and to quantitate cross-brain glucose and oxygen differences before and every 3 h during sleep. Sleep stage was graded by continuous electroencephalogram, and systemic glucose turnover was estimated by isotope dilution. Brain glucose metabolism fell from 33.6 +/- 2.2 mumol/100 g per min (mean +/- SE) before sleep (2300 h) to a mean nadir of 24.3 +/- 1.1 mumol/100 g per min at 0300 h during sleep (P = 0.001). Corresponding rates of systemic glucose utilization fell from 13.2 +/- 0.8 to 11.0 +/- 0.5 mumol/kg per min (P = 0.003). Diminished brain glucose metabolism was the product of a reduced arteriovenous glucose difference, 0.643 +/- 0.024 to 0.546 +/- 0.020 mmol/liter (P = 0.002), and cerebral blood flow, 50.3 +/- 2.8 to 44.6 +/- 1.4 cc/100 g per min (P = 0.021). Brain oxygen metabolism fell commensurately from 153.4 +/- 11.8 to 128.0 +/- 8.4 mumol/100 g per min (P = 0.045). The observed reduction in brain metabolism occurred independent of stage of central nervous system electrical activity (electroencephalographic data), and was more closely linked to duration of sleep. We conclude that a decline in brain glucose metabolism is a significant determinant of falling rates of systemic glucose utilization during sleep. Images PMID:8113391

  7. The satiety factor oleoylethanolamide impacts hepatic lipid and glucose metabolism in goldfish.

    PubMed

    Gómez-Boronat, Miguel; Velasco, Cristina; Isorna, Esther; De Pedro, Nuria; Delgado, María J; Soengas, José L

    2016-12-01

    Oleoylethanolamide (OEA) is an acylethanolamide synthesized mainly in the gastrointestinal tract with known effects in mammals on food intake and body mass through activation of peroxisome proliferator-activated receptor type α (PPARα). Since we previously demonstrated that acute treatment with OEA in goldfish resulted in decreased food intake and locomotor activity, as in mammals, we hypothesize that OEA would be involved in the control of energy metabolism in fish. Therefore, we assessed the effects of acute (for 6 h) and chronic (for 11 days) treatments with OEA (5 µg g(-1) body mass) on metabolite concentrations and enzyme activities related to glucose and lipid metabolism in liver of goldfish (Carassius auratus). In the chronic treatment, OEA impairs the increase in body mass and reduces locomotor activity, without any signs of stress. The lipolytic capacity in liver decreased after both acute and chronic OEA treatments, whereas lipogenic capacity increased after acute and decreased after chronic treatment with OEA. These results are different from those observed to date in mammalian adipose tissue, but not so different from those known in liver, and might be attributed to the absence of changes in the expression of pparα, and/or to the increase in the expression of the clock gene bmal1a after chronic OEA treatment. As for glucose metabolism, a clear decrease in the capacity of hepatic tissue to use glucose was observed in OEA-treated fish. These results support an important role for OEA in the regulation of liver lipid and glucose metabolism, and could relate to the metabolic changes associated with circadian activity and the regulation of food intake in fish.

  8. [Effect of needling at waiguan (SJ5) on brain glucose metabolism in patients with cerebral infarction].

    PubMed

    Liu, En-Tao; Wang, Shu-Xia; Huang, Yong; Lai, Xin-Sheng; Tang, Chun-Zhi; Cui, Shao-Yang

    2013-10-01

    To observe changes of brain glucose metabolism by needling at Waiguan (SJ5) in cerebral infraction (CI) patients using 18F-fluorodeoxyglucose (FDG) positron-emission computer tomography (PET/CT), thus exploring its effect and mechanisms. A total of 21 patients with CI were recruited in this study. The location of lesion was limited to the left basal ganglia by CT or MRI scan. All patients were randomly assigned to three groups. i.e., the acupoint group (Group A), the non-acupoint group (Group B), the blank control group (Group C), 7 in each group. Patients in Group A were needled at right Waiguan (SJ5). Those in Group B were needled at non-acupoint [10 mm beside Waiguan (SJ5)], whereas those in Group C did not receive any treatment. All patients underwent PET/CT head scan. All data were statistically analyzed using SPSS 13.0 Software and SPM8 Software. Compared with Group C, glucose metabolism increased in bilateral superior temporal gyrus (BA38), right superior frontal gyrus (BA9), left cingulate gyrus (BA24), left culmen and pyramid of cerebellum, and right cerebellar tonsil of cerebellum in Group A. Compared with Group C, glucose metabolism increased in bilateral superior frontal gyrus (BA6, BA9, BA10), bilateral middle frontal gyrus (BA6, BA10), left middle frontal gyrus (BA4), bilateral uncus of limbic lobe (BA36, BA38), left cingulate gyrus (BA24, BA31), left posterior cingulate gyrus (BA30), left precuneus (BA7), left inferior parietal lobule (BA4), and left lingual gyrus of occipital lobe (BA18) in Group B. Compared with Group B, glucose metabolism increased in bilateral superior temporal gyrus (BA22, BA38), right inferior frontal gyrus (BA47), left culmen and cerebellar tonsil of cerebellum in Group A. Activated encephalic regions of needling at Waiguan (SJ5) were mainly dominated in the healthy side, bilateral superior temporal gyrus, and right inferior frontal gyrus. Activated encephalic regions of cerebellum were located at the left cerebellar

  9. High environmental temperature increases glucose requirement in the developing chicken embryo.

    PubMed

    Molenaar, Roos; van den Borne, Joost J G C; Hazejager, Ewoud; Kristensen, Niels B; Heetkamp, Marcel J W; Meijerhof, Ron; Kemp, Bas; van den Brand, Henry

    2013-01-01

    Environmental conditions during the perinatal period influence metabolic and developmental processes in mammals and avian species, which could impact pre- and postnatal survival and development. The current study investigated the effect of eggshell temperature (EST) on glucose metabolism in broiler chicken embryos. Broiler eggs were incubated at a high (38.9°C) or normal (37.8°C) EST from day 10.5 of incubation onward and were injected with a bolus of [U-(13)C]glucose in the chorio-allantoic fluid at day 17.5 of incubation. After [U-(13)C]glucose administration, (13)C enrichment was determined in intermediate pools and end-products of glucose metabolism. Oxidation of labeled glucose occurred for approximately 3 days after injection. Glucose oxidation was higher in the high than in the normal EST treatment from day 17.6 until 17.8 of incubation. The overall recovery of (13)CO2 tended to be 4.7% higher in the high than in the normal EST treatment. An increase in EST (38.9°C vs 37.8°C) increased (13)C enrichment in plasma lactate at day 17.8 of incubation and (13)C in hepatic glycogen at day 18.8 of incubation. Furthermore, high compared to normal EST resulted in a lower yolk-free body mass at day 20.9 (-2.74 g) and 21.7 (-3.81 g) of incubation, a lower hepatic glycogen concentration at day 18.2 (-4.37 mg/g) and 18.8 (-4.59 mg/g) of incubation, and a higher plasma uric acid concentration (+2.8 mg/mL/+43%) at day 21.6 of incubation. These results indicate that the glucose oxidation pattern is relatively slow, but the intensity increased consistently with an increase in developmental stage of the embryo. High environmental temperatures in the perinatal period of chicken embryos increased glucose oxidation and decreased hepatic glycogen prior to the hatching process. This may limit glucose availability for successful hatching and could impact body development, probably by increased gluconeogenesis from glucogenic amino acids to allow anaerobic glycolysis.

  10. High Environmental Temperature Increases Glucose Requirement in the Developing Chicken Embryo

    PubMed Central

    Molenaar, Roos; van den Borne, Joost J. G. C.; Hazejager, Ewoud; Kristensen, Niels B.; Heetkamp, Marcel J. W.; Meijerhof, Ron; Kemp, Bas; van den Brand, Henry

    2013-01-01

    Environmental conditions during the perinatal period influence metabolic and developmental processes in mammals and avian species, which could impact pre- and postnatal survival and development. The current study investigated the effect of eggshell temperature (EST) on glucose metabolism in broiler chicken embryos. Broiler eggs were incubated at a high (38.9°C) or normal (37.8°C) EST from day 10.5 of incubation onward and were injected with a bolus of [U-13C]glucose in the chorio-allantoic fluid at day 17.5 of incubation. After [U-13C]glucose administration, 13C enrichment was determined in intermediate pools and end-products of glucose metabolism. Oxidation of labeled glucose occurred for approximately 3 days after injection. Glucose oxidation was higher in the high than in the normal EST treatment from day 17.6 until 17.8 of incubation. The overall recovery of 13CO2 tended to be 4.7% higher in the high than in the normal EST treatment. An increase in EST (38.9°C vs 37.8°C) increased 13C enrichment in plasma lactate at day 17.8 of incubation and 13C in hepatic glycogen at day 18.8 of incubation. Furthermore, high compared to normal EST resulted in a lower yolk-free body mass at day 20.9 (−2.74 g) and 21.7 (−3.81 g) of incubation, a lower hepatic glycogen concentration at day 18.2 (−4.37 mg/g) and 18.8 (−4.59 mg/g) of incubation, and a higher plasma uric acid concentration (+2.8 mg/mL/+43%) at day 21.6 of incubation. These results indicate that the glucose oxidation pattern is relatively slow, but the intensity increased consistently with an increase in developmental stage of the embryo. High environmental temperatures in the perinatal period of chicken embryos increased glucose oxidation and decreased hepatic glycogen prior to the hatching process. This may limit glucose availability for successful hatching and could impact body development, probably by increased gluconeogenesis from glucogenic amino acids to allow anaerobic glycolysis. PMID:23560054

  11. Whole Grain Products, Fish and Bilberries Alter Glucose and Lipid Metabolism in a Randomized, Controlled Trial: The Sysdimet Study

    PubMed Central

    Lankinen, Maria; Schwab, Ursula; Kolehmainen, Marjukka; Paananen, Jussi; Poutanen, Kaisa; Mykkänen, Hannu; Seppänen-Laakso, Tuulikki; Gylling, Helena; Uusitupa, Matti; Orešič, Matej

    2011-01-01

    Background Due to the growing prevalence of type 2 diabetes, new dietary solutions are needed to help improve glucose and lipid metabolism in persons at high risk of developing the disease. Herein we investigated the effects of low-insulin-response grain products, fatty fish, and berries on glucose metabolism and plasma lipidomic profiles in persons with impaired glucose metabolism. Methodology/Principal Findings Altogether 106 men and women with impaired glucose metabolism and with at least two other features of the metabolic syndrome were included in a 12-week parallel dietary intervention. The participants were randomized into three diet intervention groups: (1) whole grain and low postprandial insulin response grain products, fatty fish three times a week, and bilberries three portions per day (HealthyDiet group), (2) Whole grain enriched diet (WGED) group, which includes principally the same grain products as group (1), but with no change in fish or berry consumption, and (3) refined wheat breads (Control). Oral glucose tolerance, plasma fatty acids and lipidomic profiles were measured before and after the intervention. Self-reported compliance with the diets was good and the body weight remained constant. Within the HealthyDiet group two hour glucose concentration and area-under-the-curve for glucose decreased and plasma proportion of (n-3) long-chain PUFAs increased (False Discovery Rate p-values <0.05). Increases in eicosapentaenoic acid and docosahexaenoic acid associated curvilinearly with the improved insulin secretion and glucose disposal. Among the 364 characterized lipids, 25 changed significantly in the HealthyDiet group, including multiple triglycerides incorporating the long chain (n-3) PUFA. Conclusions/Significance The results suggest that the diet rich in whole grain and low insulin response grain products, bilberries, and fatty fish improve glucose metabolism and alter the lipidomic profile. Therefore, such a diet may have a beneficial effect

  12. Chromium supplementation alters both glucose and lipid metabolism in feedlot cattle during the receiving period.

    PubMed

    Bernhard, B C; Burdick, N C; Rathmann, R J; Carroll, J A; Finck, D N; Jennings, M A; Young, T R; Johnson, B J

    2012-12-01

    Crossbred steers (n = 20; 235 ± 4 kg) were fed for 53 d during a receiving period to determine if supplementing chromium (Cr; KemTRACE Chromium Propionate 0.04%, Kemin Industries, Des Moines, IA) would alter glucose or lipid metabolism of newly received cattle. Chromium premixes were supplemented to add 0 (Con) or 0.2 mg/kg of Cr to the total diet on a DM basis. Cattle were fitted with jugular catheters on d 52. A glucose tolerance test (GTT) and an insulin sensitivity test (IST) were conducted on d 53. Blood samples were collected from -60 to 150 min relative to each infusion. Serum was isolated to determine glucose, insulin, and NEFA concentrations. Throughout GTT, no differences were detected in glucose concentrations, glucose clearance rates (k), or preinfusion insulin concentrations (P > 0.50), but insulin concentrations postinfusion tended (P = 0.06) to be greater for the Cr-supplemented steers. This caused an increase in the insulin to glucose ratio (I:G) from 0 to 150 min postinfusion for the Cr-supplemented steers (P = 0.03). In addition, NEFA concentrations during GTT were lower (P ≤ 0.01) for Cr-supplemented steers both preinfusion and postinfusion. During IST, there was no treatment effect on glucose concentrations preinfusion (P = 0.38), but postinfusion glucose concentrations were greater (P< 0.01) in the Cr-supplemented steers. The k of Cr-supplemented steers tended (P = 0.06) to be faster than Con steers from 30 to 45 min postinfusion. During the same test, there was no treatment effect detected for insulin concentrations (P > 0.33). The I:G were not affected by treatment (P > 0.40).Concentrations of NEFA were reduced (P < 0.01) both preinfusion and postinfusion during IST for Cr-supplemented steers. Results of this study indicate that supplementation of Cr can significantly alter lipid metabolism. This suggests that these steers had less dependence on lipid metabolism for energy or sensitivity of adipose tissue to antilipolytic signals was

  13. Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach.

    PubMed

    Mallad, Ashwini; Hinshaw, Ling; Schiavon, Michele; Dalla Man, Chiara; Dadlani, Vikash; Basu, Rita; Lingineni, Ravi; Cobelli, Claudio; Johnson, Matthew L; Carter, Rickey; Kudva, Yogish C; Basu, Ananda

    2015-06-15

    To determine the effects of exercise on postprandial glucose metabolism and insulin action in type 1 diabetes (T1D), we applied the triple tracer technique to study 16 T1D subjects on insulin pump therapy before, during, and after 75 min of moderate-intensity exercise (50% V̇o2max) that started 120 min after a mixed meal containing 75 g of labeled glucose. Prandial insulin bolus was administered as per each subject's customary insulin/carbohydrate ratio adjusted for meal time meter glucose and the level of physical activity. Basal insulin infusion rates were not altered. There were no episodes of hypoglycemia during the study. Plasma dopamine and norepinephrine concentrations rose during exercise. During exercise, rates of endogenous glucose production rose rapidly to baseline levels despite high circulating insulin and glucose concentrations. Interestingly, plasma insulin concentrations increased during exercise despite no changes in insulin pump infusion rates, implying increased mobilization of insulin from subcutaneous depots. Glucagon concentrations rose before and during exercise. Therapeutic approaches for T1D management during exercise will need to account for its effects on glucose turnover, insulin mobilization, glucagon, and sympathetic response and possibly other blood-borne feedback and afferent reflex mechanisms to improve both hypoglycemia and hyperglycemia. Copyright © 2015 the American Physiological Society.

  14. Effects of intravenous lipopolysaccharide infusion on glucose and insulin dynamics in horses with equine metabolic syndrome.

    PubMed

    Tadros, Elizabeth M; Frank, Nicholas; De Witte, Fiamma Gomez; Boston, Raymond C

    2013-07-01

    To test the hypothesis that glucose and insulin dynamics during endotoxemia differ between healthy horses and horses with equine metabolic syndrome (EMS). 6 healthy adult mares and 6 horses with EMS. Each horse randomly received an IV infusion of lipopolysaccharide (20 ng/kg [in 60 mL of sterile saline {0.9% NaCl} solution]) or saline solution, followed by the other treatment after a 7-day washout period. Baseline insulin-modified frequently sampled IV glucose tolerance tests were performed 27 hours before and then repeated at 0.5 and 21 hours after infusion. Results were assessed via minimal model analysis and area under the curve values for plasma glucose and serum insulin concentrations. Lipopolysaccharide infusion decreased insulin sensitivity and increased area under the serum insulin concentration curve (treatment × time) in both healthy and EMS-affected horses, compared with findings following saline solution administration. The magnitude of increase in area under the plasma glucose curve following LPS administration was greater for the EMS-affected horses than it was for the healthy horses. Horses with EMS that received LPS or saline solution infusions had decreased insulin sensitivity over time. Glucose and insulin responses to endotoxemia differed between healthy horses and horses with EMS, with greater loss of glycemic control in EMS-affected horses. Horses with EMS also had greater derangements in glucose and insulin homeostasis that were potentially stress induced. It may therefore be helpful to avoid exposure of these horses to stressful situations.

  15. Physical Activity Dimensions Associated with Impaired Glucose Metabolism.

    PubMed

    Amadid, Hanan; Johansen, Nanna B; Bjerregaard, Anne-Louise; Vistisen, Dorte; Færch, Kristine; Brage, Søren; Lauritzen, Torsten; Witte, Daniel R; Sandbæk, Annelli; Jørgensen, Marit E

    2017-07-07

    Physical activity (PA) is important in the prevention of type 2 diabetes, yet little is known about the role of specific dimensions of PA, including sedentary time in subgroups at risk of impaired glucose metabolism (IGM). We applied a data driven decision tool to identify dimensions of PA associated with IGM across age, sex and body mass index (BMI) groups. This cross-sectional study included 1,501 individuals (mean (SD) age 65.6 (6.8) years) at high risk of type 2 diabetes from the ADDITION-PRO study. PA was measured by an individually calibrated combined accelerometer and heart rate monitor worn for 7 days. PA energy expenditure, time spent in different activity intensities, bout duration and sedentary time were considered determinants of IGM together with age, sex and BMI. Decision tree analysis was applied to identify subgroup-specific dimensions of PA associated with IGM. IGM was based on oral glucose tolerance test results and defined as fasting plasma glucose ≥ 6.1 mmol/L and/or 2-hour plasma glucose ≥ 7.8 mmol/L. Among overweight (BMI ≥ 25kg/m) men, accumulating less than 30 minutes/day of moderate-to-vigorous PA was associated with IGM, while in overweight women sedentary time was associated with IGM. Among individuals aged > 53 years with normal weight (BMI < 25kg/m), time spent in light PA was associated with IGM. None of the dimensions of PA were associated with IGM among individuals aged ≤ 53 years with normal weight. We identified subgroups in which different activity dimensions were associated with IGM. Methodology and results from this study may suggest a preliminary step towards the goal of tailoring and targeting PA interventions aimed at type 2 diabetes prevention.

  16. Transcriptional and metabolic effects of glucose on Streptococcus pneumoniae sugar metabolism

    PubMed Central

    Paixão, Laura; Caldas, José; Kloosterman, Tomas G.; Kuipers, Oscar P.; Vinga, Susana; Neves, Ana R.

    2015-01-01

    Streptococcus pneumoniae is a strictly fermentative human pathogen that relies on carbohydrate metabolism to generate energy for growth. The nasopharynx colonized by the bacterium is poor in free sugars, but mucosa lining glycans can provide a source of sugar. In blood and inflamed tissues glucose is the prevailing sugar. As a result during progression from colonization to disease S. pneumoniae has to cope with a pronounced shift in carbohydrate nature and availability. Thus, we set out to assess the pneumococcal response to sugars found in glycans and the influence of glucose (Glc) on this response at the transcriptional, physiological, and metabolic levels. Galactose (Gal), N-acetylglucosamine (GlcNAc), and mannose (Man) affected the expression of 8 to 14% of the genes covering cellular functions including central carbon metabolism and virulence. The pattern of end-products as monitored by in vivo 13C-NMR is in good agreement with the fermentation profiles during growth, while the pools of phosphorylated metabolites are consistent with the type of fermentation observed (homolactic vs. mixed) and regulation at the metabolic level. Furthermore, the accumulation of α-Gal6P and Man6P indicate metabolic bottlenecks in the metabolism of Gal and Man, respectively. Glc added to cells actively metabolizing other sugar(s) was readily consumed and elicited a metabolic shift toward a homolactic profile. The transcriptional response to Glc was large (over 5% of the genome). In central carbon metabolism (most represented category), Glc exerted mostly negative regulation. The smallest response to Glc was observed on a sugar mix, suggesting that exposure to varied sugars improves the fitness of S. pneumoniae. The expression of virulence factors was negatively controlled by Glc in a sugar-dependent manner. Overall, our results shed new light on the link between carbohydrate metabolism, adaptation to host niches and virulence. PMID:26500614

  17. 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.

  18. Valproate modulates glucose metabolism in patients with epilepsy after first exposure.

    PubMed

    Rakitin, Aleksei; Kõks, Sulev; Haldre, Sulev

    2015-11-01

    Valproate (VPA) treatment has been reported to be associated with weight gain and metabolic changes, such as hyperinsulinemia. The question of whether hyperinsulinemia and other metabolic changes are consequences of increased weight, or are instead direct results of VPA treatment, remains a matter of debate. The aim of the current study was to explore the influence of VPA treatment on glucose and insulin levels during the oral glucose tolerance test (OGTT) directly following the first intravenous (IV) administration. Sixteen patients (18-46 years old) with newly diagnosed epilepsy underwent an OGTT with 75 g glucose prior to the start of VPA treatment, as well as directly following the first IV VPA administration. We observed that plasma glucose levels during the 120 min of OGTT session following infusion of VPA were significantly lower than those measured during OGTT without VPA treatment (mean ± standard deviation [SD] 4.28 ± 0.94 mmol/l vs. 4.75 ± 1.09 mmol/l respectively, p = 0.038). However, blood concentrations of insulin and C-peptide did not differ significantly between the two measurements. This is the first study to show a potential acute glucose-lowering effect of VPA during OGTT in patients with newly diagnosed epilepsy. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

  19. A metabolic trade-off between phosphate and glucose utilization in Escherichia coli.

    PubMed

    Behrends, Volker; Maharjan, Ram P; Ryall, Ben; Feng, Lu; Liu, Bin; Wang, Lei; Bundy, Jacob G; Ferenci, Thomas

    2014-11-01

    Getting the most out of available nutrients is a key challenge that all organisms face. Little is known about how they optimize and balance the simultaneous utilization of multiple elemental resources. We investigated the effects of long-term phosphate limitation on carbon metabolism of the model organism Escherichia coli using chemostat cultures. We profiled metabolic changes in the growth medium over time and found evidence for an increase in fermentative metabolism despite the aerobic conditions. Using full-genome sequencing and competition experiments, we found that fitness under phosphate-limiting conditions was reproducibly increased by a mutation preventing flux through succinate in the tricarboxylic acid cycle. In contrast, these mutations reduced competitive ability under carbon limitation, and thus reveal a conflicting metabolic benefit in the role of the TCA cycle in environments limited by inorganic phosphate and glucose.

  20. Relation of periodontitis and metabolic syndrome with gestational glucose metabolism disorder.

    PubMed

    Bullon, Pedro; Jaramillo, Reyes; Santos-Garcia, Rocio; Rios-Santos, Vicente; Ramirez, Maria; Fernandez-Palacin, Ana; Fernandez-Riejos, Patricia

    2014-02-01

    Gestational diabetes mellitus (GDM) and metabolic syndrome have been related to periodontitis. This study's objective is to establish the relationship between them in pregnant women affected by gestational glucose metabolism disorder. In 188 pregnant women with positive O'Sullivan test (POT) results, an oral glucose tolerance test (OGTT) was performed to diagnose GDM. The mother's periodontal parameters, age, prepregnancy weight and height and body mass index (BMI), blood pressure, gestational age, and birth weight were recorded at 24 to 28 weeks of pregnancy, as well as levels of glucose, C-reactive protein, triglycerides, glycated hemoglobin (HbA1c), and total, low-density lipoprotein, high-density lipoprotein (HDL), and very-low-density lipoprotein (VLDL) cholesterol levels. Prepregnancy weight, prepregnancy BMI, systolic and diastolic blood pressure, VLDL cholesterol, and glucose parameters were higher in GDM compared with POT (P <0.05). VLDL cholesterol, triglycerides, and 2-hour OGTT were higher in patients with periodontitis than in patients without periodontitis (P <0.05). HbA1c, triglycerides, and 1- and 2-hour OGTT were positively related with probing depth and clinical attachment level; blood glucose was related only to bleeding on probing (P <0.05). HbA1c, basal OGTT, and 1- and 2-hour OGTT were positively related to prepregnancy BMI and blood pressure; HDL cholesterol was negatively related to prepregnancy BMI; C-reactive protein was positively related to prepregnancy BMI and diastolic blood pressure (P <0.05). These data support the relationships among periodontal disease and some biochemical parameters such as lipid and glucose data in pregnancy, and also among metabolic syndrome and biochemical parameters.

  1. Effect of dietary chromium-L-methionine on glucose metabolism of beef steers.

    PubMed

    Kegley, E B; Galloway, D L; Fakler, T M

    2000-12-01

    Thirty-six crossbred steers (288 +/- 3.7 kg initial BW) were used to determine the effect of Cr, as chromium-L-methionine, on glucose tolerance and insulin sensitivity in beef calves. Calves were fed a control diet or the diet supplemented with 400 or 800 microg Cr/kg of diet as chromium-L-methionine. Calves were kept in drylots (six calves/pen; two pens/dietary treatment). Steers were caught twice a day in locking headgates and individually fed their respective diets for a period of 22, 23, or 24 d prior to the metabolic challenges. Calves received a totally mixed diet containing 54% corn, 38% cottonseed hulls, and 5% soybean meal. On d 21, 22, and 23, four calves/dietary treatment were fitted with an indwelling jugular catheter. Approximately 24 h after catheterization, an intravenous glucose tolerance test (500 mg glucose/kg of BW), followed 5 h later by an intravenous insulin challenge test (0.1 IU insulin/kg of BW), was conducted. There was no effect (P > 0.10) of dietary treatment on ADG or ADFI. During the intravenous glucose tolerance test, serum insulin concentrations were increased by supplemental chromium-L-methionine (linear effect of Cr, P < 0.05). There was a time x treatment interaction (P < 0.05) on plasma glucose concentrations after the glucose infusion. Plasma glucose concentrations of calves fed 400 microg Cr/kg of diet were lower than those of controls and calves supplemented with 800 microg Cr/kg of diet (quadratic effect of Cr, P < 0.05) 5 and 10 min after the glucose infusion. Supplemental chromium-L-methionine increased the glucose clearance rate from 5 to 10 min after the insulin challenge test (linear effect of Cr, P < 0.05). Glucose half-life from 5 to 10 min after the insulin infusion was also decreased by supplemental chromium-L-methionine (linear effect of Cr, P < 0.10). These data indicate that supplemental Cr, as chromium-L-methionine, increased glucose clearance rate after an insulin infusion and increased the insulin response to

  2. Improvement in glycemia after glucose or insulin overload in leptin-infused rats is associated with insulin-related activation of hepatic glucose metabolism.

    PubMed

    Burgos-Ramos, Emma; Canelles, Sandra; Frago, Laura M; Chowen, Julie A; Arilla-Ferreiro, Eduardo; Argente, Jesús; Barrios, Vicente

    2016-01-01

    Insulin regulates glucose homeostasis through direct effects on the liver, among other organs, with leptin modulating insulin's hepatic actions. Since central leptin may modify insulin signaling in the liver, we hypothesized that leptin infusion activates hepatic glycogen synthesis following peripheral administration of a bolus of glucose or insulin, thus regulating glycemia. Oral glucose and intraperitoneal insulin tolerance tests were performed in control, intracerebroventricular leptin-treated and pair-fed rats during 14 days. An improvement in glycemia and an increase in hepatic free glucose and glycogen concentrations after glucose or insulin overload were observed in leptin-treated rats. In order to analyze whether the liver was involved in these changes, we studied activation of insulin signaling by Western blotting and multiplex bead immunoassay after leptin infusion. Our studies revealed an increase in phosphorylation of insulin receptor substrate-1 and Akt in leptin-treated rats. Examination of parameters related to glucose uptake and metabolism in the liver revealed an augment in glucose transporter 2 and a decrease in phosphoenolpyruvate carboxylase protein levels in this group. These results indicate that central leptin increases hepatic insulin signaling, associated with increased glycogen concentrations after glucose or insulin overload, leading to an improvement in glycemia.

  3. Protective effects of marein on high glucose-induced glucose metabolic disorder in HepG2 cells.

    PubMed

    Jiang, Baoping; Le, Liang; Zhai, Wei; Wan, Wenting; Hu, Keping; Yong, Peng; He, Chunnian; Xu, Lijia; Xiao, Peigen

    2016-08-15

    Our previous study has shown that Coreopsis tinctoria increases insulin sensitivity and regulates hepatic metabolism in high-fat diet (HFD)-induced insulin resistance rats. However, it is unclear whether or not marein, a major compound of C. tinctoria, could improve insulin resistance. Here we investigate the effect and mechanism of action of marein on improving insulin resistance in HepG2 cells. We investigated the protective effects of marein in high glucose-induced human liver carcinoma cell HepG2. In kinase inhibitor studies, genistein, LY294002, STO-609 and compound C were added to HepG2 cells 1h before the addition of marein. Transfection with siRNA was used to knock down LKB1, and 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG), an effective tracer, was used to detect glucose uptake. The results showed for the first time that marein significantly stimulates the phosphorylation of AMP-activated protein kinase (AMPK) and the Akt substrate of 160kDa (AS160) and enhanced the translocation of glucose transporter 1 (GLUT1) to the plasma membrane. Further study indicated that genistein (an insulin receptor tyrosine kinase inhibitor) altered the effect of marein on glucose uptake, and both LY294002 (a phosphatidylinositol 3-kinase inhibitor) and compound C (an AMP-activated protein kinase inhibitor) significantly decreased marein-stimulated 2-NBDG uptake. Additionally, marein-stimulated glucose uptake was blocked in the presence of STO-609, a CaMKK inhibitor; however, marein-stimulated AMPK phosphorylation was not blocked by LKB1 siRNA in HepG2 cells. Marein also inhibited the phosphorylation of insulin receptor substrate (IRS-1) at Ser 612, but inhibited GSK-3β phosphorylation and increased glycogen synthesis. Moreover, marein significantly decreased the expression levels of FoxO1, G6Pase and PEPCK. Consequently, marein improved insulin resistance induced by high glucose in HepG2 cells through CaMKK/AMPK/GLUT1 to promote glucose uptake

  4. Global Loss of Bmal1 Expression Alters Adipose Tissue Hormones, Gene Expression and Glucose Metabolism

    PubMed Central

    Kennaway, David John; Varcoe, Tamara Jayne; Voultsios, Athena; Boden, Michael James

    2013-01-01

    The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight). Bmal1 null mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 null mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 null male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively) on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 null mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 null mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism. PMID:23750248

  5. The role of hepatic mitochondria in the regulation of glucose metabolism in BHE rats

    SciTech Connect

    Kim, M.J.C.

    1988-01-01

    The interacting effects of dietary fat source and thyroxine treatment on the hepatic mitochondrial function and glucose metabolism were studied. In the first study, three different sources of dietary fatty acids and thyroxine treatment were used to investigate the hepatic mitochondrial thermotropic behavior in two strains of rat. The NIDDM BHE and Sprague-Dawley rats were used. Feeding coconut oil increased serum T{sub 4} levels and T{sub 4} treatment increased serum T{sub 3} levels in the BHE rats. In the mitochondria from BHE rats fed coconut oil and treated with T{sub 4}, the transition temperature disappeared due to a decoupling of succinate supported respiration. This was not observed in the Sprague-Dawley rats. In the second study, two different sources of dietary fat and T{sub 4} treatment were used to investigate hepatic mitochondrial function. Coconut oil feeding increased Ca{sup ++}Mg{sup ++}ATPase and Mg{sup ++}ATPase. T{sub 4} treatment had potentiated this effect. T{sub 4} increased the malate-aspartate shuttle and {alpha}-glycerophosphate shuttle activities. In the third study, the glucose turnover rate from D-({sup 14}C-U)/(6-{sup 3}H)-glucose and gluconeogeneis from L-({sup 14}C-U)-alanine was examined. Dietary fat or T{sub 4} did not affect the glucose mass. T{sub 4} increased the irreversible fractional glucose turnover rate.

  6. The "metabolic syndrome" is less useful than random plasma glucose to screen for glucose intolerance.

    PubMed

    El Bassuoni, Eman A; Ziemer, David C; Kolm, Paul; Rhee, Mary K; Vaccarino, Viola; Tsui, Circe W; Kaufman, Jack M; Osinski, G Eileen; Koch, David D; Narayan, K M Venkat; Weintraub, William S; Phillips, Lawrence S

    2008-09-01

    To compare the utility of metabolic syndrome (MetS) to random plasma glucose (RPG) in identifying people with diabetes or prediabetes. RPG was measured and an OGTT was performed in 1155 adults. Test performance was measured by area under the receiver-operating-characteristic curve (AROC). Diabetes was found in 5.1% and prediabetes in 20.0%. AROC for MetS with fasting plasma glucose (FPG) was 0.80 to detect diabetes, and 0.76 for diabetes or prediabetes--similar to RPG alone (0.82 and 0.72). However, the AROC for MetS excluding fasting plasma glucose was lower: 0.69 for diabetes (p<0.01 vs. both RPG and MetS with FPG), and 0.69 for diabetes or prediabetes. AROCs for MetS with FPG and RPG were comparable and higher for recognizing diabetes in blacks vs. whites, and females vs. males. MetS with FPG was superior to RPG for identifying diabetes only in subjects with age <40 or BMI <25. MetS features can be used to identify risk of diabetes, but predictive usefulness is driven largely by FPG. Overall, to identify diabetes or prediabetes in blacks and whites with varying age and BMI, MetS is no better than RPG--a more convenient and less expensive test.

  7. Evolution of E. coli on [U-13C]Glucose Reveals a Negligible Isotopic Influence on Metabolism and Physiology

    PubMed Central

    Sandberg, Troy E.; Long, Christopher P.; Gonzalez, Jacqueline E.; Feist, Adam M.; Antoniewicz, Maciek R.; Palsson, Bernhard O.

    2016-01-01

    13C-Metabolic flux analysis (13C-MFA) traditionally assumes that kinetic isotope effects from isotopically labeled compounds do not appreciably alter cellular growth or metabolism, despite indications that some biochemical reactions can be non-negligibly impacted. Here, populations of Escherichia coli were adaptively evolved for ~1000 generations on uniformly labeled 13C-glucose, a commonly used isotope for 13C-MFA. Phenotypic characterization of these evolved strains revealed ~40% increases in growth rate, with no significant difference in fitness when grown on either labeled (13C) or unlabeled (12C) glucose. The evolved strains displayed decreased biomass yields, increased glucose and oxygen uptake, and increased acetate production, mimicking what is observed after adaptive evolution on unlabeled glucose. Furthermore, full genome re-sequencing revealed that the key genetic changes underlying these phenotypic alterations were essentially the same as those acquired during adaptive evolution on unlabeled glucose. Additionally, glucose competition experiments demonstrated that the wild-type exhibits no isotopic preference for unlabeled glucose, and the evolved strains have no preference for labeled glucose. Overall, the results of this study indicate that there are no significant differences between 12C and 13C-glucose as a carbon source for E. coli growth. PMID:26964043

  8. Vinegar Consumption Increases Insulin-Stimulated Glucose Uptake by the Forearm Muscle in Humans with Type 2 Diabetes

    PubMed Central

    Mitrou, Panayota; Maratou, Eirini; Lambadiari, Vaia; Dimitriadis, Panayiotis; Spanoudi, Filio; Raptis, Sotirios A.; Dimitriadis, George

    2015-01-01

    Background and Aims. Vinegar has been shown to have a glucose-lowering effect in patients with glucose abnormalities. However, the mechanisms of this effect are still obscure. The aim of this randomised, crossover study was to investigate the effect of vinegar on glucose metabolism in muscle which is the most important tissue for insulin-stimulated glucose disposal. Materials and Methods. Eleven subjects with DM2 consumed vinegar or placebo (at random order on two separate days, a week apart), before a mixed meal. Plasma glucose, insulin, triglycerides, nonesterified fatty acids (NEFA), and glycerol were measured preprandially and at 30–60 min for 300 min postprandially from the radial artery and from a forearm vein. Muscle blood flow was measured with strain-gauge plethysmography. Glucose uptake was calculated as the arteriovenous difference of glucose multiplied by blood flow. Results. Vinegar compared to placebo (1) increased forearm glucose uptake (p = 0.0357), (2) decreased plasma glucose (p = 0.0279), insulin (p = 0.0457), and triglycerides (p = 0.0439), and (3) did not change NEFA and glycerol. Conclusions. In DM2 vinegar reduces postprandial hyperglycaemia, hyperinsulinaemia, and hypertriglyceridaemia without affecting lipolysis. Vinegar's effect on carbohydrate metabolism may be partly accounted for by an increase in glucose uptake, demonstrating an improvement in insulin action in skeletal muscle. This trial is registered with Clinicaltrials.gov NCT02309424. PMID:26064976

  9. Parameters of Glucose and Lipid Metabolism Affect the Occurrence of Colorectal Adenomas Detected by Surveillance Colonoscopies.

    PubMed

    Kim, Nam Hee; Suh, Jung Yul; Park, Jung Ho; Park, Dong Il; Cho, Yong Kyun; Sohn, Chong Il; Choi, Kyuyong; Jung, Yoon Suk

    2017-03-01

    Limited data are available regarding the associations between parameters of glucose and lipid metabolism and the occurrence of metachronous adenomas. We investigated whether these parameters affect the occurrence of adenomas detected on surveillance colonoscopy. This longitudinal study was performed on 5289 subjects who underwent follow-up colonoscopy between 2012 and 2013 among 62171 asymptomatic subjects who underwent an initial colonoscopy for a health check-up between 2010 and 2011. The risk of adenoma occurrence was assessed using Cox proportional hazards modeling. The mean interval between the initial and follow-up colonoscopy was 2.2±0.6 years. The occurrence of adenomas detected by the follow-up colonoscopy increased linearly with the increasing quartiles of fasting glucose, hemoglobin A1c (HbA1c), insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides measured at the initial colonoscopy. These associations persisted after adjusting for confounding factors. The adjusted hazard ratios for adenoma occurrence comparing the fourth with the first quartiles of fasting glucose, HbA1c, insulin, HOMA-IR, and triglycerides were 1.50 [95% confidence interval (CI), 1.26-1.77; p(trend)<0.001], 1.22 (95% CI, 1.04-1.43; p(trend)=0.024), 1.22 (95% CI, 1.02-1.46; p(trend)=0.046), 1.36 (95% CI, 1.14-1.63; p(trend)=0.004), and 1.19 (95% CI, 0.99-1.42; p(trend)=0.041), respectively. In addition, increasing quartiles of low-density lipoprotein-cholesterol and apolipoprotein B were associated with an increasing occurrence of adenomas. The levels of parameters of glucose and lipid metabolism were significantly associated with the occurrence of adenomas detected on surveillance colonoscopy. Improving the parameters of glucose and lipid metabolism through lifestyle changes or medications may be helpful in preventing metachronous adenomas.

  10. Metabolic and behavioural effects of sucrose and fructose/glucose drinks in the rat.

    PubMed

    Sheludiakova, Anastasia; Rooney, Kieron; Boakes, Robert A

    2012-06-01

    Overconsumption of sugar-sweetened beverages, in particular carbonated soft drinks, promotes the development of overweight and obesity and is associated with metabolic disturbances, including intrahepatic fat accumulation and metabolic syndrome. One theory proposes that drinks sweetened with high-fructose corn syrup are particularly detrimental to health, as they contain fructose in its 'free' monosaccharide form. This experiment tested whether consuming 'free' fructose had a greater impact on body weight and metabolic abnormalities than when consumed 'bound' within the disaccharide sucrose. Male Hooded Wistar rats were given free access for 56 days to 10% sucrose (Group Suc), 10%, 50/50 fructose/glucose (Group FrucGluc) or water control drinks (Group Control), plus chow. Caloric intake and body weights were measured throughout the protocol, and the following metabolic indices were determined between days 54 and 56: serum triglycerides, liver triglycerides, retroperitoneal fat and oral glucose tolerance. Animals with access to sugar beverages consumed 20% more calories, but did not show greater weight gain than controls. Nevertheless, they developed larger abdominal fat pads, higher triglyceride levels and exhibited impaired insulin/glucose homeostasis. Comparison of the two sugars revealed increased fasting glycaemia in the FrucGluc group, but not in Suc group, whereas the Suc group was more active in an open field. A metabolic profile indicating increased risk of diabetes mellitus and cardiovascular disease was observed in animals given access to sugar-sweetened beverages. Notably, 'free' fructose disrupted glucose homeostasis more than did 'bound' fructose, thus posing a greater risk of progression to type 2 diabetes.

  11. Focal adhesion kinase-promoted tumor glucose metabolism is associated with a shift of mitochondrial respiration to glycolysis.

    PubMed

    Zhang, J; Gao, Q; Zhou, Y; Dier, U; Hempel, N; Hochwald, S N

    2016-04-14

    Cancer cells often gains a growth advantage by taking up glucose at a high rate and undergoing aerobic glycolysis through intrinsic cellular factors that reprogram glucose metabolism. Focal adhesion kinase (FAK), a key transmitter of growth factor and anchorage stimulation, is aberrantly overexpressed or activated in most solid tumors, including pancreatic ductal adenocarcinomas (PDACs). We determined whether FAK can act as an intrinsic driver to promote aerobic glycolysis and tumorigenesis. FAK inhibition decreases and overexpression increases intracellular glucose levels during unfavorable conditions, including growth factor deficiency and cell detachment. Amplex glucose assay, fluorescence and carbon-13 tracing studies demonstrate that FAK promotes glucose consumption and glucose-to-lactate conversion. Extracellular flux analysis indicates that FAK enhances glycolysis and decreases mitochondrial respiration. FAK increases key glycolytic proteins, including enolase, pyruvate kinase M2 (PKM2), lactate dehydrogenase and monocarboxylate transporter. Furthermore, active/tyrosine-phosphorylated FAK directly binds to PKM2 and promotes PKM2-mediated glycolysis. On the other hand, FAK-decreased levels of mitochondrial complex I can result in reduced oxidative phosphorylation (OXPHOS). Attenuation of FAK-enhanced glycolysis re-sensitizes cancer cells to growth factor withdrawal, decreases cell viability and reduces growth of tumor xenografts. These observations, for the first time, establish a vital role of FAK in cancer glucose metabolism through alterations in the OXPHOS-to-glycolysis balance. Broadly targeting the common phenotype of aerobic glycolysis and more specifically FAK-reprogrammed glucose metabolism will disrupt the bioenergetic and biosynthetic supply for uncontrolled growth of tumors, particularly glycolytic PDAC.

  12. Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial.

    PubMed

    de Courten, Barbora; Jakubova, Michaela; de Courten, Maximilian Pj; Kukurova, Ivica Just; Vallova, Silvia; Krumpolec, Patrik; Valkovic, Ladislav; Kurdiova, Timea; Garzon, Davide; Barbaresi, Silvia; Teede, Helena J; Derave, Wim; Krssak, Martin; Aldini, Giancarlo; Ukropec, Jozef; Ukropcova, Barbara

    2016-05-01

    Carnosine is a naturally present dipeptide in humans and an over-the counter food additive. Evidence from animal studies supports the role for carnosine in the prevention and treatment of diabetes and cardiovascular disease, yet there is limited human data. This study investigated whether carnosine supplementation in individuals with overweight or obesity improves diabetes and cardiovascular risk factors. In a double-blind randomized pilot trial in nondiabetic individuals with overweight and obesity (age 43 ± 8 years; body mass index 31 ± 4 kg/m(2) ), 15 individuals were randomly assigned to 2 g carnosine daily and 15 individuals to placebo for 12 weeks. Insulin sensitivity and secretion, glucose tolerance (oral glucose tolerance test), blood pressure, plasma lipid profile, skeletal muscle ((1) H-MRS), and urinary carnosine levels were measured. Carnosine concentrations increased in urine after supplementation (P < 0.05). An increase in fasting insulin and insulin resistance was hampered in individuals receiving carnosine compared to placebo, and this remained significant after adjustment for age, sex, and change in body weight (P = 0.02, P = 0.04, respectively). Two-hour glucose and insulin were both lower after carnosine supplementation compared to placebo in individuals with impaired glucose tolerance (P < 0.05). These pilot intervention data suggest that carnosine supplementation may be an effective strategy for prevention of type 2 diabetes. © 2016 The Obesity Society.

  13. Integration of ChREBP-Mediated Glucose Sensing into Whole Body Metabolism.

    PubMed

    Baraille, Floriane; Planchais, Julien; Dentin, Renaud; Guilmeau, Sandra; Postic, Catherine

    2015-11-01

    Since glucose is the principal energy source for most cells, many organisms have evolved numerous and sophisticated mechanisms to sense glucose and respond to it appropriately. In this context, cloning of the carbohydrate responsive element binding protein has unraveled a critical molecular link between glucose metabolism and transcriptional reprogramming induced by glucose. In this review, we detail major findings that have advanced our knowledge of glucose sensing.

  14. Glucose metabolism during fasting is altered in experimental porphobilinogen deaminase deficiency.

    PubMed

    Collantes, María; Serrano-Mendioroz, Irantzu; Benito, Marina; Molinet-Dronda, Francisco; Delgado, Mercedes; Vinaixa, María; Sampedro, Ana; Enríquez de Salamanca, Rafael; Prieto, Elena; Pozo, Miguel A; Peñuelas, Iván; Corrales, Fernando J; Barajas, Miguel; Fontanellas, Antonio

    2016-04-01

    Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks when hepatic heme synthesis is activated by endogenous or environmental factors including fasting. While the molecular mechanisms underlying the nutritional regulation of hepatic heme synthesis have been described, glucose homeostasis during fasting is poorly understood in porphyria. Our study aimed to analyse glucose homeostasis and hepatic carbohydrate metabolism during fasting in PBGD-deficient mice. To determine the contribution of hepatic PBGD deficiency to carbohydrate metabolism, AIP mice injected with a PBGD-liver gene delivery vector were included. After a 14 h fasting period, serum and liver metabolomics analyses showed that wild-type mice stimulated hepatic glycogen degradation to maintain glucose homeostasis while AIP livers activated gluconeogenesis and ketogenesis due to their inability to use stored glycogen. The serum of fasted AIP mice showed increased concentrations of insulin and reduced glucagon levels. Specific over-expression of the PBGD protein in the liver tended to normalize circulating insulin and glucagon levels, stimulated hepatic glycogen catabolism and blocked ketone body production. Reduced glucose uptake was observed in the primary somatosensorial brain cortex of fasted AIP mice, which could be reversed by PBGD-liver gene delivery. In conclusion, AIP mice showed a different response to fasting as measured by altered carbohydrate metabolism in the liver and modified glucose consumption in the brain cortex. Glucose homeostasis in fasted AIP mice was efficiently normalized after restoration of PBGD gene expression in the liver. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Increased maternal nighttime cortisol concentrations in late gestation alter glucose and insulin in the neonatal lamb

    PubMed Central

    Antolic, Andrew; Feng, Xiaodi; Wood, Charles E; Richards, Elaine M; Keller-Wood, Maureen

    2015-01-01

    Previous studies in our laboratory have shown that a modest chronic increase in maternal cortisol concentrations impairs maternal glucose metabolism and increases the incidence of perinatal stillbirth. The dramatic outcomes prevented our ability to study the effects of maternal hypercortisolemia on neonatal growth, glucose metabolism, and hypothalamo–pituitary–adrenal axis response. Therefore, we developed a model in which pregnant ewes are infused for 12 h/day at 0.5 mg·kg–1·day–1 from day 115 of gestation until delivery (˜145), elevating nighttime plasma cortisol concentrations. This pattern of elevation of cortisol mimics that in patients with elevated evening cortisol concentrations, as in Cushing’s syndrome or chronic depression. Plasma cortisol, glucose, insulin, and electrolytes were measured during pregnancy and postpartum in control and cortisol-infused ewes and their postnatal lambs for the first 14 days after delivery. Neonatal growth and plasma ACTH, aldosterone, renin activity, and electrolytes, and organ weights at 14 days of age were also measured. Infusion of cortisol increased maternal plasma cortisol during pregnancy but not postpartum, and did not alter neonatal ACTH or cortisol. Although maternal glucose and insulin concentrations were not changed by the maternal infusion of cortisol, neonatal plasma glucose was increased and plasma insulin was decreased compared to those in the control group. Neonatal ponderal index and kidney weight were reduced, left ventricular wall thickness was increased, and plasma sodium and creatinine were increased after maternal cortisol infusion. These results suggest that excess maternal cortisol concentrations in late gestation alter growth, glucose and insulin regulation, and organ maturation in the neonate. PMID:26371232

  16. TAp63 is a master transcriptional regulator of lipid and glucose metabolism

    PubMed Central

    Su, Xiaohua; Gi, Young Jin; Chakravarti, Deepavali; Chan, Io Long; Zhang, Aijun; Xia, Xuefeng; Tsai, Kenneth Y.; Flores, Elsa R.

    2012-01-01

    SUMMARY TAp63 prevents premature aging suggesting a link to genes that regulate longevity. Further characterization of TAp63−/− mice revealed that these mice develop obesity, insulin resistance, and glucose intolerance, similar to those seen in mice lacking two key metabolic regulators, Silent information regulator T1 (Sirt1) and AMPK. While the roles of Sirt1 and AMPK in metabolism have been well studied, their upstream regulators are not well understood. We found that TAp63 is important in regulating energy metabolism by accumulating in response to metabolic stress and transcriptionally activating Sirt1, AMPKα2, and LKB1 resulting in increased fatty acid synthesis and decreased fatty acid oxidation. Moreover, we found that TAp63 lowers blood glucose levels in response to metformin. Restoration of Sirt1, AMPKα2, and LKB1 in TAp63−/− mice rescued some of the metabolic defects of the TAp63−/− mice. Our study defines a role for TAp63 in metabolism and weight control. PMID:23040072

  17. Fatty acid metabolism during maturation affects glucose uptake and is essential to oocyte competence.

    PubMed

    Paczkowski, M; Schoolcraft, W B; Krisher, R L

    2014-10-01

    Fatty acid β-oxidation (FAO) is essential for oocyte maturation in mice. The objective of this study was to determine the effect of etomoxir (a FAO inhibitor; 100 μM), carnitine (1 mM), and palmitic acid (1 or 100 μM) during maturation on metabolism and gene expression of the oocyte and cumulus cells, and subsequent embryo development in the mouse. Carnitine significantly increased embryo development, while there was a decrease in development following maturation with 100 μM palmitic acid or etomoxir (P<0.05) treatment. Glucose consumption per cumulus-oocyte complex (COC) was decreased after treatment with carnitine and increased following etomoxir treatment (P<0.05). Intracellular oocyte lipid content was decreased after carnitine or etomoxir exposure (P<0.05). Abundance of Slc2a1 (Glut1) was increased after etomoxir treatment in the oocyte and cumulus cells (P<0.05), suggesting stimulation of glucose transport and potentially the glycolytic pathway for energy production when FAO is inhibited. Abundance of carnitine palmitoyltransferase 2 (Cpt2) tended to increase in oocytes (P=0.1) after treatment with 100 μM palmitic acid and in cumulus cells after exposure to 1 μM palmitic acid (P=0.07). Combined with carnitine, 1 μM palmitic acid increased the abundance of Acsl3 (P<0.05) and Cpt2 tended to increase (P=0.07) in cumulus cells, suggesting FAO was increased during maturation in response to stimulators and fatty acids. In conclusion, fatty acid and glucose metabolism are related to the mouse COC, as inhibition of FAO increases glucose consumption. Stimulation of FAO decreases glucose consumption and lipid stores, positively affecting subsequent embryo development, while an overabundance of fatty acid or reduced FAO negatively affects oocyte quality.

  18. Effects of chronic noise on glucose metabolism and gut microbiota–host inflammatory homeostasis in rats

    PubMed Central

    Cui, Bo; Gai, Zhihui; She, Xiaojun; Wang, Rui; Xi, Zhuge

    2016-01-01

    Chronic noise exposure has been implicated in increased risk of diabetes. However, there is limited experimental evidence of the mechanisms linking chronic noise stress and glucose metabolism. We addressed this in the present study by examining glucose metabolism, immune response, and changes in gut microbiota/host inflammatory homeostasis in rats exposed to noise for 30 consecutive days. Chronic noise exposure increased blood glucose and corticosterone levels for at least 14 days after cessation of noise. Stressed rats also exhibited elevated levels of glycogen and triglyceride in the liver and impaired hepatic insulin production via insulin-induced insulin receptor/insulin receptor substrate 1/glycogen synthase kinase 3β signalling, which persisted for 3–14 days after cessation of noise exposure. Chronic noise altered the percentage of Proteobacteria and Actinobacteria in the gut, increasing Roseburia but decreasing Faecalibacterium levels in the cecum relative to controls. Immunoglobulin A, interleukin 1β, and tumor necrosis factor α levels were also elevated in the intestine of these animals, corresponding to noise-induced abnormalities in glucose regulation and insulin sensitivity. These results suggest that lifelong environmental noise exposure could have cumulative effects on diabetes onset and development resulting from alterations in gut microbiota composition and intestinal inflammation. PMID:27811997

  19. Xylose-induced dynamic effects on metabolism and gene expression in engineered Saccharomyces cerevisiae in anaerobic glucose-xylose cultures.

    PubMed

    Alff-Tuomala, Susanne; Salusjärvi, Laura; Barth, Dorothee; Oja, Merja; Penttilä, Merja; Pitkänen, Juha-Pekka; Ruohonen, Laura; Jouhten, Paula

    2016-01-01

    Xylose is present with glucose in lignocellulosic streams available for valorisation to biochemicals. Saccharomyces cerevisiae has excellent characteristics as a host for the bioconversion, except that it strongly prefers glucose to xylose, and the co-consumption remains a challenge. Further, since xylose is not a natural substrate of S. cerevisiae, the regulatory response it induces in an engineered strain cannot be expected to have evolved for its utilisation. Xylose-induced effects on metabolism and gene expression during anaerobic growth of an engineered strain of S. cerevisiae on medium containing both glucose and xylose medium were quantified. The gene expression of S. cerevisiae with an XR-XDH pathway for xylose utilisation was analysed throughout the cultivation: at early cultivation times when mainly glucose was metabolised, at times when xylose was co-consumed in the presence of low glucose concentrations, and when glucose had been depleted and only xylose was being consumed. Cultivations on glucose as a sole carbon source were used as a control. Genome-scale dynamic flux balance analysis models were simulated to analyse the metabolic dynamics of S. cerevisiae. The simulations quantitatively estimated xylose-dependent flux dynamics and challenged the utilisation of the metabolic network. A relative increase in xylose utilisation was predicted to induce the bi-directionality of glycolytic flux and a redox challenge even at low glucose concentrations. Remarkably, xylose was observed to specifically delay the glucose-dependent repression of particular genes in mixed glucose-xylose cultures compared to glucose cultures. The delay occurred at a cultivation time when the metabolic flux activities were similar in the both cultures.

  20. [Role of the sweet taste receptor in glucose metabolism: no sweets for diabetes?].

    PubMed

    Nomura, Masatoshi; Kawahara, Yuta

    2015-01-01

    Type 2 diabetes is closely associated with our daily diets and has become a global health problem with increasing number of patients. Maintaining energy homeostasis is essentially required for the treatment of diabetes. Energy metabolism starts with taking in a meal. Nutrients including amino acids, fatty acids and glucose in the digest have been shown to act on the neuroendocrine cells in the gastrointestinal (GI) tract, and thereby play important roles in energy homeostasis. Therefore, the GI tract is now recognized as a sensor system for nutrient signals. Taste receptor type 1 member 2 (T1R2) is known to function as a co-receptor with T1R3 to detect sweet chemicals in the taste buds. It has been proposed that the T1R2/T1R3 receptor complex acts as sweet sensor in the intestine, and plays a pivotal role in sensing sugars and maintaining glucose homeostasis through incretin secretion. To clarify the physiological roles of T1R2 in glucose homeostasis, T1r2-lacZ knock-in/knock-out mice were generated. We found lacZ gene expression in the GI tract where T1r3 expression has been reported. Interestingly, the T1r2-lacZ knock-in mice showed impaired glucose tolerance on oral glucose challenge but not on intraperitoneal injection. However, the fasting glucose level in T1r2-lacZ knock-in mice was comparable to that in wild type mice. These results suggest an important role of the sweet taste receptor system in the intestine when stimulated by glucose. Therefore, the roles of T1R2 will be presented and the mechanism for metabolic homeostasis will be discussed.

  1. Chronic central leptin infusion modulates the glycemia response to insulin administration in male rats through regulation of hepatic glucose metabolism.

    PubMed

    Burgos-Ramos, Emma; Canelles, Sandra; Rodríguez, Amaia; Gómez-Ambrosi, Javier; Frago, Laura M; Chowen, Julie A; Frühbeck, Gema; Argente, Jesús; Barrios, Vicente

    2015-11-05

    Leptin and insulin use overlapping signaling mechanisms to modify hepatic glucose metabolism, which is critical in maintaining normal glycemia. We examined the effect of an increase in central leptin and insulin on hepatic glucose metabolism and its influence on serum glucose levels. Chronic leptin infusion increased serum leptin and reduced hepatic SH-phosphotyrosine phosphatase 1, the association of suppressor of cytokine signaling 3 to the insulin receptor in liver and the rise in glycemia induced by central insulin. Leptin also decreased hepatic phosphoenolpyruvate carboxykinase levels and increased insulin's ability to phosphorylate insulin receptor substrate-1, Akt and glycogen synthase kinase on Ser9 and to stimulate glucose transporter 2 and glycogen levels. Peripheral leptin treatment reproduced some of these changes, but to a lesser extent. Our data indicate that leptin increases the hepatic response to a rise in insulin, suggesting that pharmacological manipulation of leptin targets may be of interest for controlling glycemia. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. Glucose starvation is required for insulin stimulation of glucose uptake and metabolism in cultured microvascular endothelial cells

    SciTech Connect

    Gerritsen, M.E.; Burke, T.M.; Allen, L.A.

    1988-03-01

    In the present study we determined the uptake and disposition of glucose in serum-deprived rabbit coronary microvessel endothelial (RCME) cells. RCME cells exhibited stereospecific hexose uptake inhibited by cytochalasin B. Pretreatment of the RCME cells with potassium cyanide or 2,4-dinitrophenol inhibited 2-deoxyglucose uptake but not 3-O-methylglucose transport. A major proportion (30-60%) of the 2-deoxyglucose present in the RCME cells was not phosphorylated. These two observations suggested that the rate-limiting step in the uptake of 2-deoxyglucose was not transport but rather the phosphorylation of 2-deoxyglucose to 2-deoxyglucose 6-phosphate. When glucose-deprived cells were incubated 2 hr with (U-14C)glucose the disposition of the label was as follows: glycogen 60%, acid-soluble fraction 30%, and lipid less than 5%. In contrast glucose-fed cells exhibited lower overall glucose incorporation, and a slightly different disposition: glycogen 45%, acid-soluble fraction 50%, and lipid 5%. Glucose-deprived RCME cells also exhibited greater basal levels of 2-deoxyglucose uptake compared to glucose-fed cells. RCME cells incubated in the absence of glucose and serum for 16 hr exhibited dose-dependent insulin stimulation of hexose uptake and subsequent metabolism to macromolecules (i.e., glycogen and the acid-soluble fraction). Significant effects of insulin were observed with concentrations as low as 2 x 10(-10) M, well within the physiological range. In contrast, cells preincubated in serum-free culture medium containing 5.5 mM glucose did not exhibit insulin-enhanced hexose uptake or glucose metabolism (even at doses as high as 10(-7) M). These studies indicate that the effects of insulin on rabbit coronary microvascular endothelial cell glucose uptake and metabolism require both serum and glucose deprivation.

  3. Effect of enhanced iron chelation therapy on glucose metabolism in patients with beta-thalassaemia major.

    PubMed

    Farmaki, Kalistheni; Angelopoulos, Nicholas; Anagnostopoulos, George; Gotsis, Efstathios; Rombopoulos, Grigorios; Tolis, George

    2006-08-01

    Recently introduced chelation regimens that combine deferoxamine (DFO) and deferiprone have been shown to have greater efficacy in promoting iron excretion than either chelator alone and have been associated with rapid reduction of the iron load in the heart and liver, and with reversal of cardiac dysfunction. It is unclear whether this combined therapy could be associated with a reduction in iron load or decline in the severity of iron-induced endocrinopathies. Starting in January 2001, 42 patients with beta-thalassaemia major, previously maintained on subcutaneous DFO only, were switched to combined treatment with DFO and deferiprone. The primary endpoint was to investigate the effects of this therapy on the glucose metabolism characteristics of this population. Combination therapy markedly decreased ferritin levels (638 +/- 1345 vs. 2991 +/- 2093 microg/l, P < 0.001). Glucose responses were improved at all times during an oral glucose tolerance test, particularly in patients in early stages of glucose intolerance. Glucose quantitative secretion also decreased significantly with combined therapy, while no significant change occurred in insulin levels in any group. Insulin secretion, according to the homeostasis assessment model, markedly increased in all groups, while overall reduction in insulin sensitivity did not reach statistical significance. This study showed that the combination of DFO and deferiprone was associated with an improvement in liver iron deposition and glucose intolerance.

  4. [Comparative characteristics of glucose metabolism in the liver of rats under acute alcohol and morphine intoxication].

    PubMed

    Lelevich, S V

    2011-01-01

    The comparative analysis effect of acute alcohol and morphine intoxications on rats on hepatic glycolysis and pentose phosphate pathway was done. The dose-dependent inhibitory effect of ethanol on activity of limiting enzymes of these metabolic ways, as well as anaerobic reorientation of glucose metabolism was recognised with the increase of the dose of the intake alcohol. Morfine (10 mg/kg) activated enymes of glycolysis and pentose phosphate pathway, but in contrast to ethanol it did not influence these parameters at the dose 20 or 40 mg/kg.

  5. Correlations between magnetic resonance spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy

    PubMed Central

    Weissenborn, Karin; Ahl, Björn; Fischer‐Wasels, Daniela; van den Hoff, Joerg; Hecker, Hartmut; Burchert, Wolfgang; Köstler, Herbert

    2007-01-01

    Background Hepatic encephalopathy is considered to be mainly caused by increased ammonia metabolism of the brain. If this hypothesis is true, cerebral glucose utilisation, which is considered to represent brain function, should be closely related to cerebral ammonia metabolism. The aim of the present study was to analyse whether cerebral ammonia and glucose metabolism in cirrhotic patients with early grades of hepatic encephalopathy are as closely related as could be expected from current hypotheses on hepatic encephalopathy. Methods 13N‐ammonia and 18F‐fluorodesoxyglucose positron emission tomography, magnetic resonance imaging and magnetic resonance spectroscopy (MRS) were performed in 21 cirrhotic patients with grade 0–1 hepatic encephalopathy. Quantitative values of cerebral ammonia uptake and retention rate and glucose utilisation were derived for several regions of interest and were correlated with the MRS data of the basal ganglia, white matter and frontal cortex. Results A significant correlation between plasma ammonia levels and cerebral ammonia metabolism, respectively, and MRS alterations could be shown only for white matter. In contrast, MRS alterations in all three regions studied were significantly correlated with the glucose utilisation of several brain regions. Cerebral ammonia and glucose metabolism were not correlated. Conclusion Increase of cerebral ammonia metabolism is an important but not exclusive causal factor for the development of hepatic encephalopathy. PMID:17660226

  6. Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism.

    PubMed

    Wartchow, Krista Minéia; Tramontina, Ana Carolina; de Souza, Daniela F; Biasibetti, Regina; Bobermin, Larissa D; Gonçalves, Carlos-Alberto

    2016-06-01

    Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B.

  7. Changes in Glucose and Glutamine Lymphocyte Metabolisms Induced by Type I Interferon α

    PubMed Central

    Navarro, Francisco; Bacurau, Aline V. N.; Vanzelli, Andréa; Meneguello-Coutinho, Marcela; Uchida, Marco C.; Moraes, Milton R.; Almeida, Sandro S.; Wasinski, Frederick; Barros, Carlos C.; Würtele, Martin; Araújo, Ronaldo C.; Costa Rosa, Luís F. B.; Bacurau, Reury F. P.

    2010-01-01

    In lymphocytes (LY), the well-documented antiproliferative effects of IFN-α are associated with inhibition of protein synthesis, decreased amino acid incorporation, and cell cycle arrest. However, the effects of this cytokine on the metabolism of glucose and glutamine in these cells have not been well investigated. Thus, mesenteric and spleen LY of male Wistar rats were cultured in the presence or absence of IFN-α, and the changes on glucose and glutamine metabolisms were investigated. The reduced proliferation of mesenteric LY was accompanied by a reduction in glucose total consumption (35%), aerobic glucose metabolism (55%), maximal activity of glucose-6-phosphate dehydrogenase (49%), citrate synthase activity (34%), total glutamine consumption (30%), aerobic glutamine consumption (20.3%) and glutaminase activity (56%). In LY isolated from spleen, IFNα also reduced the proliferation and impaired metabolism. These data demonstrate that in LY, the antiproliferative effects of IFNα are associated with a reduction in glucose and glutamine metabolisms. PMID:21234393

  8. Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model.

    PubMed

    Zou, JiangHuan; Xiong, XiWen; Lai, BeiBei; Sun, Min; Tu, Xin; Gao, Xiang

    2015-04-01

    Bone was reported as a crucial organ for regulating glucose homeostasis. In this study, we found that Phex mutant mice (PUG), a model of human X-linked hypophosphatemic rickets (XLH), displayed metabolic abnormality in addition to abnormal phosphate homeostasis, skeletal deformity and growth retardation. Glucose tolerance was elevated with enhanced insulin sensitivity in PUG, though circulating insulin level decreased. Interestingly, bone mineral density defects and glucose metabolic abnormality were both rescued by adding phosphorus- and calcium-enriched supplements in daily diet. Serum insulin level, glucose tolerance and insulin sensitivity showed no differences between PUG and wild-type mice with rescued osteocalcin (OCN) following treatment. Our study suggested that OCN is a potential mediator between mineral homeostasis and glucose metabolism. This investigation brings a new perspective on glucose metabolism regulation through skeleton triggered mineral homeostasis and provides new clues in clinical therapeutics of potential metabolic disorders in XLH patients.

  9. Ameliorating effect of chromium administration on hepatic glucose metabolism in streptozotocin-induced experimental diabetes.

    PubMed

    Sundaram, Bhuvaneshwari; Singhal, Kirti; Sandhir, Rajat

    2012-01-01

    Chromium has been recognized as an essential trace element that plays an important role in carbohydrate metabolism. However, the molecular mechanisms involved in its action are not clear. This study was undertaken to understand the mechanism of chromium action in experimental diabetes. Streptozotocin-induced diabetic animals were administered chromium as chromium picolinate (CrP) at a daily dose of 1 mg/kg body weight for a period of 4 weeks. It was observed that chromium complexed with picolinate was effective in lowering plasma glucose levels as well as was able to alleviate polyphagia, polydipsia, and weight loss in diabetic animals. Administration of chromium was also found to normalize glycogen content in liver of diabetic animals to near control levels. The reduction in plasma glucose levels by chromium was accompanied by increase in activity of glycolytic enzymes (e.g., glucokinase, phosphofructokinase, and pyruvate kinase) and by suppression in activity of gluconeogenic enzymes (e.g., glucose-6-phosphatase and phosphoenolpyruvate carboxykinase) in liver. Hepatic glucose uptake was found to be increased by chromium supplementation as demonstrated by decrease in Km and increase in Vmax values in diabetic animals. Chromium levels were lower in the liver of diabetic rats when compared with that of control rats. A negative correlation was observed between plasma glucose and chromium concentration in patients with diabetes. The data suggests that chromium supplementation as CrP is beneficial in correcting hyperglycemia, implying that the modulation of the glucose metabolism by chromium may be therapeutically beneficial in the treatment of diabetes.

  10. Physiologic action of glucagon on liver glucose metabolism

    PubMed Central

    Ramnanan, C. J.; Edgerton, D. S.; Kraft, G.; Cherrington, A. D.

    2017-01-01

    Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion. PMID:21824265

  11. [Analysis of the influence of iron overload in glucose metabolism in thalassemia major patients].

    PubMed

    Liang, L Y; Lao, W Q; Meng, Z; Zhang, L N; Hou, L L; Ou, H; Liu, Z L; He, Z W; Luo, X Y; Fang, J P

    2017-06-02

    Objective: This study aimed at determining the characteristics of the glucose homeostasis and its relationship with iron overload of the patients with β-thalassemia major (β-TM). Method: From Sun Yat-sen Memorial Hospital between January 2014 and December 2015, a total of 57 transfusion-dependent β-TM patients with 5-18 years old were enrolled in this study and fasting blood glucose(FBG) and insulin level, serum ferritin (SF), serum iron, transferrin, total iron binding capacity, unsaturated iron binding capacity were determined.Insulin resistance index (IRI), insulin sensitivity index and β-cell function index (BFI) were also estimated. Besides, in 36 patients cardiac T2* and liver T2* were estimated. Result: (1) Four patients(7%) with β-TM were diagnosed diabetes mellitus, and 14(24%) had impaired fasting glucose. (2) The incidence of abnormal glucose metabolism was significantly different according to levels of SF and degrees of the cardiac iron overload(χ(2)=9.737, P<0.05; χ(2)=17.027, P<0.05). It rose while the level of SF increased and the degree of cardiac iron overload aggravated. (3) The incidence of abnormal glucose level was not significantly different in cases with different degree of liver iron overload.The severe group of liver iron overload had significantly higher levels of INS, HOMA-βFI, HOMA-ISI, HOMA-βFI than the non-severe group (Z=-2.434, -2.515, F=8.658, all P<0.05), while no differences were found in the level of FBG, HOMA-βFI between two groups. (4) The result of logistic regression analysis indicated that the cardiac T2* was a significant predictor for the incidence of abnormal glucose metabolism in TM patients (P=0.035, OR=1.182%, 95%CI=1.048 to 1.332). Conclusion: The high prevalence of abnormal glucose metabolism in β-TM patients was mainly closely related with the internal iron overload, especially in organs.The cardiac T2* was an independent risk factor for the incidence of abnormal glucose metabolism in TM patients.

  12. Antilipolytic drug boosts glucose metabolism in prostate cancer.

    PubMed

    Andersen, Kim Francis; Divilov, Vadim; Koziorowski, Jacek; Pillarsetty, NagaVaraKishore; Lewis, Jason S

    2013-05-01

    The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts. Subcutaneous tumors were produced in nude mice by injection of PC3 and CWR22Rv1 PCa cells. The mice were divided into two groups (Acipimox vs. controls). Acipimox (50mg/kg) was administered by oral gavage 1h before injection of tracers. 1h after i.v. co-injection of 8.2MBq (222 ± 6.0 μCi) (18)F-FDG and~0.0037 MBq (0.1 μCi) (14)C-acetate, (18)F-FDG imaging was performed using a small-animal PET scanner. Counting rates in reconstructed images were converted to activity concentrations. Quantification was obtained by region-of-interest analysis using dedicated software. The mice were euthanized, and blood samples and organs were harvested. (18)F radioactivity was measured in a calibrated γ-counter using a dynamic counting window and decay correction. (14)C radioactivity was determined by liquid scintillation counting using external standard quench corrections. Counts were converted into activity, and percentage of the injected dose per gram (%ID/g) tissue was calculated. FDG biodistribution data in mice with PC3 xenografts demonstrated doubled average %ID/g tumor tissue after administration of Acipimox compared to controls (7.21 ± 1.93 vs. 3.59 ± 1.35, P=0.02). Tumor-to-organ ratios were generally higher in mice treated with Acipimox. This was supported by PET imaging data, both semi-quantitatively (mean tumor FDG uptake) and visually (tumor-to-background ratios). In mice with CWR22Rv1 xenografts there was no effect of Acipimox on FDG uptake, either in biodistribution or PET imaging. (14)C-acetate uptake was unaffected in PC3 and CWR22Rv1 xenografts. In mice with PC3 PCa xenografts, acute administration of Acipimox increases tumor uptake of (18)F-FDG with general improvements in tumor-to-background ratios. Data

  13. Microglia, amyloid, and glucose metabolism in Parkinson's disease with and without dementia.

    PubMed

    Edison, Paul; Ahmed, Imtiaz; Fan, Zhen; Hinz, Rainer; Gelosa, Giorgio; Ray Chaudhuri, K; Walker, Zuzana; Turkheimer, Federico E; Brooks, David J

    2013-05-01

    [(11)C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [(11)C]PIB-PET is a marker of amyloid, while [(18)F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [(11)C](R)PK11195, [(18)F]FDG, and [(11)C]PIB PET scans. Parametric maps of [(11)C](R)PK11195 binding potential, rCMRGlc, and [(11)C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [(11)C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression.

  14. Microglia, Amyloid, and Glucose Metabolism in Parkinson's Disease with and without Dementia

    PubMed Central

    Edison, Paul; Ahmed, Imtiaz; Fan, Zhen; Hinz, Rainer; Gelosa, Giorgio; Ray Chaudhuri, K; Walker, Zuzana; Turkheimer, Federico E; Brooks, David J

    2013-01-01

    [11C](R)PK11195-PET measures upregulation of translocator protein, which is associated with microglial activation, [11C]PIB-PET is a marker of amyloid, while [18F]FDG-PET measures cerebral glucose metabolism (rCMRGlc). We hypothesize that microglial activation is an early event in the Parkinson's disease (PD) spectrum and is independent of the amyloid pathology. The aim of this study is to evaluate in vivo the relationship between microglial activation, amyloid deposition, and glucose metabolism in Parkinson's disease dementia (PDD) and PD subjects without dementia. Here, we evaluated 11 PDD subjects, 8 PD subjects without dementia, and 24 control subjects. Subjects underwent T1 and T2 MRI, [11C](R)PK11195, [18F]FDG, and [11C]PIB PET scans. Parametric maps of [11C](R)PK11195 binding potential, rCMRGlc, and [11C]PIB uptake were interrogated using region of interest and SPM (statistical parametric mapping) analysis. The PDD patients showed a significant increase of microglial activation in anterior and posterior cingulate, striatum, frontal, temporal, parietal, and occipital cortical regions compared with the controls. The PD subjects also showed a statistically significant increase in microglial activation in temporal, parietal, and occipital regions. [11C]PIB uptake was marginally increased in PDD and PD. There was a significant reduction in glucose metabolism in PDD and PD. We have also demonstrated pixel-by-pixel correlation between mini-mental state examination (MMSE) score and microglial activation, and MMSE score and rCMRGlc. In conclusion, we have demonstrated that cortical microglial activation and reduced glucose metabolism can be detected early on in this disease spectrum. Significant microglial activation may be a factor in driving the disease process in PDD. Given this, agents that affect microglial activation could have an influence on disease progression. PMID:23303049

  15. Type 2 Diabetes and Breast Cancer: The Interplay between Impaired Glucose Metabolism and Oxidant Stress

    PubMed Central

    Ferroni, Patrizia; Riondino, Silvia; Buonomo, Oreste; Palmirotta, Raffaele; Guadagni, Fiorella; Roselli, Mario

    2015-01-01

    Metabolic disorders, especially type 2 diabetes and its associated complications, represent a growing public health problem. Epidemiological findings indicate a close relationship between diabetes and many types of cancer (including breast cancer risk), which regards not only the dysmetabolic condition, but also its underlying risk factors and therapeutic interventions. This review discusses the advances in understanding of the mechanisms linking metabolic disorders and breast cancer. Among the proposed mechanisms to explain such an association, a major role is played by the dysregulated glucose metabolism, which concurs with a chronic proinflammatory condition and an associated oxidative stress to promote tumour initiation and progression. As regards the altered glucose metabolism, hyperinsulinaemia, both endogenous due to insulin-resistance and drug-induced, appears to promote tumour cell growth through the involvement of innate immune activation, platelet activation, increased reactive oxygen species, exposure to protumorigenic and proangiogenic cytokines, and increased substrate availability to neoplastic cells. In this context, understanding the relationship between metabolic disorders and cancer is becoming imperative, and an accurate analysis of these associations could be used to identify biomarkers able to predict disease risk and/or prognosis and to help in the choice of proper evidence-based diagnostic and therapeutic protocols. PMID:26171112

  16. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

    PubMed

    Muoio, Deborah M; Noland, Robert C; Kovalik, Jean-Paul; Seiler, Sarah E; Davies, Michael N; DeBalsi, Karen L; Ilkayeva, Olga R; Stevens, Robert D; Kheterpal, Indu; Zhang, Jingying; Covington, Jeffrey D; Bajpeyi, Sudip; Ravussin, Eric; Kraus, William; Koves, Timothy R; Mynatt, Randall L

    2012-05-02

    The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.

  17. Kinetics of metabolism of glucose, propionate and CO2 in steers as affected by injecting phlorizin and feeding propionate

    SciTech Connect

    Veenhuizen, J.J.; Russell, R.W.; Young, J.W.

    1988-11-01

    Effects of injecting phlorizin subcutaneously and/or feeding propionate on metabolism of glucose, propionate and CO2 were determined for four steers used in a 4 x 4 Latin square design. Isotope dilution techniques were used to determine a four-pool kinetic solution for the flux of carbon among plasma glucose, rumen propionate, blood CO2 and rumen CO2. Injecting 1 g of phlorizin twice daily for 19 d resulted in 7.1 mol glucose C/d being excreted in urine. The basal glucose production of 13.4 mol C/d was increased to 17.9 mol C/d with phlorizin. There was no change in glucose oxidation or propionate production. The percentage of plasma glucose derived from propionate was unaffected by phlorizin, but 54 +/- 0.4% of total propionate was converted to plasma glucose during phlorizin treatment versus 40 +/- 0.6% during the basal treatment. When propionate was fed (18.3 mol C/d) glucose production increased to 21.2 mol C/d from the basal value of 13.4 mol C/d, and propionate oxidation to CO2 increased to 14.9 mol C/d from the basal value of 4.1 mol C/d. Glucose derived from propionate was 43 +/- 5% for the basal treatment and 67 +/- 3% during propionate feeding. The percentage of propionate converted to plasma glucose and blood and rumen CO2 was not affected by feeding propionate. An increased need for glucose, because of glucose excretion during phlorizin treatment, caused an increased utilization of propionate for gluconeogenesis, but an increased availability of propionate caused an increase in glucose production without affecting the relative distribution of carbon from propionate.

  18. Plasma triglycerides after oral glucose load specifically associate with metabolic risk markers in healthy type 2 diabetes offspring.

    PubMed

    Vossen, Michaela; Tödter, Klaus; Altenburg, Christiane; Beisiegel, Ulrike; Scheja, Ludger

    2011-07-01

    To assess the potential of plasma triglycerides measured after glucose load as biomarker for insulin resistance and cardiovascular risk. An oral glucose tolerance test (OGTT, n=91) was performed in healthy type 2 diabetes offspring. Plasma lipids, lipoproteins, glucose and hormones were quantified in fasting and post-challenge samples. During the OGTT total plasma triglycerides decreased in most subjects, however, they increased in some individuals and this increase was strongly associated with metabolic risk factors. Subjects with increasing triglycerides (n=18) were more obese and insulin resistant than those with the most pronounced triglyceride decrease (n=18), as indicated by higher HOMA-IR, BMI and waist circumference. Correlation analysis (n=91) demonstrated that the changes of total plasma and VLDL-associated triglycerides between 0 h and 2 h (Δ-TG, Δ-VLDL-T) were strongly associated with risk factors. Δ-TG, and especially Δ-VLDL-T, correlated better than fasting triglycerides with waist circumference, waist-to-hip ratio and fasting glucose. The correlations remained significant after adjustment for gender, age and HDL cholesterol. The observed increase of triglycerides after glucose load in subjects with signs of insulin resistance and obesity suggests that post-glucose triglyceride change is a potential novel biomarker for early detection of metabolic risk. The specific association of post-glucose triglyceride change with abdominal obesity and fasting glucose suggests a link to hepatic steatosis and insulin resistance. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Tumor glucose metabolism imaged in vivo in small animals with whole-body photoacoustic computed tomography.

    PubMed

    Chatni, Muhammad Rameez; Xia, Jun; Sohn, Rebecca; Maslov, Konstantin; Guo, Zijian; Zhang, Yu; Wang, Kun; Xia, Younan; Anastasio, Mark; Arbeit, Jeffrey; Wang, Lihong V

    2012-07-01

    With the increasing use of small animals for human disease studies, small-animal whole-body molecular imaging plays an important role in biomedical research. Currently, none of the existing imaging modalities can provide both anatomical and glucose molecular information, leading to higher costs of building dual-modality systems. Even with image co-registration, the spatial resolution of the molecular imaging modality is not improved. Utilizing a ring-shaped confocal photoacoustic computed tomography system, we demonstrate, for the first time, that both anatomy and glucose uptake can be imaged in a single modality. Anatomy was imaged with the endogenous hemoglobin contrast, and glucose metabolism was imaged with a near-infrared dye-labeled 2-deoxyglucose.

  20. Tumor glucose metabolism imaged in vivo in small animals with whole-body photoacoustic computed tomography

    NASA Astrophysics Data System (ADS)

    Chatni, Muhammad Rameez; Xia, Jun; Sohn, Rebecca; Maslov, Konstantin; Guo, Zijian; Zhang, Yu; Wang, Kun; Xia, Younan; Anastasio, Mark; Arbeit, Jeffrey; Wang, Lihong V.

    2012-07-01

    With the increasing use of small animals for human disease studies, small-animal whole-body molecular imaging plays an important role in biomedical research. Currently, none of the existing imaging modalities can provide both anatomical and glucose molecular information, leading to higher costs of building dual-modality systems. Even with image co-registration, the spatial resolution of the molecular imaging modality is not improved. Utilizing a ring-shaped confocal photoacoustic computed tomography system, we demonstrate, for the first time, that both anatomy and glucose uptake can be imaged in a single modality. Anatomy was imaged with the endogenous hemoglobin contrast, and glucose metabolism was imaged with a near-infrared dye-labeled 2-deoxyglucose.

  1. [The synergistic effect of FGF-21 and insulin on regulating glucose metabolism and its mechanism].

    PubMed

    Yu, Dan; Sun, Cui-Yu; Sun, Guo-Peng; Ren, Gui-Ping; Ye, Xian-Long; Zhu, Sheng-Long; Wang, Wen-Fei; Xu, Peng-Fei; Li, Shu-Jie; Wu, Qiang; Niu, Ze-Shan; Sun, Tian; Liu, Ming-Yao; Li, De-Shan

    2014-07-01

    Previous studies proposed that the synergistic effect of fibroblast growth factor-21 (FGF-21) and insulin may be due to the improvement of insulin sensitivity by FGF-21. However, there is no experimental evidence to support this. This study was designed to elucidate the mechanism of synergistic effect of FGF-21 and insulin in the regulation of glucose metabolism. The synergistic effect of FGF-21 and insulin on regulating glucose metabolism was demonstrated by investigating the glucose absorption rate by insulin resistance HepG2 cell model and the blood glucose chances in type 2 diabetic db/db mice after treatments with different concentrations of FGF-21 or/and insulin; The synergistic metabolism was revealed through detecting GLUT1 and GLUT4 transcription levels in the liver by real-time PCR method. The experimental results showed that FGF-21 and insulin have a synergistic effect on the regulation of glucose metabolism. The results of real-time PCR showed that the effective dose of FGF-21 could up-regulate the transcription level of GLUT1 in a dose-dependent manner, but had no effect on the transcription level of GLUT4. Insulin (4 u) alone could up-regulate the transcription level of GLUT4, yet had no effect on that of GLUT1. Ineffective dose 0.1 mg kg(-1) FGF-21 alone could not change the transcription level of GLUT1 or GLUT4. However, when the ineffective dose 0.1 mg x kg(-1) FGF-21 was used in combination with insulin (4 u) significantly increased the transcription levels of both GLUT1 and GLUT4, the transcription level of GLUT1 was similar to that treated with 5 time concentration of FGF-21 alone; the transcription level of GLUT4 is higher than that treated with insulin (4 u) alone. In summary, in the presence of FGF-21, insulin increases the sensitivity of FGF-21 through enhancing GLUT1 transcription. Vice versa, FGF-21 increases the sensitivity of insulin by stimulating GLUT4 transcription in the presence of insulin. FGF-21 and insulin exert a synergistic

  2. In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake.

    PubMed

    Gorres, Brittany K; Bomhoff, Gregory L; Morris, Jill K; Geiger, Paige C

    2011-04-15

    Previous studies suggest oestrogen receptor α (ERα) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERα modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERα activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg⁻¹), oestradiol benzoate (EB; 20 μg kg⁻¹), the ERβ agonist diarylpropionitrile (DPN, 10 mg kg⁻¹) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting.Ac