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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
Diabetes 1996 Nov
PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

The enzyme activities of mitochondrial glycerol phosphate dehydrogenase (mGPD) (EC 1.1.99.5) and pyruvate carboxylase (PC) (EC 6.4.1.1) have been reported to be low in the pancreatic islet of several rodent models of NIDDM. The present study was undertaken to discern whether mGPD is abnormal in the Zucker diabetic fatty (ZDF) rat (ZDF/Gmi-fa/fa), an animal model of NIDDM in which insulin secretion is unable to counteract the insulin resistance associated with the obesity that characterizes this model. Experiments were performed in prediabetic 6-week-old ZDF rats in comparison with 12-week-old overtly hyperglycemic animals and, as controls, Zucker lean (ZL) rats (ZDF/Gmi-+/fa or -+/+) and Wistar rats (+/+) of the same ages. The enzyme activity of mGPD was 32 and 18% of normal in islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001 by analysis of variance). The activity of PC, which like mGPD is relatively abundant in the pancreatic islet, was 17 and 10% of normal in the islets of 6- and 12-week-old ZDF rats, respectively (P < 0.001). The activity of mGPD was normal in islets from ZL rats. However, PC activity was slightly lower in islets of 6- (51% of normal, P = 0.007) and 12-week-old (67% of normal, P = 0.01) ZL rats. The amounts of mGPD protein, as judged from Western analysis, and of PC protein, as judged from probing transblots with streptavidin that binds to biotin-containing enzymes, roughly correlated with the enzyme activities. This indicates that the decreased enzyme activities are caused by the decreased net synthesis of these enzymes rather than by the decreased activity of a normal amount of enzyme. The enzyme activity of succinate dehydrogenase, a control for mGPD, was normal in the ZL and ZDF rats. An incidental finding of the current study was the discovery of beta-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase in the islet. Levels of these enzymes were also normal. Although reductions in mGPD and PC may contribute to the abnormal insulin secretion present in overt diabetes, they are modest compared with the severe reductions seen in inherited inborn errors of metabolism. Because of this and because more than a single enzyme is affected and the enzymes in the islet are diminished in more than one rodent model of NIDDM, these reductions are unlikely to represent the primary genetic defect in the ZDF rat. Since ZDF rats are euglycemic at 6 weeks of age and ZL animals are euglycemic throughout life and since these animals demonstrate low enzyme activities, this evidence suggests that it is not hyperglycemia but rather some other component of the diabetic syndrome that is responsible for the reductions in these enzymes.
Diabetes 1996 Nov
PMID:Low mitochondrial glycerol phosphate dehydrogenase and pyruvate carboxylase in pancreatic islets of Zucker diabetic fatty rats. 886 70

The mechanism of inhibition of gluconeogenesis by phenylalkanoic acids was studied in vitro and in vivo. In vitro production of 14CO2 from labeled glucose or palmitate was not inhibited at 4 mM, a concentration of phenylacetic acid that inhibited gluconeogenesis from lactate/pyruvate. In vitro studies with isolated mitochondria showed that the CoA ester of phenylacetic acid was formed. The parent phenylalkanoic acid had no effect on purified pyruvate carboxylase activity, but phenylacetyl CoA ester decreased pyruvate carboxylation in a concentration-dependent manner. Phenylacetic acid inhibited gluconeogenesis in isolated rat liver cells from 10 mM lactate/1 mM pyruvate (decreased 39%, P < 0.05), but not 10 mM L-glutamine or [14C]aspartate, showing that the inhibition of gluconeogenesis occurred at the level of pyruvate carboxylase. A 20 mg bolus with infusion of 1 mg/min of phenylpropionic acid decreased blood glucose levels of normal [110 +/- 12 to 66 +/- 11 mg/dL, N = 7, P < 0.05 (unpaired Student's t-test vs control)] and streptozocin diabetic rats [295 +/- 14 to 225 +/- 12 mg/dL, N = 7, P < 0.01 (paired t-test vs basal)]. Hepatic glucose production in control and diabetic rats was suppressed under conditions where liver glycogen was depleted, indicating that gluconeogenesis had been inhibited in vivo. The results suggest the possibility that the inappropriate overproduction of glucose can be controlled by inhibitors of pyruvate carboxylase. This class of inhibitors may be useful in the treatment of non-insulin-dependent diabetes mellitus.
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PMID:In vitro and in vivo suppression of gluconeogenesis by inhibition of pyruvate carboxylase. 896 65

Pyruvate carboxylase [EC 6.4.1.1] is a member of the family of biotin-dependent carboxylases and is found widely among eukaryotic tissues and in many prokaryotic species. It catalyses the ATP-dependent carboxylation of pyruvate to form oxaloacetate which may be utilised in the synthesis of glucose, fat, some amino acids or their derivatives and several neurotransmitters. Diabetes and hyperthyroidism increase the level of expression of pyruvate carboxylase in the long term, while its activity in the short term is controlled by the intramitochondrial concentrations of acetyl-CoA and pyruvate. Many details of this enzyme's regulation are yet to be described in molecular terms. However, progress towards this goal and towards understanding the relationship of pyruvate carboxylase structure to its catalytic reaction mechanism, has been enormously enhanced recently by the cloning and sequencing of genes and cDNAs encoding the approximately 130 kDa subunit of this homotetramer. Defects in the expression or biotinylation of pyruvate carboxylase in humans almost invariably results in early death or at best a severely debilitating psychomotor retardation, clearly reflecting the vital role it plays in intermediary metabolism in many tissues including the brain.
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PMID:Pyruvate carboxylase. 959 48

To better define the modifications of liver gluconeogenesis and citric acid cycle, or Krebs' cycle, activity induced by insulin deficiency and the effects of metformin on these abnormalities, we infused livers isolated from postabsorptive or starved normal and streptozotocin-induced diabetic rats with pyruvate and lactate (labeled with [3-13C]lactate) with or without the simultaneous infusion of metformin. Lactate and pyruvate uptake and glucose production were calculated. The 13C-labeling pattern of liver glutamate was used to calculate, according to Magnusson's model, the relative fluxes through Krebs' cycle and gluconeogenesis. These relative fluxes were converted into absolute values using substrate balances. In normal rats, starvation increased gluconeogenesis, the flux through pyruvate carboxylase-phosphoenolpyruvate carboxykinase (PC-PEPCK), and the ratio of PC to pyruvate dehydrogenase (PDH) flux (P < 0.05); metformin induced only a moderate decrease in the PC:PDH ratio. Livers from postabsorptive diabetic rats had increased lactate and pyruvate uptakes (P < 0.05); their metabolic fluxes resembled those of starved control livers, with increased gluconeogenesis and flux through PC-PEPCK. Starvation induced no further modifications in the diabetic group. Metformin decreased glucose output from the liver of starved diabetic rats (P < 0.05). The flux through PC-PEPCK and also pyruvate kinase were decreased (P < 0.05) by metformin in both groups of diabetic rats. In conclusion, insulin deficiency increased in this model of diabetes gluconeogenesis through enhanced uptake of substrate and increased flux through PC-PEPCK; metformin decreased glucose production by reducing the flux through PC-PEPCK.
Diabetes 1999 Jun
PMID:Modifications of citric acid cycle activity and gluconeogenesis in streptozotocin-induced diabetes and effects of metformin. 1034 12

The glucose-fatty acid cycle of Randle entails two elements: decreased pyruvate dehydrogenase (PDH) activity, which inhibits glucose oxidation, and inhibition of phosphofructokinase (PFK) by a rise in citrate so that glucose-6-phosphate (G-6-P) levels increase, thereby inhibiting hexokinase activity and hence glucose utilization. Chronic exposure of islets to long-chain fatty acids (FA) is reported to lower PDH activity, but the effect on glucose oxidation and glucose-induced insulin secretion is uncertain. We investigated rat islets that were cultured for 4 days with 0.25 mmol/l oleate/5.5 mmol/l glucose. Glucose oxidation was doubled at 2.8 mmol/l glucose and unchanged at 27.7 mmol/l glucose in the FA-cultured islets despite a 35% decrease in assayed PDH activity. Pyruvate content was increased 60%, which may well compensate for the decreased PDH activity and maintain flux through the citric acid cycle. However, a greater diversion of pyruvate metabolism through the pyruvate-malate shuttle is suggested by unchanged pyruvate carboxylase Vmax and a fourfold higher release of malate from isolated mitochondria. The FA-cultured islets also showed increased basal glucose usage and insulin secretion together with a lowered level of G-6-P and 50% reductions in citrate synthase Vmax and the citrate content. Thus, the effects of chronic FA exposure on islet glucose metabolism differ from the glucose-fatty acid interactions reported in some other tissues.
Diabetes 1999 Sep
PMID:Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets. 1048 Jun 4

The hypothesis proposing that anaplerosis and cataplerosis play an important role in fuel signaling by providing mitochondrially derived coupling factors for stimulation of insulin secretion was tested. A rise in citrate coincided with the initiation of insulin secretion in response to glucose in INS-1 beta-cells. The dose dependence of glucose-stimulated insulin release correlated closely with those of the cellular contents of citrate, malate, and citrate-derived malonyl-CoA. The glucose-induced elevations in citrate, alpha-ketoglutarate, malonyl-CoA, and the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium reduction state, an index of beta-cell metabolic activity, were unaffected by the Ca2+ chelator EGTA. Glucose induced a rise in both mitochondrial and cytosolic citrate and promoted efflux of citrate from the cells. The latter amounted to approximately 20% of glucose carbons entering the glycolytic pathway. Phenylacetic acid, a pyruvate carboxylase inhibitor, reduced the glucose-induced rise in citrate in INS-1 cells and insulin secretion in both INS-1 cells and rat islets. The results indicate the feasibility of a pyruvate/citrate shuttle in INS-1 beta-cells, allowing the regeneration of NAD+ in the cytosol and the formation of cytosolic acetyl-CoA, malonyl-CoA, and NADPH. The data suggest that anaplerosis and cataplerosis are early signaling events in beta-cell activation that do not require a rise in Ca2+. It is proposed that citrate is a signal of fuel abundance that contributes to beta-cell activation in both the mitochondrial and cytosolic compartments and that a major fate of anaplerotic glucose carbons is external citrate.
Diabetes 2000 May
PMID:Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion. 1090 79

Tight glycemic control during diabetic pregnancy has been shown to significantly reduce the occurrence of congenital malformations and other effects of maternal diabetes on the offspring. However, intensive insulin therapy often causes recurring acute maternal hypoglycemia, which has been found to be harmful to the developing fetus, although the mechanisms involved are not clear. The aim of our work was to study the effect of acute insulin-induced maternal hypoglycemia on glucose metabolism in the fetal brain. To this end, near-term pregnant New Zealand rabbits were rendered hypoglycemic, and [U-(13)C]glucose was infused into maternal circulation. The metabolic fate of the (13)C-labeled glucose was then studied in fetal brain extracts by (13)C NMR isotopomer analysis, together with conventional biochemical assays of glucose and lactate levels in both plasma and brain. For comparison [U-(13)C]glucose was also administered to insulin-induced hypoglycemic young adult rabbits. Our results showed that while plasma glucose levels were significantly reduced (approximately 70%) relative to controls, no changes in cerebral glucose levels could be detected. Lactate levels were found to be significantly decreased in hypoglycemic fetal plasma and brain. No differences in lactate levels between control and hypoglycemic young rabbit plasma and brain were observed. These differences were attributed to the utilization of lactate as an energy substrate in the fetal brain, but not in the adult brain. Higher relative (13)C enrichments of most glucose metabolites, except lactate, in the hypoglycemic fetal and young rabbit brains, observed by (13)C NMR, stem from reduced endogenous plasma glucose pools, thereby diluting the labeled glucose to a lower extent. The relative glucose (or glucose-derived lactate) flux via the pyruvate carboxylase and pyruvate dehydrogenase pathways (PC/PDH ratio) was not altered under hypoglycemic conditions in the fetal brain for both glutamine and glutamate, but significantly increased in the adult brain for both glutamine and glutamate. The presented data indicate the ability of the fetal brain to maintain energy metabolism during acute hypoglycemia, via lactate utilization. The increase in the adult PC/PDH ratio was suggested by us to stem from increased PC activity, in order to replenish TCA cycle intermediates.
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PMID:Effect of acute insulin-induced hypoglycemia on fetal versus adult brain fuel utilization, assessed by (13)C MRS isotopomer analysis of [U-(13)C]glucose metabolites. 1111 Nov 61

The neurological consequences of diabetes mellitus have recently been receiving greater attention in both clinical and experimental settings. The deleterious effect of hyperglycemia and altered oxidative substrate availability on the diabetic brain is the subject of many studies. The aim of the present study was to examine the effect of the altered metabolic environment, namely, hyperglycemia and hyperketonemia, on glucose metabolism in the diabetic brain. More specifically, we examined the effect of diabetes on the glucose flux via the pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) pathways and subsequent metabolism in the tricarboxylic acid cycles in neurons and glia. To this end, [U-(13)C]glucose was infused into the circulation of alloxan-induced diabetic young adult rabbits, and the [(13)C]glucose metabolites were subsequently studied in brain extracts by (13)C-NMR. Significantly elevated brain glucose levels were found. In the hyperketonemic rabbits, elevated cerebral levels of beta-hydroxybutyrate (beta-HBA) were found. Alterations in the labeling patterns of glutamine in the hyperketonemic group lead to the conclusion that the elevated beta-HBA levels inhibit glucose metabolism, mostly in glia. This results in accumulation of glucose in the diabetic brain. In addition, altered levels of glutamine, glutamate, and GABA were also attributed to the effect of beta-HBA on brain metabolism. The possible role of these metabolic perturbations in causing neurological damage remains to be investigated.
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PMID:Effect of endogenous beta-hydroxybutyrate on glucose metabolism in the diabetic rabbit brain: a (13)C-magnetic resonance spectroscopy study of [U-(13)C]glucose metabolites. 1128 49

At variance with the current view that only liver and kidney are gluconeogenic organs, because both are the only tissues to express glucose-6-phosphatase (Glc6Pase), we have recently demonstrated that the Glc6Pase gene is expressed in the small intestine in rats and humans and that it is induced in insulinopenic states such as fasting and diabetes. We used a combination of arteriovenous balance and isotopic techniques, reverse transcription-polymerase chain reaction, Northern blot analysis, and enzymatic activity assays. We report that rat small intestine can release neosynthesized glucose in mesenteric blood in insulinopenia, contributing 20-25% of total endogenous glucose production. Like liver glucose production, small intestine glucose production is acutely suppressed by insulin infusion. In the small intestine, glutamine and, to a much lesser extent, glycerol are the precursors of glucose, whereas alanine and lactate are the main precursors in liver. Accounting for these metabolic fluxes: 1) the phosphoenolpyruvate carboxykinase gene (required for the utilization of glutamine) is strongly induced at the mRNA and enzyme levels in insulinopenia; 2) the glycerokinase gene is expressed, but not induced; 3) the pyruvate carboxylase gene (required for the utilization of alanine and lactate) is repressed by 80% at the enzyme level in insulinopenia. These studies identify small intestine as a new insulin-sensitive tissue and a third gluconeogenic organ, possibly involved in the pathophysiology of diabetes.
Diabetes 2001 Apr
PMID:Rat small intestine is an insulin-sensitive gluconeogenic organ. 1128 37


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