Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously found that long-term exposure to fatty acids impairs glucose-induced insulin release. In the present study, we investigated whether impairment is related to decreased pyruvate dehydrogenase (PDH) and increased PDH kinase activity. Rat pancreatic islets were cultured for 48 h in RPMI-1640 medium with or without 0.125 mmol/l palmitate. Potentiation of insulin responses to succinic acid monomethylester (SAM) by 10 mmol/l acetate and pyruvate were subsequently compared in order to assess whether generation of acetyl-coenzyme A (CoA) from pyruvate was deficient in the intact beta-cell. Potentiation by acetate was similar in control and palmitate-preexposed islets. In contrast, pyruvate potentiated SAM-induced response by 122% in control but by only 39% in palmitate-exposed islets (P < 0.001). In extracts of palmitate-exposed islets, the active (unphosphorylated) form of PDH was decreased by 50% and total PDH activity (assessed after phosphatase treatment) by 25%. The proportion of active form to total PDH activity was also reduced (42.7 +/- 2.6% after palmitate vs. 66.6 +/- 4.3% in control islets, P < 0.01). In the same preparations, PDH kinase activity was enhanced 1.7-fold by palmitate in terms of the rate constant of ATP-dependent inactivation of PDH (P < 0.05). To test for a role of free (not PDH-bound) kinase, a PDH-free mitochondrial fraction was prepared, and its kinase activity was tested against a pig heart PDH preparation. Free kinase activity was increased 1.9-fold in palmitate-treated islets (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Palmitate-induced beta-cell insensitivity to glucose is coupled to decreased pyruvate dehydrogenase activity and enhanced kinase activity in rat pancreatic islets. 769 6

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity. Human islets were obtained from the beta-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/L palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/L glucose) inhibited the postculture insulin response to 27 mmol/L glucose by 40% and 42% (P < 0.01 for difference). Inhibition was partly prevented by coculture with 1 mumol/L etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P < 0.05 for effect of etomoxir). Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/L). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 mumol/L added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P < 0.01). These effects were partly prevented by etomoxir (P < 0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P < 0.05) vs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P < 0.05). The effects of ketones were tested by 48-h exposure to beta-hydroxybutyrate (beta-D-OHB). Ten millimoles of D-beta-OHB per L inhibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P < 0.001). Half-maximal inhibitory effects of D-beta-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/L. Inhibition by D-beta-OHB was partially reversed by etomoxir, whereas exposure to D-beta-OHB failed to affect PDH and PDH kinase activities. We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in both type 1 and type 2 diabetes.
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PMID:Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans. 774 4

This review examines the molecular mechanisms underlying substrate competition between glucose and lipid in starvation and in insulin-resistant states. We demonstrate that lipid-derived substrates are oxidized in preference to glucose by skeletal muscle in vivo during prolonged starvation. An accelerated and exaggerated lipolytic and ketogenic response to starvation in late pregnancy is associated with more rapid suppression of glucose oxidation by the maternal skeletal-muscle mass. These benign adaptations to changes in lipid availability (which occur secondarily to changes in carbohydrate supply and demand) contrast with the well-documented detrimental effects to health of an inappropriately high supply of dietary lipid. We present results that indicate that the prolonged consumption of a diet high in saturated fat is associated with a stable enhancement of pyruvate dehydrogenase (PDH) kinase activity at least in two oxidative tissues--liver and heart. This long-term enhancement of PDH kinase activity is concomitant with the development of whole-body insulin resistance and adds a new dimension to the potential role of dietary composition in the pathogenesis of insulin resistance.
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PMID:The pyruvate dehydrogenase complex: nutrient control and the pathogenesis of insulin resistance. 778 39

The Glucose Fatty Acid Cycle as formulated 30 years ago and reviewed in the Minkowski lecture in 1966 described short term effects of fatty acids (minutes) to decrease uptake, glycolysis and oxidation of glucose in heart and skeletal muscles. Such short term effects have since been extended to include inhibition of glucose uptake and glycolysis and stimulation of gluconeogenesis in liver and these effects have also been convincingly demonstrated in man in vivo. More recently a longer term effect of fatty acid metabolism to decrease glucose oxidation (hours) has been shown in heart and skeletal muscle and liver. This effect increases the specific activity of pyruvate dehydrogenase kinase, which in turn results in enhanced phosphorylation and inactivation of the pyruvate dehydrogenase complex. Activity of the pyruvate dehydrogenase complex is the major determinant of glucose oxidation rate. It seems likely that longer term effects of fatty acids on this and other aspects of glucose metabolism could be important in the development of insulin resistance in diabetes mellitus in man.
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PMID:Mechanisms modifying glucose oxidation in diabetes mellitus. 782 31

Glucose is essential for the energy metabolism of some cells and conservation of glucose is obligatory for survival during starvation. The principal site of this glucose conservation is the mitochondrial pyruvate dehydrogenase (PDH) complex, which is regulated by reversible phosphorylation (phosphorylation is inactivating). In cells in which glucose oxidation is switched off during starvation, fatty acids are used as fuel, and acetyl CoA and NADH formed by beta-oxidation promote phosphorylation of PDH complex by activation of PDH kinase. A longer-term mechanism further increases PDH kinase activity in response to cAMP and products of beta-oxidation of fatty acids. Coordinated inhibition of glycolytic flux mediated by effects of citrate on PFK1 and PFK2 in muscles and liver results in an associated inhibition of glucose uptake. Similar mechanisms lead to impaired glucose oxidation in diabetes.
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PMID:Glucose fatty acid interactions and the regulation of glucose disposal. 792 13

In this review, we evaluate the relative regulatory importance of specific strategic enzymes (in particular glycogen synthase, acetyl-CoA carboxylase [ACC] and the pyruvate dehydrogenase complex [PDH]) for carbohydrate utilization as an anabolic precursor and as an energy substrate during the nutritional transitions between the fed and fasted states. The involvement of the specific protein kinases contributing to the inactivation of these enzymes by phosphorylation [cyclic AMP-dependent protein kinase, AMP-activated protein kinase and PDH kinase] in achieving each regulatory response is also assessed. We demonstrate a striking temporal correlation between hepatic glycogen mobilization and PDH and ACC inactivation by phosphorylation during the immediate postabsorptive period; in contrast, rates of hepatic glycogen synthesis and PDH and ACC expressed activities do not change in parallel during refeeding. The results are consistent with shifting of the primary sites of control for overall hepatic carbon flux during the fed-to-starved and starved-to-fed nutritional transitions achieved, at least in part, by a complex pattern of regulation by protein phosphorylation and metabolites which is critically dependent on the precise nutritional status. Data are also presented that demonstrate asynchronous suppression of glucose uptake/phosphorylation and pyruvate oxidation in cardiac and skeletal muscle during progressive starvation. Analogous asynchrony is observed in the reactivation of these processes in cardiac and skeletal muscle during refeeding after starvation. We provide evidence in support of the concept that selective suppression of pyruvate oxidation in oxidative muscles during early starvation and during the initial phase of refeeding is achieved because of differential sensitivity of glucose uptake/phosphorylation and pyruvate oxidation to lipid-fuel utilization. We discuss the relative importance of regulatory events governing local fatty acid production and utilization (via lipoprotein lipase and carnitine palmitoyltransferase 1, respectively) or overall fatty acid supply (dictated by events at the adipocyte) for fuel utilization by muscle during nutritional transitions. Finally, we assess the regulatory importance of glycogen synthesis in determining overall rates of glucose clearance by skeletal muscle during alimentary hyperglycemia and hyperinsulinemia.
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PMID:Mechanisms involved in the coordinate regulation of strategic enzymes of glucose metabolism. 810 32

The review examines the mechanisms regulating the activities of the two key enzymes determining rates of glucose and fatty acid oxidation, i.e., the pyruvate dehydrogenase (PDH) complex and the carnitine palmitoyltransferase (CPT) system. The review also evaluates the regulatory importance of gene expression in the control of tissue fuel selection within the context of substrate competition between glucose and fatty acids. It identifies a strong indirect input of nutrient-gene interactions in the control of pyruvate oxidation through the regulated provision of pyruvate as a substrate for PDH and as an inhibitor of PDH kinase. Nutrient-gene interactions are also identified in relation to the regulation of CPT I activity by malonyl-CoA (inhibitor) and by the provision of long-chain acyl-CoA (substrate/activator), the latter via the hydrolysis of plasma or tissue triacylglycerol (by lipoprotein lipase and hormone-sensitive lipase, respectively). We discuss how such regulation is reinforced by long-term modulation of PDH kinase-specific activity and CPT I maximal activity. We also explore the role of mechanisms operating at the levels of the PDH complex and the CPT system that act to promote and accelerate a switch in fuel utilization once a committed change in nutrient supply has been established. In particular, we discuss the regulatory influences exerted by altered sensitivities of PDH kinase to inhibition by pyruvate and CPT I to inhibition by malonyl-CoA, respectively.
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PMID:Interactive regulation of the pyruvate dehydrogenase complex and the carnitine palmitoyltransferase system. 829 90

The pyruvate dehydrogenase (PDH) complex undergoes reversible phosphorylation catalyzed by a PDH kinase (inactivating) and a PDH phosphatase (activating). In skeletal muscle, a decreased proportion of active PDH (PDHa) complex limits glucose oxidation in insulin-deficient states. The time-course for reactivation of the PDH complex by insulin in skeletal muscle of diabetic rats is important to understanding the potential mode of the action of insulin in regulating glucose metabolism. A single injection of insulin (1 U/kg) completely reversed the effects of alloxan-diabetes on PDHa activity within 1 hour. The normalization of the effects of diabetes on PDHa activity by insulin was maintained for a minimum of 6 hours. The increase in PDHa activity occurred before an insulin-induced decrease in plasma free fatty acids levels, demonstrating a dissociation between the antilipolytic effects of insulin and its ability to activate the PDH complex. PDH kinase activity was not normalized to control values following a single injection of insulin. Therefore, acute (1 to 6 hours) insulin-mediated activation of the PDH complex does not result from a decrease in PDH kinase activity. However, longer-term insulin therapy (1 U/kg body weight; twice daily) restored both PDHa and PDH kinase activities. The results are consistent with the hypothesis that activation of the PDH complex immediately following insulin administration is not mediated by a decreased PDH kinase activity. However, with daily insulin therapy in diabetes, activation of the PDH complex results from decreased PDH kinase activity.
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PMID:Insulin-induced activation of pyruvate dehydrogenase complex in skeletal muscle of diabetic rats. 849 17

We studied the effects of fatty acid oxidation on insulin secretion of db/db mice and underlying molecular mechanisms of these effects. At 2-3 months of age, db/db mice were markedly obese, hyperglycemic, and hyperinsulinemic. Serum free fatty acid (FFA) levels were increased in 2-month-old (1.5 +/- 0.1 vs. 1.1 +/- 0.1 mmol/l, P < 0.05) and 3-month-old (1.9 +/- 0.1 vs. 1.2 +/- 0.1 mmol/l, P < 0.01) mice compared with the age and sex-matched db/+ mice serving as controls. Glucose-induced insulin release from db/db islets was markedly decreased compared with that from db/+ islets and was specifically ameliorated (by 54% in 2-month-old and 38% in 3-month-old mice) by exposure to a carnitine palmitoyltransferase I inhibitor, etomoxir (1 micromol/l). Etomoxir failed to affect the insulin response to alpha-ketoisocaproate. The effect of etomoxir on glucose-induced insulin release was lost after culturing db/db islets in RPMI medium containing 22 mmol/l glucose but no fatty acid. Culture of db/+ islets with 0.125 mmol/l palmitate led to a decrease in glucose-induced insulin secretion, which was partially reversible by etomoxir. Both islet glucose oxidation and the ratio of glucose oxidation to utilization were decreased in db/db islets. Etomoxir significantly enhanced glucose oxidation by 60% and also the ratio of oxidation to glucose utilization (from 27 +/- 2.5 to 37 +/-3.0%, P < 0.05). Pyruvate dehydrogenase (PDH) activity was decreased in islets of db/db mice (75 +/-4.2 vs. 91 +/- 2.9 nU/ng DNA, P < 0.01), whereas PDH kinase activity was increased (rate of PDH inactivation -0.25 +/- 0.02 vs. - 0.11 +/- 0.02/min, P < 0.0 1). These abnormalities were partly but not wholly reversed by a 2-h preexposure to etomoxir. In conclusion, elevated FFA levels in the db/db mouse diminish glucose-induced insulin secretion by a glucose-fatty acid cycle in which fatty acid oxidation inhibits glucose oxidation by decreasing PDH activity and increasing PDH kinase activities.
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PMID:A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse. 862 Oct 7

Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.
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PMID:Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. 872 66


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