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

To determine the effect of insulin-dependent diabetes mellitus (IDDM) on rates and pathways of hepatic glycogen synthesis, as well as flux through hepatic pyruvate dehydrogenase, we used 13C-nuclear magnetic resonance spectroscopy to monitor the peak intensity of the C1 resonance of the glucosyl units of hepatic glycogen, in combination with acetaminophen to sample the hepatic UDP-glucose pool and phenylacetate to sample the hepatic glutamine pool, during a hyperglycemic-hyperinsulinemic clamp using [1-13C]-glucose. Five subjects with poorly controlled IDDM and six age-weight-matched control subjects were clamped at a mean plasma glucose concentration of approximately 9 mM and mean plasma insulin concentrations approximately 400 pM for 5 h. Rates of hepatic glycogen synthesis were similar in both groups (approximately 0.43 +/- 0.09 mumol/ml liver min). However, flux through the indirect pathway of glycogen synthesis (3 carbon units-->-->glycogen) was increased by approximately 50% (P < 0.05), whereas the relative contribution of pyruvate oxidation to TCA cycle flux was decreased by approximately 30% (P < 0.05) in the IDDM subjects compared to the control subjects. These studies demonstrate that patients with poorly controlled insulin-dependent diabetes mellitus have augmented hepatic gluconeogenesis and relative decreased rates of hepatic pyruvate oxidation. These abnormalities are not immediately reversed by normalizing intraportal concentrations of glucose, insulin, and glucagon and may contribute to postprandial hyperglycemia.
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PMID:13C-nuclear magnetic resonance spectroscopy studies of hepatic glucose metabolism in normal subjects and subjects with insulin-dependent diabetes mellitus. 798 93

The diurnal pattern of the activity of the pyruvate dehydrogenase complex (PDHC) was studied in the heart and liver of gold-thioglucose (GTG)-obese mice and age-matched controls. The diurnal pattern of lipogenesis was also measured in the liver. Both lean and obese mice had one main eating period, from 20:00 to 24:00 h. Eating produced no change in serum glucose of control mice but there was a significant rise in serum insulin and triacylglycerols. There was also a 3-fold increase in cardiac PDHC activity and a 3-fold increase in hepatic lipogenesis in the control mice, but little change in hepatic PDHC activity. GTG-obese mice were hyperglycaemic, hyperinsulinaemic and hypertriglyceridaemic at all times studied, with significant increases in these parameters being seen in response to eating. Eating produced little change in cardiac PDHC activity, but there was a 5-fold increase in hepatic PDHC activity, paralleled by a 10-fold increase in hepatic lipogenesis. Hepatic PDHC activity was significantly higher in GTG-obese mice at all times except 16:00 h. The simultaneous rise of hepatic PDHC activity, lipogenesis and serum triacylglycerols in GTG-obese mice suggests an increased utilization of glucose for lipogenesis. The lack of change in heart PDHC activity in GTG-obese mice over 24 h suggests that a general decrease in PDHC activity may contribute to the development of the glucose intolerance and insulin resistance of obesity and non-insulin-dependent diabetes. However, it appears that a different level of metabolic control allows hepatic PDHC activity of the same obese animals to increase in response to hyperinsulinaemia and contribute to the higher rates of lipogenesis seen in obese mice.
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PMID:Diurnal patterns of cardiac and hepatic pyruvate dehydrogenase complex activity in gold-thioglucose-obese mice. 824 Feb 85

A causative factor in the development of diabetes-induced heart dysfunction may be abnormalities in myocardial energy metabolism. Using 13C-NMR spectroscopy, we investigated the effects of experimentally induced diabetes (streptozotocin 65 mg/kg, i.v.) on glucose metabolism and contractile function in the isolated perfused rat heart. Hearts from streptozotocin-treated and untreated control rats were perfused with 11 mM [1-13C]glucose as substrate and 1H-decoupled 13C-spectra recorded for up to 90 min. Incorporation of label from [1-13C]glucose into lactate and glutamate was observed in hearts from control animals, consistent with metabolism through glycolysis and TCA cycle, respectively. Diabetic hearts did not incorporate label into lactate or glutamate. Addition of insulin (0.05 U/ml) to the buffer resulted in the appearance of [3-13C]lactate, although glutamate labeling was not observed. Addition of insulin plus dichloroacetate (2 mM) resulted in incorporation of label from [1-13C]glucose into 2-, 3- and 4-13C-glutamate, indicating glucose entry into the TCA cycle. Addition of insulin, or insulin plus dichloroacetate to control hearts did not alter labeling of either lactate or glutamate. Cardiac function in hearts from the diabetic group was depressed compared to controls and declined significantly over the duration of the experiment. These studies show that concomitant with a decrease in cardiac function, glucose oxidation is profoundly inhibited following the induction of diabetes with streptozotocin. These observations are consistent with a combination of decreased glucose transport and a decrease in pyruvate dehydrogenase activity.
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PMID:A 13C-NMR study of glucose oxidation in the intact functioning rat heart following diabetes-induced cardiomyopathy. 826 54

Maintenance of plasma glucose concentrations within a narrow range despite wide fluctuations in the demand (e.g. vigorous exercise) and supply (e.g. large carbohydrate meals) of glucose results from coordination of factors that regulate glucose release into and removal from the circulation. On a moment-to-moment basis these processes are controlled mainly by insulin and glucagon, whose secretion is reciprocally influenced by the plasma glucose concentration. In the resting postabsorptive state, release of glucose from the liver (equally via glycogenolysis and gluconeogenesis) is the key regulated process. Glycogenolysis depends on the relative activities of glycogen synthase and phosphorylase, the latter being the more important. The activities of fructose-1,6-diphosphatase, phosphoenolpyruvate carboxylkinase and pyruvate dehydrogenase regulate gluconeogenesis, whose main precursors are lactate, glutamine and alanine. In the postprandial state, suppression of liver glucose output and stimulation of skeletal muscle glucose uptake are the most important factors. Glucose disposal by insulin-sensitive tissues is regulated initially at the transport step and the mainly by glycogen synthase, phosphofructokinase and pyruvate dehydrogenase. Hormonally induced changes in intracellular fructose 2,6-bisphosphate concentrations play a key role in muscle glycolytic flux and both glycolytic and gluconeogenic flux in the liver. Under stressful conditions (e.g. hypoglycaemia, trauma, vigorous exercise), increased secretion of other hormones such as adrenaline, cortisol and growth hormone, and increased activity of the sympathetic nervous system, come into play; their actions to increase hepatic glucose output and to suppress tissue glucose uptake are partly mediated by increases in tissue fatty acid oxidation. In diabetes, the most common disorder of glucose homeostasis, fasting hyperglycaemia, results primarily from excessive release of glucose by the liver due to increased gluconeogenesis; postprandial hyperglycaemia results from both impaired suppression of hepatic glucose release and impaired skeletal muscle glucose uptake. These abnormalities are usually due to the combination of impaired insulin secretion and tissue resistance to insulin, the causes of which remain to be determined.
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PMID:Control of glycaemia. 837 4

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

The current study was undertaken to examine the impact that obesity and non-insulin-dependent diabetes mellitus (NIDDM) have on the ability of glucose to stimulate its own uptake and oxidation in muscle. Euglycemic and hyperglycemic clamp experiments were performed with somatostatin infusions so that insulin could be replaced to basal levels or to physiological hyperinsulinemia. Arteriovenous leg balance methods were used to measure the pathways of leg muscle glucose uptake, oxidation, and storage. Percutaneous biopsies of the vastus lateralis muscle were taken to determine the pyruvate dehydrogenase complex or glycogen synthase activities. During basal insulin replacement, obese compared with lean nondiabetic subjects had higher values for glucose uptake, respiratory quotient, and glucose oxidation (all P<0.05) and a higher proportion of leg energy expenditure derived from glucose. Obese NIDD patients had a greater reliance on fat calories than lean diabetics during basal insulin replacement (P< 0.05). Hyperinsulinemia increased leg glucose metabolism (P<0.001) in all groups, but obese NIDD patients were significantly more insulin resistant. Hyperglycemia in NIDDM compensated for insulin resistance to the extent that rates of glucose metabolism were the same as those for nondiabetics studied at euglycemia. When nondiabetics were studied at hyperglycemia matched to the diabetics, the insulin resistance was still readily apparent.
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PMID:Interaction of carbohydrate and fat fuels in human skeletal muscle: impact of obesity and NIDDM. 863 94

The objective of this study was to determine whether a defect in mitochondrial respiratory function accompanies the development of diabetic cardiomyopathy. The hypothesis tested in this study is that a decrease in Ca2+ uptake into mitochondria may prevent the stimulation of Ca(2+)-sensitive matrix dehydrogenases and the rate of ATP synthesis. Streptozotocin (55 mg/kg)-induced diabetic rats were used as a model of insulin-dependent diabetes mellitus. Hearts from 4-wk diabetic rats had basal heart rates and rates of contraction and relaxation similar to control. Isoproterenol caused a similar increase in the rate of contraction in diabetic and control hearts, whereas the peak rate of relaxation was reduced in diabetic hearts. Mitochondrial Ca2+ uptake was reduced in mitochondria from diabetic hearts after 2 wk of diabetes. Na(+)-induced Ca2+ release was unchanged. State 3 respiration rate was depressed in mitochondria from diabetic rats only when the respiration was supported by the substrate of a Ca(2+)-regulated matrix enzyme. The pyruvate dehydrogenase activity was reduced in diabetic mitochondria compared with that of control. It was concluded that mitochondria from diabetic hearts had a decreased capacity to upregulate ATP synthesis via stimulation of Ca(2+)-sensitive matrix dehydrogenases. The impairment in the augmentation of ATP synthesis rate accompanies a decreased rate of relaxation during increased work load.
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PMID:Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart. 876 Jan 75

Acetyl-CoA provision to the synaptoplasmic compartment of cholinergic nerve terminals plays a regulatory role in the synthesis of acetylcholine. The disturbances in glucose utilization and in decarboxylation of the end product of its metabolism pyruvate, are considered to be significant factors causing cholinergic deficits in several diseases of the central nervous system. In this article we review data concerning role of acetyl-CoA in patomechanisms of disturbances of cholinergic metabolism in Alzheimers disease, thiamine deficiency, inherited defects of pyruvate dehydrogenase and diabetes.
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PMID:Disturbances of acetyl-CoA, energy and acetylcholine metabolism in some encephalopathies. 878 93

Different isoenzymes of pyruvate dehydrogenase kinase (PDK) inhibit the mitochondrial pyruvate dehydrogenase complex by phosphorylation of the E1alpha subunit, thus contributing to the regulation of glucose metabolism. By positional cloning in the 7q21.3-q22.1 region linked with insulin resistance and non-insulin-dependent diabetes mellitus in the Pima Indians, we identified a gene encoding an additional human PDK isoform, as evidenced by its amino acid sequence identity (>65%) with other mammalian PDKs, and confirmed by biochemical analyses of the recombinant protein. We performed detailed comparative analyses of the gene, termed PDK4, in insulin-resistant and insulin-sensitive Pima Indians, and detected five DNA variants with comparable frequencies in both subject groups. Using quantitative reverse transcription polymerase chain reaction, we found that the variants identified in the promoter and 5'-untranslated region did not correlate with differences in mRNA level in skeletal muscle and adipose tissue. We conclude that alterations in PDK4 are unlikely to be the molecular basis underlying the observed linkage at 7q21.3-q22.1 in the Pima Indians. Information about the genomic organization and promoter sequences of PDK4 will be useful in studies of other members of this family of mitochondrial protein kinases that are important for the regulation of glucose metabolism.
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PMID:Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. 879 99

The mammalian heart is normally well oxygenated and anaerobic glycolysis is extremely rare except for the production of extra ATP during extreme exercise like a marathon race. Anaerobic glycolysis plays a role when there is a serious impairment in coronary blood flow such as during heart attack and open heart surgery. The control of glycolysis in ischemic myocardial tissue appears to be extremely complex. During aerobic glycolysis, phosphofructokinase is the most important regulatory enzyme that controls the energy requirements of the cell. Under anaerobic conditions, however, glyceraldehyde-3-phosphate dehydrogenase becomes the key enzyme because it responds promptly to any changes in the essential supply of co-factors for oxidation. The conversion of pyruvate to acetyl CoA (aerobic metabolism) involves a series of chain reactions primarily catalyzed by pyruvate dehydrogenase complex which is situated at the cross roads between both aerobic and anaerobic glycolysis. It is important to remember that substrate utilization is carefully controlled by substrate availability. During aerobic metabolism, control mechanisms using fatty acids, lactate and glucose as energy substrates regulate the rate of ATP production according to energy demand. This precise mechanism is upset during ischemia and post-ischemic reperfusion for reasons discussed in this review. The demand for ATP can no longer be met by its supply because of severely reduced anaerobic glycolysis and significantly inhibited beta-oxidation of fatty acids. The impairment of bioenergetics is discussed in the context of several diseases such as cardiomyopathy, heart failure, diabetes, arrhythmias, cardiac surgery, heart-lung transplantation, and also in aging and oxidative stress. The regulation of energy metabolism in preconditioned heart is also discussed. Finally, methods used to preserve energy in ischemic myocardium are summarized and quantitation of the high-energy phosphates is discussed. This review challenges scientists to discover drugs which will stimulate energy supply during myocardial ischemia.
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PMID:Bioenergetics, ischemic contracture and reperfusion injury. 880 94


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