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

1. Previous studies showed that the activation of pyruvate dehydrogenase within intact rat heart mitochondria of pyruvate is much diminished in mitochondria from starved or diabetic animals [see Kerbey, Randle, Cooper, Whitehouse, Pask & Denton (1976) Biochem. J. 154, 327-348]. In the present study, diminished responses to added Ca2+ and ADP were also found in these mitochondria. 2. Starvation or diabetes did not affect the mitochondrial respiratory control ratio of the ATP content. Moreover, starvation and diabetes did not alter the response of the intramitochondrial Ca2+-sensitive enzyme, 2-oxoglutarate dehydrogenase, to changes in the extramitochondrial concentration of Ca2+ and 2-oxoglutarate, thus indicating that there were no appreciable changes in the distribution of Ca2+ and H+ across the mitochondrial inner membrane. 3. Pyruvate, Ca2+ and ADP were found to have synergistic effects on pyruvate dehydrogenase activity, particularly in mitochondria from starved and diabetic rats. 4. The results suggest that the effects of diabetes and starvation on pyruvate dehydrogenase are not brought about by changes in the distribution of these effectors across the mitochondrial inner membrane or by changes in the intrinsic sensitivity of the kinase or phosphatase of the pyruvate dehydrogenase system to pyruvate, Ca2+ or ADP; rather it is probably that there is an increase in the maximum activity of kinase relative to that of the phosphatase. 6. The results also lend further support to the hypothesis that adrenaline may bring about the activation of pyruvate dehydrogenase in the rat heart by an increase in the intramitochondrial concentration of Ca2+.
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PMID:Studies on the interactions of Ca2+ and pyruvate in the regulation of rat heart pyruvate dehydrogenase activity. Effects of starvation and diabetes. 709 23

Four patients with severe lactic acidosis associated with septic shock were treated with sodium dichloroacetate (DCA) (50 mg/kg body wt), an activator of pyruvate dehydrogenase. All patients were in a group with an expected mortality rate of 90-100%, based on previous studies. In one patient, treatment with DCA was associated with a decrease in blood lactate levels from 11.2 mM before treatment to 0.8 mM 16 h later. Markedly elevated blood pyruvate and alanine levels also decreased to normal. After treatment, the arterial blood pH rose to 7.53, and vasopressor agents were no longer needed to support blood pressure. Some degree of biochemical improvement was also noted in the other cases in whom the blood lactate levels before treatment were 15, 17, and 31 mM. However, all three patients eventually died of refractory acidosis.
Diabetes Care
PMID:Treatment of severe lactic acidosis with dichloroacetate. 715 55

1. Inactive pyruvate dehydrogenase phosphate complexes were partially purified from hearts of fed, starved or alloxan-diabetic rats by using conditions that prevent phosphorylation or dephosphorylation. 2. Unoccupied sites of phosphorylation were assayed by incorporation of 32P from [gamma-32P]ATP into the complexes. Total sites of phosphorylation were assayed by the same method after complete reactivation, and thus dephosphorylation, of complexes by incubation with pyruvate dehydrogenase phosphate phosphatase. Occupancy is assumed from the difference (total sites--unoccupied sites). Percentage incorporation into individual sites was measured by high-voltage electrophoresis after tryptic digestion. 3. Values (means +/- S.E.M., in nmol of phosphate/unit of inactive complex) for total sites, occupied sites and percentage occupancies, with numbers of observations in parentheses were: fed, 2.1 +/- 0.04, 1.15 +/- 0.04, 54.8 +/- 1.6% (39); starved, 2.05 +/- 0.03, 1.85 +/- 0.03, 90.2 +/- 1.4% (28); alloxan-diabetic, 1.99 +/- 0.03, 1.72 +/- 0.03, 86.4 +/- 1.4% (68%). 4. Values (means +/- S.E.M. for percentage occupancy) for individual sites of phosphorylation in pyruvate dehydrogenase phosphate given in the order sites 1, 2 and 3 were : fed, 100 +/- 2.7, 27.8 +/- 1.6, 33.9 +/- .9; starved, 100 +/- 1.4, 76.2 +/- 2.0, 92.4 +/- 1.5; alloxan-diabetic, 100 +/- 1.2, 64.0 +/- 1.7, 94.6 +/- 1.4. 5. It is concluded that starvation or alloxan-diabetes leads to a 2--3-fold increase in the occupancy of phosphorylation sites 2 and 3 in pyruvate dehydrogenase phosphate in rat heart in vivo.
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PMID:Occupancy of sites of phosphorylation in inactive rat heart pyruvate dehydrogenase phosphate in vivo. 730 68

Immunochemical techniques were used to study the effect of streptozotocin-induced diabetes on the amounts of pyruvate carboxylase and pyruvate dehydrogenase and on their rates of synthesis and degradation. Livers from diabetic rats had twice the pyruvate carboxylase activity of livers from normal rats when expressed in terms of DNA or body weight. The changes in catalytic activity closely paralleled changes in immunoprecipitable enzyme protein. Relative rates of synthesis determined by pulse-labelling studies showed that the ratio of synthesis of pyruvate carboxylase to that of average mitochondrial protein was increased 2.0-2.5 times in diabetic animals over that of control animals. Other radioisotopic studies indicated that the rate of degradation of this enzyme was not altered significantly in diabetic rats, suggesting that the increase in this enzyme was due to an increased rate of synthesis. Similar experiments with pyruvate dehydrogenase, the first component of the pyruvate dehydrogenase complex, showed that livers from diabetic rats had approximately the same amount of immunoprecipitable enzyme protein as the control animals, but a larger proportion of the enzyme was in its inactive state. The rates of synthesis and degradation of pyruvate dehydrogenase were not affected significantly by diabetes.
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PMID:Effect of streptozotocin-induced diabetes mellitus on the turnover of rat liver pyruvate carboxylase and pyruvate dehydrogenase. 747 23

Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogenase proteins, and their specific mRNAs were identified in fused myotubes. Insulin and IGF-I stimulated 2-deoxyglucose uptake twofold with half-maximal stimulation by insulin at 0.98 +/- 0.12 nmol/l and maximal stimulation at 17.5 nmol/l. Acute insulin treatment (33 nmol/l) doubled glycogen synthase activity and glucose incorporation into glycogen while increasing pyruvate dehydrogenase approximately 30%. In cells cultured from NIDDM subjects, both basal (6.9 +/- 1.0 vs. 13.0 +/- 1.7 pmol.mg protein-1.min-1) and acute insulin-stimulated transport (13.5 +/- 2.0 vs. 22.4 +/- 1.3 pmol.mg protein-1.min-1) were significantly reduced compared with nondiabetic control subjects (both P < or = 0.005). GLUT1 protein content of total membranes from NIDDM subjects was decreased compared with control subjects, while GLUT4 levels were similar between groups. A significant correlation (r = 0.65, P < or = 0.05) was present when maximal rates of insulin-stimulated glucose transport in cell culture from subjects were compared with their corresponding in vivo glucose disposal determined by hyperinsulinemic glucose clamp. In summary, differentiated human skeletal muscle cultures exhibit biochemical and molecular features of insulin-stimulated glucose transport and intracellular enzyme activity comparable with the in vivo situation. Defective insulin-stimulated glucose transport persists in muscle cultures from NIDDM subjects and resembles the reduced insulin-mediated glucose uptake present in vivo. We conclude that this technique provides a relevant cellular model to study insulin action and glucose metabolism in normal subjects and determine the mechanisms of insulin resistance in NIDDM.
Diabetes 1995 Aug
PMID:Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. 762

Lipoic acid (alpha-lipoic acid, thioctic acid) is applied as a therapeutic agent in various diseases accompanied by polyneuropathia such as diabetes mellitus. The stereoselectivity and specificity of lipoic acid for the pyruvate dehydrogenase complex and its component enzymes from different sources has been studied. The dihydrolipoamide dehydrogenase component from pig heart has a clear preference for R-lipoic acid, a substrate which reacts 24 times faster than the S-enantiomer. Selectivity is more at the stage of the catalytic reaction than of binding. The Michaelis constants of both enantiomers are comparable (Km = 3.7 and 5.5 mM for R- and S-lipoic acid, respectively) and the S-enantiomer inhibits the R-lipoic acid dependent reaction with an inhibition constant similar to its Michaelis constant. When three lipoic acid homologues were tested, RS-1,2-dithiolane-3-caproic acid was one carbon atom longer than lipoic acid, while RS-bisnorlipoic acid and RS-tetranorlipoic acid were two and four carbon atoms shorter, respectively. All are poor substrates but bind to and inhibit the enzyme with an affinity similar to that of S-lipoic acid. No essential differences with respect to its reaction with lipoic acid enantiomers and homologues exist between free and complex-bound dihydrolipoamide dehydrogenase. Dihydrolipoamide dehydrogenase from human renal carcinoma has a higher Michaelis constant for R-lipoic acid (Km = 18 mM) and does not accept the S-enantiomer as a substrate. Both enantiomers of lipoic acid are inhibitors of the overall reaction of the bovine pyruvate dehydrogenase complex, but stimulate the respective enzyme complexes from rat as well as from Escherichia coli. The S-enantiomer is the stronger inhibitor, the R-enantiomer the better activator. The two enantiomers have no influence on the partial reaction of the bovine pyruvate dehydrogenase component, but do inhibit this enzyme component from rat kidney. The implications of these results are discussed.
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PMID:Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex. 766 66

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)
Diabetes 1995 Apr
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

In circulating lymphocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM) subnormal pyruvate dehydrogenase (PDH) activity returns to normal following patient treatment with sulfonylurea (gliclazide, 80 mg twice daily/5 weeks). Moreover, in vitro in cells from diabetic patients exposed to insulin at 50 microU/mL PDH activation also occurs; in cells of controls the same happens for insulin at 5 microU/mL, whereas at 50 microU/mL inhibition takes place. Therefore, the low PDH activity in cells of NIDDM patients might be caused by defective insulin control on the enzyme and its recovery in gliclazide-treated patients by drug-mediated removal of the defect. The validity of the hypothesis was verified in this study where cells of NIDDM patients before and after gliclazide treatment were exposed, in vitro, to insulin at 5 and 50 microU/mL and then tested for PDH activity. In such conditions, the profile of PDH behavior in treated patients was no longer comparable to that in untreated patients but closer to that in euglycemic controls, thus supporting the view that the recovery of PDH activity in NIDDM patients following gliclazide treatment might be the expression of an additional effect that the drug would have in these patients, aimed to renew cell responsiveness to insulin.
J Diabetes Complications
PMID:Effect of sulfonylurea agents on pyruvate dehydrogenase activity in circulating lymphocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM). 783 97

Impairments of both basal and insulin-stimulated oxidative (Gox) and nonoxidative (Nox) glucose metabolism are documented to exist in non-insulin-dependent diabetes mellitus (NIDDM). Although these defects have been well characterized during insulin stimulation, little is known about the effects of basal insulin or its deficiency on intracellular glucose metabolism in NIDDM. To determine the physiological significance of basal insulin in the maintenance of glucose metabolism in NIDDM, we studied nine subjects with NIDDM in the basal and insulin-deficient state produced by 3 hours of somatostatin (SRIF) infusion (0.08 pmol/kg/min). Glucose turnover rates were quantified by [3-3H]glucose turnover, and substrate oxidation was assessed by a combination of indirect calorimetry and urinary nitrogen measurements. Skeletal muscle glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities were also measured in the basal state and during SRIF infusion. Basal glucose levels were maintained during SRIF infusion by exogenous glucose infusion (12.5 +/- 0.9 mmol/L in the basal state v 12.8 +/- 0.8 during SRIF infusion, P = NS). During the last hour of SRIF infusion, plasma C-peptide levels declined by 88% from 0.73 +/- 0.11 to 0.09 +/- 0.02 nmol/L (P < .001), and serum insulin concentrations were undetectable (< 14 pmol/L). During insulinopenic conditions, rates of glucose uptake (GU) were decreased by 12% from basal level of 2.26 +/- 0.13 to 1.99 +/- 0.12 mg/kg/min (P < .05), and were entirely accounted for by reduced rates of Gox (1.01 +/- 0.10 to 0.65 +/- 0.14 mg/kg/min, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of basal insulin in maintenance of intracellular glucose metabolic pathways in non-insulin-dependent diabetes mellitus. 785 64

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


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