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

The pyruvate dehydrogenase and branched-chain 2-oxoacid dehydrogenase complexes of animal mitochondria are inactivated by phosphorylation of serine residues, and reactivated by dephosphorylation. In addition, phosphorylated branched-chain complex is reactivated, apparently without dephosphorylation, by a protein or protein-associated factor present in liver and kidney mitochondria but not in heart or skeletal muscle mitochondria. Interconversion of the branched-chain complex may adjust the degradation of branched-chain amino acids in different tissues in response to supply. Phosphorylation is inhibited by branched-chain ketoacids, ADP and TPP. The pyruvate dehydrogenase complex is almost totally inactivated (99%) by starvation or diabetes, the kinase reactions being accelerated by products of fatty acid oxidation and by a protein or protein-associated factor induced by starvation or diabetes. There are three sites of phosphorylation, but only sites 1 and 2 are inactivating. Site 1 phosphorylation accounts for 98% of inactivation except during dephosphorylation when its contribution falls to 93%. Sites 2 and 3 are only fully phosphorylated when the complex is fully inactivated (starvation, diabetes). Phosphorylation of sites 2 and 3 inhibits reactivation by phosphatase. The phosphatase reaction is activated by Ca2+ (which may mediate effects of muscle work) and possibly by uncharacterized factors mediating insulin action in adipocytes.
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PMID:Mitochondrial 2-oxoacid dehydrogenase complexes of animal tissues. 613 8

Adenine nucleotide translocase (EC 3.6.1.3.), pyruvate dehydrogenase (active and total forms, EC 1.2.4.1) and the long chain acyl CoA content were measured in liver and kidney from normal and alloxan-diabetic rats. The long chain acyl CoA content was significantly increased in liver, but not in kidney, in the diabetic group. Adenine nucleotide translocase activity was decreased in liver and raised in the kidney of alloxan-diabetic rats relative to the control group. Pyruvate dehydrogenase (active) was inhibited to a similar degree in both tissues in diabetes. The results are discussed in the light of the possible regulatory role of long chain acyl CoA and the diverse metabolic demands of the two tissues in diabetes.
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PMID:Differential response of liver and kidney adenine nucleotide translocase and pyruvate dehydrogenase activity to alloxan diabetes. The possible regulatory role of long chain acyl CoA. 630 7

We studied certain metabolic requirements for insulin-induced increases in phospholipids, and the relationship of phospholipid changes to the insulin-induced activation of pyruvate dehydrogenase, in rat adipocytes and fat pads in vitro. Increases in the contents of phosphatidylinositol and phosphatidylserine mass were maximal in rat fat pads within 10 min of incubation with insulin, and preceded or accompanied measurable increases in pyruvate dehydrogenase activity. In dose-response studies, the contents of these phospholipids and pyruvate dehydrogenase activity increased in parallel in response to increasing concentrations of insulin. Cycloheximide and puromycin inhibited insulin-induced increases in the mass of both of these phospholipids, as well as (in confirmation of previous reports) pyruvate dehydrogenase activity. Effects of insulin on phospholipid metabolism and pyruvate dehydrogenase were found to require an exogenous carbohydrate source, and fructose was nearly as effective as glucose in this regard. Insulin-induced increases in phosphatidylinositol and phosphatidylserine were demonstrated in the mitochondrial fraction, which is also the subcellular locus of pyruvate dehydrogenase. The present findings suggest that there is a relationship between insulin-induced increases in phospholipids and pyruvate dehydrogenase activity, but the nature of this relationship remains to be defined.
Diabetes 1984 Jul
PMID:The mechanism of action of insulin on phospholipid metabolism in rat adipose tissue. Requirement for protein synthesis and a carbohydrate source, and relationship to activation of pyruvate dehydrogenase. 632 60

The total activity of pyruvate dehydrogenase (PDH) complex in rat hind-limb muscle mitochondria was 76.4 units/g of mitochondrial protein. The proportion of complex in the active form was 34% (as isolated), 8-14% (incubation with respiratory substrates) and greater than 98% (incubation without respiratory substrates). Complex was also inactivated by ATP in the presence of oligomycin B and carbonyl cyanide m-chlorophenylhydrazone. Ca2+ (which activates PDH phosphatase) and pyruvate or dichloroacetate (which inhibit PDH kinase) each increased the concentration of active PDH complex in a concentration-dependent manner in mitochondria oxidizing 2-oxoglutarate/L-malate. Values giving half-maximal activation were 10 nM-Ca2+, 3 mM-pyruvate and 16 microM-dichloroacetate. Activation by Ca2+ was inhibited by Na+ and Mg2+. Mitochondria incubated with [32P]Pi/2-oxoglutarate/L-malate incorporated 32P into three phosphorylation sites in the alpha-chain of PDH; relative rates of phosphorylation were sites 1 greater than 2 greater than 3, and of dephosphorylation, sites 2 greater than 1 greater than 3. Starvation ( 48h ) or induction of alloxan-diabetes had no effect on the total activity of PDH complex in skeletal-muscle mitochondria, but each decreased the concentration of active complex in mitochondria oxidizing 2-oxoglutarate/L-malate and increased the concentrations of Ca2+, pyruvate or dichloracetate required for half-maximal reactivation. In extracts of mitochondria the activity of PDH kinase was increased 2-3-fold by 48 h starvation or alloxan-diabetes, but the activity of PDH phosphatase was unchanged.
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PMID:Reversible phosphorylation of pyruvate dehydrogenase in rat skeletal-muscle mitochondria. Effects of starvation and diabetes. 633 93

An insulin-sensitive subcellular system was developed from rat adipocytes consisting of plasma membranes and mitochondria. Direct addition of insulin, concanavalin A or anti-insulin receptor antibody to this system resulted in the production of a mediator substance from the plasma membrane that caused dephosphorylation of the alpha subunit of pyruvate dehydrogenase in the mitochondria with concomitant activation of the enzyme. The mediator activated pyruvate dehydrogenase by activating the pyruvate dehydrogenase phosphatase and not by inhibiting the pyruvate dehydrogenase kinase. This was similar to the mechanism by which insulin causes activation of the enzyme in the intact cell. The insulin-sensitive mediator material from the adipocyte plasma membrane was acid-stable with a molecular weight of 1,000 to 1,500. Our laboratory has shown that the mediator that activates pyruvate dehydrogenase was present in intact adipocytes, hepatoma cells, and IM-9 lymphocytes. Insulin altered the amount or activity of the mediator consistent with the effect of the hormone on the cell. Other laboratories have shown similar effects on skeletal muscle and liver. We have shown the mediator to mimic insulin action on the low Km cyclic adenosine monophosphate (AMP) phosphodiesterase and the (calcium++-magnesium++)-adenosine triphosphatase (Ca++-Mg++)-ATPase of adipocyte plasma membranes in addition to pyruvate dehydrogenase. Other laboratories have shown the mediator to activate glycogen synthase. A body of direct and indirect evidence exists that demonstrates that more than one mediator exists. The chemical nature of the mediator is unknown but probably represents a new family of intracellular mediators of hormone action. These mediators may have clinical relevance in postreceptor defects of obesity and type II diabetes (noninsulin-dependent diabetes mellitus).
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PMID:The chemical mediators of insulin action: possible targets for postreceptor defects. 633 85

To further define the mechanism(s) of insulin resistance in the liver associated with diabetes and fasting, we evaluated the ability of insulin to release an activator of pyruvate dehydrogenase activity from a liver particulate fraction. Insulin reproduceably and significantly enhanced the release of mediator from the liver particulate fraction of control animals. The particulate fractions from fasted and diabetic animals were resistant to this effect of insulin. Refeeding and insulin treatment, respectively, restored responsiveness to insulin. These data support the concept that alterations at or near the plasma membrane can be responsible for or accompany the insulin resistance observed in the liver in fasting and diabetes mellitus.
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PMID:Insulin resistance in the liver in fasting and diabetes mellitus: the failure of insulin to stimulate the release of a chemical modulator of pyruvate dehydrogenase. 634 Jun 85

Cultured human fibroblasts represent an appropriate model for studying both insulin receptor interaction and hormone responsiveness. We have investigated the properties of the pyruvate dehydrogenase multi-enzyme complex (PDC) and have studied the effects of various concentrations of porcine and biosynthetic human insulin (BHI) on the activity of the enzyme. Under optimal conditions of the assay, both BHI and porcine insulin activated PDC in a dose-dependent fashion in which full activation of the enzyme was achieved with 10(-8) M insulin. The half-maximal concentration for porcine and human insulin was similar, occurring at the level of 5 X 10(-9) M for activation of the PDC of human fibroblasts. We conclude that the PDC of cultured human fibroblasts is activated by both human and porcine insulin at a comparable physiologic concentration. Human fibroblasts may therefore serve as a useful model to study insulin action in isolated human tissue.
Diabetes 1984 Jul
PMID:Activation of pyruvate dehydrogenase complex by porcine and biosynthetic human insulin in cultured human fibroblasts. 637 23

The effects of increased cardiac work and availability of pyruvate on the activation of pyruvate dehydrogenase (PDH) was studied in hearts isolated from diabetic rats. Diabetes resulted in complete inactivation of myocardial PDH. At low levels of cardiac work, PDH in hearts perfused with glucose or glucose plus insulin as substrate remained in the inactive form even after 25 min of in vitro perfusion indicating that the factors causing inactivation in the diabetic animal were not easily reversed in vitro. Raising the level of ventricular pressure development from 60 to 180 mmHg caused only a small increase in the percent of active PDH (from 0.3 to 16%). Comparable values in control hearts were 61 and 96% active PDH. Addition of high levels of perfusate pyruvate along with glucose increased the percent active PDH from 0.3 to 45 at 60 mmHg ventricular pressure. Although pyruvate increased active PDH the effect was much less than in normal hearts (85% active under comparable conditions). Increased ventricular pressure development (180 mmHg) in diabetic hearts receiving pyruvate caused a further activation of PDH to 66% but again this effect was much less than occurred in normal hearts (96% active). Inactivation of PDH in hearts from diabetic animals could not be accounted for by high mitochondrial levels of known effectors such as NADH/NAD, acetyl CoA/CoA and ATP/ADP. Increasing cardiac work resulted in decreased mitochondrial levels of NADH, acetyl CoA and ATP, but these changes had little effect on PDH activity. The date indicate that PDH in hearts of diabetic animals is resistant to activation by increased cardiac work and high tissue levels of pyruvate.
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PMID:Effects of increased cardiac work on pyruvate dehydrogenase activity in hearts from diabetic animals. 687 84

The effect of halothane anaesthesia on the activity of the mitochondrial enzyme pyruvate dehydrogenase was studied in starved lactating rats. Extracts of freeze-clamped mammary gland and liver were assayed for pyruvate dehydrogenase activity. The fraction of the enzyme in the phosphorylated inactive form was increased greatly by starvation or by streptozotocin diabetes, and halothane anaesthesia did not disturb this effect. In starved animals not exposed to halothane, injection of insulin led to a rapid increase in the active fraction of the enzyme in mammary gland but not in liver. In animals under halothane anaesthesia this effect of insulin was largely abolished. The combination of starvation and halothane anaesthesia may impair mitochondrial accumulation of calcium which may be involved in the stimulation of pyruvate dehydrogenase by insulin.
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PMID:Halothane anaesthesia can block insulin stimulation of pyruvate dehydrogenase activity in mammary glands of 24-hour starved lactating rats. 700 Jan 4

Insulin treatment of adipocytes increased the amount or activity of a low molecular weight, acid-stable material which, when isolated from intact adipocytes by heat extraction and subsequent Sephadex G25 chromatography, yielded a single active fraction that stimulated mitochondrial pyruvate dehydrogenase by activating the phosphatase and not by altering the kinase activity. Phosphatase activation was demonstrated by the ability of the active material to increase pyruvate dehydrogenase activity in the absence of ATP and by the ability of NaF, a phosphatase inhibitor, to this stimulation. Involvement of the kinase in this activation mechanism was eliminated by the fact that, in the presence of ATP, (1) NaF completely blocked the stimulation of pyruvate dehydrogenase by the active fraction, and (2) the stimulation of pyruvate dehydrogenase by dichloroacetic acid, a kinase inhibitor, was additive to the stimulation caused by the active fraction. This active fraction may contain an intracellular chemical mediator or second messenger for insulin.
Diabetes 1980 Oct
PMID:Isolation from rat adipocytes of a chemical mediator for insulin activation of pyruvate dehydrogenase. 700 67


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