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

The relation between food intake and enzyme activity of the small intestine and rate of intestinal absorption were studied in rats 15 days after induction of alloxan diabetes. Diabetic rats were given an ad lib. semisynthetic diet or a restricted diet on the basis of either daily intake or body weight. The rates of absorption of 5 mMD-galactose and L-valine were determined in vitro by the everted sac method. The rates of absorption of the substances, expressed per unit weight or per length of intestine, were higher in diabetic rats than in controls, regardless of the amount of food consumed. Maltase and sucrase activities were significantly increased in diabetic rats, regardless of the amount of food consumed. The activity of intestinal alkaline phosphatase was increased in diabetic rats fed ad lib., but not in those on a restricted diet. These findings suggest that in alloxan diabetic rats the increased disaccharidase activity in the small intestine is due to insulin deficiency, and that the increased activity of alkaline phosphatase is only a secondary effect of insulin deficiency, caused by increased food intake resulting from insulin deficiency.
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PMID:Effect of food intake on intestinal absorption and mucosal hydrolases in alloxan diabetic rats. 698 35

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

The activity of branched-chain alpha-keto acid (BCKA) dehydrogenase was increased after preincubation of liver and muscle mitochondria of control rats. Preincubation depleted mitochondrial ATP. Addition of ATP prevented the activation of BCKA dehydrogenase as well as reversed the activity of a fully activated enzyme to normal. Inhibition of phosphatase blocked the activation of BCKA dehydrogenase. There was a small or no increase in BCKA dehydrogenase activity when mitochondria from tissues of fasted, diabetic, and clofibrate-treated rats were preincubated. In fasted and diabetic rats, ATP was either less effective or failed to reverse the increased dehydrogenase activity in preincubated mitochondria. The concentration of ATP in liver and muscle mitochondria of diabetic rats was approximately one-half that of the control rats. We conclude that (a) in the fed state approximately 30-40% of BCKA dehydrogenase exists in the active form. The enzyme can be fully activated by preincubation of mitochondria which causes the depletion of ATP. Phosphatase is necessary for this activation. (b) In fasted, diabetic, and clofibrate-treated rats, approximately 70-100% of the enzyme exists in the active form which may be related to the mitochondrial depletion of ATP in vivo, and (c) while ATP can reverse the activation in control rats, it fails to do so in diabetic rats suggesting that other metabolic alterations may be involved in the regulation of BCKA dehydrogenase in diabetes.
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PMID:Role of ATP in the regulation of branched-chain alpha-keto acid dehydrogenase activity in liver and muscle mitochondria of fed, fasted, and diabetic rats. 706 67

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

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

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 response to insulin, several proteins are phosphorylated on tyrosine and on serine/threonine residues. Decreased phosphorylation of signaling peptides by a defective insulin receptor kinase may be a cause of insulin resistance. Accordingly, inhibition of the appropriate phosphatases might increase the phosphorylation state of these signaling peptides and thereby elicit increased glucose transport. The purpose of this study was to examine the effect of the serine/threonine phosphatase inhibitor okadaic acid and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate on 2-deoxyglucose transport in insulin-resistant human skeletal muscle. All three phosphatase inhibitors stimulated 2-deoxyglucose transport in insulin-resistant skeletal muscle. These data suggest that these compounds have bypassed a defect in at least one of the signaling pathways leading to glucose transport. Furthermore, maximal transport rates induced by the simultaneous presence of insulin and phosphatase inhibitor in insulin-resistant muscle were equal to insulin-stimulated rates in lean control subjects. However, both vanadate alone and vanadate plus insulin stimulated 2-deoxyglucose transport significantly more in insulin-sensitive tissue than in insulin-resistant tissue. These results demonstrate that although vanadate is able to stimulate glucose transport in insulin-resistant muscle, it is not able to normalize transport to the same rate achieved in insulin-sensitive muscle.
Diabetes 1995 Jun
PMID:Okadaic acid, vanadate, and phenylarsine oxide stimulate 2-deoxyglucose transport in insulin-resistant human skeletal muscle. 778 33

Impairment of glucose-induced insulin secretion in non-insulin-dependent diabetes mellitus (NIDDM) may be caused by GLUT 2 underexpression in the pancreatic beta cell, a mutation of the glucokinase gene, glucose 6-phosphatase overactivity, FAD-linked glycerophosphate dehydrogenase deficiency, a mitochondrial DNA defect and/or a secondary phenomenon of so-called glucotoxicity possibly involving glycogen accumulation in the beta-cell. It is proposed tht the methyl esters of succinic acid and related molecules may represent new tools with which to bypass these defects in glucose transport, phosphorylation and further catabolism and, hence, to stimulate both proinsulin biosynthesis and insulin release in NIDDM.
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PMID:The beta cell in NIDDM: giving light to the blind. 782 38

Insulin stimulates glucose uptake and non-oxidative glucose metabolism (predominantly glycogen synthesis) in skeletal muscle. Among other things, insulin resistance is characterized by a subnormal insulin-stimulated glucose disposal, and it appears to be associated with an increased risk for development of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present investigation has been to elucidate the mechanism of action of insulin on non-oxidative glucose metabolism both during conditions of insulin resistance and during physiological modification of glucose metabolism. To do so, the effect of insulin was investigated both with respect to its initial activation of the insulin receptor kinase and the terminal step of the signal pathway, namely stimulation of the glycogen synthase. From needle biopsies of human skeletal muscle (vastus lateralis) cellular membranes were solubilized and the insulin receptors were partially purified by affinity chromatography using wheat germ agglutinin. Subsequently insulin binding and the insulin-stimulated tyrosine kinase activity were characterized. The insulin receptor kinase activity did not change during physiological modification of the glucose metabolism (exercise training, acute exercise, growth hormone exposure or experimental hyperglycemia). No specific abnormalities of the insulin receptor kinase activity were revealed in insulin-dependent diabetes (IDDM) or in common NIDDM. In addition, insulin receptor kinase activity did not change during dietary or sulphonylurea treatment of NIDDM. Glucose deposition as glycogen in muscle is regulated by glycogen synthase (GS), which during insulin stimulation undergoes dephosphorylation and becomes more active at physiological concentrations of glucose-6-phosphate. Recently, insulin was shown to stimulate a cascade of phosphorylation-dependent kinases which ultimately activate a glycogen-bound subunit of a phosphatase (G-subunit of phosphatase-1) which promotes dephosphorylation GS by the catalytic subunit. The quantity of the GS enzyme (GStot) in muscle may be reduced in the diabetes disease. However, it may increase during physical training of insulin-dependent diabetic patients. GStot is not altered during acute exposure to insulin, hyperglycemia or muscle contraction. The insulin stimulation of GS is reduced in insulin resistant NIDDM patients. However, once the hyperglycemia and the insulin resistance is ameliorated during treatment with diet or sulphonylurea drugs the activation of GS improves. Growth hormone-induced transient insulin resistance in non-diabetic subjects, is accompanied by a reduced insulin stimulation of GS. Experimentally induced hyperglycemia in normal subjects has no influence on GS activation by insulin. After an acute exercise bout the GS in muscle becomes activated. The mechanism of this post-exercise GS activation is still unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin receptor function and glycogen synthase activity in human skeletal muscle. Physiology and pathophysiology. 803 33

To assess the role of insulin receptor (IR) tyrosine kinase in human insulin resistance, we examined the kinase activity of IR of skeletal muscle biopsies from eight lean and five obese nondiabetics and six obese subjects with noninsulin-dependent diabetes mellitus (NIDDM). Biopsies were taken during euglycemic clamps at insulin infusion rates of 0, 40, 120, and 1200 mU/m2.min. IRs were immobilized on insulin agarose beads, and autophosphorylation and histone 2B phosphorylation were measured. Phosphatase and protease inhibitors preserved the in vivo phosphorylation state of the IRs. Glucose disposal rates (GDR) were reduced according to insulin dose by 23-30% in the obese (P < 0.05) and 43-64% in the NIDDM subjects (P < 0.0005). IR autophosphorylation was increased up to 9-fold in controls and was reduced (P = 0.04) in NIDDM compared to obese subjects. Histone-2B kinase was increased up to 6-fold in controls and was reduced by 50% in NIDDM. Kinase values by both methods were similar in lean and obese controls. In vivo stimulation of kinase was well correlated to the increase in GDR, as was the decrement in kinase in NIDDM to the decrement in GDR. These results suggest that defects in muscle IR kinase are significant in the in vivo insulin resistance of NIDDM, but not that of obesity.
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PMID:Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. 810 37


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