Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
PMID:Mitochondrial 2-oxoacid dehydrogenase complexes of animal tissues. 613 8

The effects of diabetes mellitus on glycogen synthase and its activating system (synthase phosphatase) were studied using human polymorphonuclear leukocytes (PMN). PMN were obtained from control subjects and diabetic patients by a gradient sedimentation technique. Enzyme activities of endogenous synthase-l and total synthase were not statistically different in diabetic and control cells. For measurement of endogenous synthase phosphatase, cells were sonicated in 50 mM Tris buffer (pH 7.5) and incubated at 30 degrees C. Conversion of synthase-D to -l and the maximum percent synthase-l attained were decreased in homogenates of diabetic cells. There was no correlation between the plasma glucose concentration and the rate of conversion of synthase-D to -l. Synthase phosphatase activities were also measured using a purified synthase-D substrate. Under these experimental conditions, glycogen synthase phosphatase activities did not differ in control and diabetic cells. These results are consistent with a diabetes-induced defect in conversion of endogenous synthase-D to -l at the level of the synthase enzyme rather than at that of the activating phosphatase.
Diabetes 1980 Mar
PMID:Impaired glycogen synthase activating system in human diabetic polymorphonuclear leukocytes. 624 32

This study was initiated to determine whether glycogen phosphorylase activation was defective in hearts of alloxan diabetic rats. When hearts were perfused by gravity flow for 1 to 10 min with various concentrations of epinephrine, activation of glycogen phosphorylase in the diabetic was significantly greater at every time and epinephrine concentration than that seen in the normal. Cyclic AMP accumulation and protein kinase activation by epinephrine in the diabetic were not appreciably different or were lower than the normal responses to the hormone. The effects of epinephrine on cAMP and protein kinase were blocked in both normal and diabetic hearts by propranolol. While the beta blocker prevented phosphorylase activation in the normal hearts, it did not block phosphorylase activation by epinephrine in the diabetic hearts. Likewise, the alpha agonist phenylephrine activated phosphorylase in the diabetic but not in the normal hearts. While glucagon produced the same phosphorylase hypersensitivity in diabetic hearts, the cAMP and protein kinase responses were not altered by diabetes. Phosphorylase phosphatase activity was found to be unaltered by either epinephrine or diabetes, whereas phosphorylase kinase activation by epinephrine in the diabetic was double the normal response. These data are consistent with a diabetes-related unmasking of an alpha effect on cardiac phosphorylase activation and an unexplained increase in the sensitivity of phosphorylase kinase activation by protein kinase.
 ...
PMID:A hypersensitivity of glycogen phosphorylase activation in hearts of diabetic rats. 625 85

Perfused livers from normal and alloxan-diabetic rats were studied to determine whether the diabetes-related decrease in glycogen synthase phosphatase was due to an alteration of the synthase molecule, an increase in synthase phosphatase activity inhibition by phosphorylase a, or generation of inhibitor of the phosphatase. With purified rat liver synthase as substrate for the phosphatase, the diabetic tissue remained 90-95% deficient in the ability to catalyze synthase D to I conversion, showing that the defect cannot be solely due to an altered substrate. When synthase phosphatase assays were carried out in the presence of rat liver glycogen phosphorylase antiserum, phosphatase activity remained 70-75% deficient in diabetic tissue. Therefore, the defect cannot be attributed to increased inhibition of synthase phosphatase by increased amounts of phosphorylase a. When synthase phosphatase assays were run by mixing extracts from normal and diabetic livers, phosphatase activity was additive, indicating that a phosphatase inhibitor was probably not involved in the phosphatase deficiency in the diabetic. These data are consistent with the hypothesis that the diabetes-related defect in glucose regulation of hepatic glycogen synthase is due to a molecular alteration or a deficiency of a specific glycogen synthase phosphatase.
 ...
PMID:Alteration of hepatic glycogen synthase phosphatase activity by insulin deficiency. 626 5

Isolated perfused hearts from control Bio-Breeding/Worcester (BB/W) rats and spontaneously diabetic BB/W rats were studied to determine whether metabolic abnormalities that are expressed in alloxan-diabetic rats in the regulation of enzymes involved in glycogen metabolism could be observed in this non-chemically induced insulin-deficient rat. Perfusion of hearts from control rats with 10(-8) M insulin for 10 min resulted in activation of glycogen synthase (30% synthase I without insulin to 44% synthase I with insulin). Perfusion of hearts from BB/W diabetic rats demonstrated a lack of acute synthase activation with insulin and a 45% decrease in synthase phosphatase activity. Perfusion of hearts from BB/W diabetic rats with 0.28 microM epinephrine for 1 min resulted in a greater activation of phosphorylase (44% phosphorylase a) than that observed in BB/W control hearts (31% phosphorylase a) perfused under the same conditions. Epinephrine produced similar changes in cyclic AMP accumulation, protein kinase activation, and phosphorylase kinase activation in perfused hearts of BB/W control and diabetic rats. Further, phosphorylase phosphatase activities were not changed by epinephrine or insulin deficiency. These studies further document metabolic abnormalities in the BB/W diabetic rat that are attributable to insulin deficiency in a non-chemically induced model for insulin-dependent diabetes.
 ...
PMID:Altered regulation of cardiac glycogen metabolism in spontaneously diabetic rats. 631 7

Hepatocytes from normal fed rats and from chronically (90 h) alloxan-diabetic rats were compared. The rate and the extent of activation of glycogen synthase in response to 60 mM-glucose were greatly decreased in diabetes. During incubation of gel-filtered extracts from broken hepatocytes, diabetes only decreased the rate of the activation, which became ultimately complete in either preparation. Synthase phosphatase activity, as measured by the activation of purified hepatic synthase b, was decreased in chronic diabetes. The decrease was proportional to the severity of the diabetes, and reached 90% when the plasma glucose concentration was greater than or equal to 55 mM. In contrast, phosphorylase phosphatase activity was not decreased. Synthase phosphatase activity was progressively restored by treatment with insulin for 20-68 h. During the induction of diabetes and during insulin treatment there was a good correlation between the activity of synthase phosphatase and the maximal activation of synthase in glucose-stimulated hepatocytes from the same livers. The decreased activity of synthase phosphatase in diabetes cannot be explained by an inhibitor. The decrease was much less marked when synthase phosphatase was assayed by the dephosphorylation of 32P-labelled synthase from muscle. This observation suggested a loss of only one component of synthase phosphatase. Cross-combination of subcellular fractions from control rats and from diabetic rats showed a preferential loss of G-component, with little or no loss of S-component. No G-component could be detected in severe diabetes. The concentration of G-component is therefore of critical importance in the glucose-induced activation of glycogen synthase in the liver.
 ...
PMID:The hepatic defect in glycogen synthesis in chronic diabetes involves the G-component of synthase phosphatase. 632 Aug 6

Protein phosphatase activities have recently been classified into two major groups of enzymes termed type 1 and type 2. In the present study, this classification scheme has been used to explore the types of protein phosphatase activities found in rat heart, liver, and skeletal muscle, and to determine the type of protein phosphatase activity affected by diabetes. Protein phosphatase activities have been measured under conditions designed to minimize the influence of effectors of these enzymes, and a thermostable protein phosphatase inhibitor, termed inhibitor-2, has been used as a probe to specifically inhibit type 1 protein phosphatase. The specific activity of protein phosphatase-1 in extracts of heart, liver, and skeletal muscle from control rats ranged between 0.34 and 0.44 U/mg protein. The specific activity of a type 2 enzyme, termed protein phosphatase-2A, was approximately the same as protein phosphatase-1 in the case of skeletal muscle extracts, but was about 50% higher than type 1 in extracts from liver and heart. The only significant effect of diabetes was on hepatic protein phosphatase-1 in which a 50% decrease in specific activity was noted. Therefore, the effect of diabetes appeared to be confined to protein phosphatase-1 and this effect was only seen in liver.
Diabetes 1984 Jun
PMID:Protein phosphatase-1 and -2A activities in heart, liver, and skeletal muscle extracts from control and diabetic rats. 632 37

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.
 ...
PMID:Reversible phosphorylation of pyruvate dehydrogenase in rat skeletal-muscle mitochondria. Effects of starvation and diabetes. 633 93

Glycogen synthase in skeletal muscle of 3-day alloxan-diabetic rats was found to be in a less active state than in normal muscle. Both the activity ratio (activity without G6P divided by activity with 7.2 mM G6P at 4.4 mM UDPG, pH 7.8) and fractional velocity (activity with 0.25 mM G6P divided by activity with 10 mM G6P at 0.03 mM UDPG, pH 6.9) were significantly lower in the diabetic tissue. Correspondingly, the S0.5 for UDPG and A0.5 for G6P were significantly higher in diabetic tissue, suggesting decreased affinity for substrate and activator, respectively. The kinetic changes in the diabetic synthase were identical whether the alloxan-treated animals were maintained on insulin for 7 days prior to withdrawal for 3 days, or studied 3 days immediately after alloxan treatment. The diabetes-induced changes in synthase could be reversed by injecting the diabetic rat with insulin 10 min prior to sacrifice. After insulin treatment, the S0.5 for UDPG and A0.5 for G6P decreased to control levels or lower and the activity ratios and fractional velocities increased to control levels or higher. The activity of glycogen synthase phosphatase was not decreased in diabetic skeletal muscle. This observation, coupled with the rapid response of the diabetic synthase to in vivo insulin treatment, suggests that, unlike the phosphatase in cardiac muscle and liver, the glycogen synthase phosphatase in skeletal muscle is not altered by the diabetic state.
 ...
PMID:Glycogen synthase in diabetic rat skeletal muscle: activation by insulin. 681 78

Rats with streptozotocin-induced diabetes stop growing, develop high cholesterol and triacylglycerol levels in plasma, and have decreased activity of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC 1.1.1.34), in liver and increased activity in small intestine. They also eat more than normal. To determine the contribution of hyperphagia to these changes in lipid metabolism, we restricted intake of chow to the amount eaten ad lib by normal rats. Rats were meal-fed for 8 or 22 days from the time diabetes was induced. This regimen normalized reductase activity in both liver and intestine at mid-dark and mid-light, and all but eliminated high plasma cholesterol and triacylglycerol levels, although plasma insulin remained low and glucose remained high. Activation of hepatic reductase by endogenous phosphatase in vitro was reduced in hyperphagic diabetic rats but was normal in diabetic rats eating a normal amount of food. We conclude that hyperphagia, rather than direct effects of insulin deficiency as is usually assumed, is responsible for perturbations of lipid metabolism in chronically diabetic rats. These results support the proposal that hyperphagia increases the input of dietary and newly synthesized cholesterol from the small intestine, and that this increased input raises plasma cholesterol level and inhibits reductase activity in liver.
 ...
PMID:Preventing hyperphagia normalizes 3-hydroxy-3-methylglutaryl-CoA reductase activity in small intestine and liver of diabetic rats. 695 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>