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

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

Insulin treatment significantly altered the elution profile of deproteinized muscle extracts chromatographed on Sephadex G-25 columns, particularly in fraction II, which contains the insulin mediator. Further purification of fraction II by high-voltage paper electrophoresis at pH 1.9 and 3.5 resulted in two active fractions. Fraction 1 leads to 4 stimulated the cyclic AMP-dependent protein kinase and inhibited glycogen synthase phosphoprotein phosphatase, and may be a novel substance. Fractions 1 leads to 6 and 3 leads to 6 inhibited the cyclic AMP-dependent protein kinase and stimulated glycogen synthase phosphatase. It is proposed that the insulin mediator is present in fractions 1 leads to 6 and 3 leads to 6.
Diabetes 1980 Aug
PMID:Studies on the insulin mediator. II. Separation of two antagonistic biologically active materials from fraction II. 625 25

The effects of diabetes on hepatic carbohydrate metabolism were investigated in spontaneously diabetic Bio-Breeding Worcester (BB/W) rats. The juvenile-onset-type syndrome displayed by these animals is characterized by beta-cell destruction with subsequent ketosis-prone insulinopenia. Livers from diabetic animals demonstrated increased adenosine 3',5'-cyclic monophosphate levels but subnormal total protein and glycogen content. Isolated perfused livers of diabetic BB/W rats demonstrated an increased rate of glucose production from [14C]lactate and an impaired rate of glycogen synthesis. These data were consonant with hepatic enzyme studies demonstrating markedly increased activities of component gluconeogenic (glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphoenolpyruvate carboxykinase) and glycogenolytic (glycogen phosphorylase) enzymes with decreased activities of glycolytic (hexokinase, pyruvate kinase) and glycogenic (glycogen synthase) enzymes. These findings agree with previous studies using alloxan- and streptozotocin-induced diabetic animals and suggest that accelerated hepatic gluconeogenesis and impaired glucose utilization are pathognomonic of all insulin-deficient diabetic syndromes.
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PMID:Hepatic carbohydrate metabolism in the spontaneously diabetic Bio-Breeding Worcester rat. 625 45

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.
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PMID:Alteration of hepatic glycogen synthase phosphatase activity by insulin deficiency. 626 5

Streptozotocin-induced maternal diabetes has been shown to alter developmental patterns of carbohydrate-metabolizing enzyme activities, glycogen deposition and surfactant levels in late fetal rat lung in a tissue-specific manner, as follows: (a) marked reduction in glycogen synthase a activity, due to aberrant interconversion between active and inactive forms of the enzyme; less glycogen was thus accumulated; (b) lowered activities of hexokinase, phosphofructokinase and pyruvate kinase at term; (c) reduced disaturated phosphatidylcholine (surfactant) concentrations. The diminished synthesis and accumulation of glycogen and glycolytic capacity in the lungs of fetuses of diabetic mothers has been related to reduction in surfactant level, which underlies respiratory distress syndrome frequently encountered in neonates of diabetic pregnancies.
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PMID:Effects of maternal diabetes on the development of carbohydrate-metabolizing enzymes, glycogen deposition and surface active phospholipid levels in fetal rat lung. 630 58

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.
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PMID:Altered regulation of cardiac glycogen metabolism in spontaneously diabetic rats. 631 7

Glucose and gluconeogenic substrates promote the activation of hepatic glycogen synthase in vivo and in vitro; activation occurs as inactive glycogen synthase D is dephosphorylated to active glycogen synthase I by glycogen synthase phosphatase. Impairments of glycogen accumulation and glycogen synthase activation in diabetes have been attributed to decreased glycogen synthase phosphatase activity. To determine the role of glycogen synthase phosphatases associated with cytosol and smooth endoplasmic reticulum in the impairment of glycogen synthase activation, livers of normal and streptozotocin-diabetic fed rats were sampled by freeze-clamping before and after perfusion with a mixture of 25 mM glucose, 10 mM glutamine, 4 mM lactate, and 1 mM pyruvate. Perfusion induced activation of glycogen synthase in normal rats, but activation was reduced in the diabetic rats in proportion to the severity of insulin deficiency (r = 0.72, P less than 0.0001). There was also a close correlation between insulin levels and glycogen synthase phosphatase activities of both cytosol (r = 0.76, P less than 0.0001) and SER (r = 0.71, P less than 0.0001) fractions. In contrast, glycogen phosphorylase phosphatase activity and inactivation of glycogen phosphorylase during perfusion were normal in the diabetic livers. This is the first demonstration that glycogen synthase phosphatase activities in both soluble and SER fractions of liver cells are closely related to circulating insulin levels, and that the impairment of glycogen synthesis in diabetes may result from deficient glycogen synthase phosphatase activity in both cell compartments.
Diabetes 1983 Dec
PMID:Impaired glycogenic substrate activation of glycogen synthase is associated with depressed synthase phosphatase activity in diabetic rat liver. 631 99

The mechanism by which exogenous glucose stimulates the incorporation of hepatic glucose-6-phosphate into glycogen in fasted rats has not been clearly delineated. We gave glucose intragastrically over a 3.5-h period during which liver glycogen was deposited at linear rates. Simultaneous primed continuous infusion of [2-3H] or [3-3H]glucose established that under these conditions absolute carbon flow through hepatic glucose-6-phosphatase was greatly suppressed. After 1 h, hepatic [UDP-glucose] and [glucose-6-phosphate] had fallen by 50-60% and the former remained low throughout the experiment. By contrast, [glucose-6-phosphate] rebounded to its initial value by 2 h and remained at this level during the subsequent hour. We interpret the data as follows. Exogenous glucose, in addition to acting as a precursor of liver glucose-6-phosphate, causes diversion of the latter away from free glucose formation and into glycogen synthesis. The fall in [UDP-glucose] is in accord with a glucose-induced activation of glycogen synthase, as proposed by Hers (Annu. Rev. Biochem. 1976; 45:167-89.). However, the fall-rise sequence of glucose-6-phosphate concentration constitutes the first direct evidence in vivo for simultaneous inhibition at the level of glucose-6-phosphatase.
Diabetes 1984 Feb
PMID:Evidence for suppression of hepatic glucose-6-phosphatase with carbohydrate feeding. 631 14

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.
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PMID:The hepatic defect in glycogen synthesis in chronic diabetes involves the G-component of synthase phosphatase. 632 Aug 6

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


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