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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 on basal calcium metabolism and the response to endocrine stimulation were studied in hepatocytes from acute and long term diabetic rats. Hepatocyte calcium sequestration and turnover were increased in both acute and chronic diabetes. Cytosolic free calcium (Cai2+) was significantly increased in the chronic diabetics, but the rise in Cai2+ evoked by epinephrine, angiotensin, vasopressin, and glucagon was depressed. The blunted stimulation of phosphorylase-alpha activity in the diabetics was influenced by a 50-60% decrease in total cell activity of glycogen phosphorylase and the decreased rise in cytosolic free calcium. Insulin replacement corrected both basal and stimulated changes in the acute diabetes model. Depressed [3H]inositol trisphosphate formation in response to epinephrine or vasopressin and increased intracellular organelle calcium buffering were observed in hepatocytes from diabetic animals; both may effect the diminished rise in Cai2+. Several possible causes for the depressed rise in Cai2+ after stimulation in chronic diabetic animals were eliminated: 1) the number and affinity of alpha 1-adrenergic receptors for epinephrine were normal; 2) the initial rise in calcium influx evoked by epinephrine or vasopressin was not depressed; and 3) the ability of inositol trisphosphate to release calcium from intracellular organelles was not changed. The results suggest that the diabetic changes in calcium-mediated endocrine regulation of hepatic carbohydrate metabolism contribute to the general pathology of the disease.
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PMID:Effect of diabetes on hormone-stimulated and basal hepatocyte calcium metabolism. 255 50

Alloxan diabetes induced in white rats by intraperitoneal injection of alloxan-monohydrate (15 mg/100 g body weight) was used to study changes in the glycogen phosphorylase a and b, phosphoprotein phosphatases and hexokinase activities under insulin deficiency conditions. Among the enzymes studied, an increase in muscle phosphorylase a activity as well as the a/b ratio have been obtained. In diabetic muscle phosphoprotein phosphatases and hexokinase activities were diminished. AMP increased the liver glycogen phosphorylase activity twice in diabetic rats whereas in normal animals the enzyme was less sensitive to this effector. The changes in liver hexokinase activity at diabetes were not connected and correlated with the altered phosphorylase and protein phosphatase activities. The logical chain of probable molecular events taking place in muscle glycogen metabolism under the conditions of insulin deficiency is offered.
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PMID:Changes in the activity of enzymes, participating in glycogen metabolism of alloxan diabetic rats. 255 79

Treatment of pancreatic acini from diabetic rats with insulin resulted in a dose-dependent increase in the phosphorylation of ribosomal protein S6 when analyzed by two-dimensional gel electrophoresis. To study the presence of the protein kinase mediating this phosphorylation, soluble extracts of intact acini that had been previously treated with insulin were prepared and assayed for protein kinase activity with rat pancreatic ribosomes as a substrate. Activation of S6 kinase activity, observed in a time-dependent manner, was maximal after 20-30 min and, in a dose-dependent manner, was half-maximal at 1 nM and maximal at 10 nM insulin concentration. Based on cofactor requirements, substrate specificity, and a slow activation of the enzyme, the S6 kinase was distinct from cAMP-dependent, Ca2+-calmodulin-dependent, and Ca2+-phospholipid-dependent protein kinases and protease-activated kinase II. The S6 kinase activated by insulin was highly specific for the ribosomal protein S6 when compared with various substrates, including casein, glycogen synthase, phosphorylase b, phosvitin, histone HIII-S, and histone HVIII-S. Protein S6 phosphorylation in intact acini and activation of the S6 kinase by insulin showed similar dose-response curves, consistent with the S6 kinase being responsible for the protein S6 phosphorylation in intact acini. The comparison of the dose-response curves for S6 phosphorylation and protein synthesis in acini suggests that there is a close correlation between these two insulin actions.
Diabetes 1989 May
PMID:Insulin and ribosomal protein S6 kinase in rat pancreatic acini. 265 25

Whereas total cardiac glycogen phosphorylase activity appears to be unaffected by severe insulin deficiency, a diabetes-induced decreased in hepatic glycogen phosphorylase activity has been demonstrated by our laboratory and others using liver extracts, isolated perfused liver, and cultured hepatocytes. The loss of activity in diabetic liver can be correlated with a drop in protein levels. Using primary cultures of cells from normal and diabetic rats and phosphorylase specific antibodies, we found a corresponding decrease in phosphorylase synthesis in diabetic hepatocytes cultured for 2 days in a serum-free, chemically defined medium. When hepatocytes are cultured in the presence of insulin, triiodothyronine, and cortisol, there is a significant recovery in the rate of phosphorylase synthesis after 3 days. Over the 3-day time period, there is no significant difference in the rate of phosphorylase degradation in normal compared with diabetic hepatocytes. Total protein synthesis in both hepatocytes and cardiomyocytes is unaffected by diabetes, as is phosphorylase synthesis in cultured cardiomyocytes.
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PMID:Phosphorylase synthesis in diabetic hepatocytes and cardiomyocytes. 266 20

1. Hearts of diabetic rats gradually accumulate glycogen, although the activities of glycogen synthase and glycogen phosphorylase are altered in favor of a depletion of glycogen. 2. Phosphorylase in diabetic hearts has been reported to be even more activated in response to adrenaline than controls. 3. The situation is further complicated by the fact that in rat heart two isoenzymes of phosphorylase are present. Therefore we have studied the properties of phosphorylases purified from diabetic rat heart in more detail. 4. This investigation revealed that compared to controls: (A) the amount of enzyme protein which could be isolated from diabetic animals is drastically lower; (B) the affinities towards glycogen and inorganic phosphate are decreased; (C) the activation by phosphorylase kinase is delayed; and (D) the inactivation by protein phosphatase-1 is accelerated. 5. We conclude that all of the reported changes in diabetes might contribute to a phosphorylase system less able to catalyze glycogen breakdown effectively.
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PMID:Activation and inactivation of glycogen phosphorylase isoenzymes purified from diabetic rat heart. 274 7

Muscle homogenates representing slow-twitch oxidative, fast-twitch oxidative-glycolytic, fast-twitch glycolytic, and mixed fiber types were prepared from normal, diabetic, and insulin-treated diabetic rats. Diabetes was induced by injection of 80 mg . kg-1 of streptozotocin. The activities of citrate synthase, succinate dehydrogenase, and 3-hydroxyacyl-CoA dehydrogenase were employed as markers of oxidative potential, whereas phosphorylase, hexokinase, and phosphofructokinase activities were used as an indication of glycolytic capacity. Diabetes was associated with a general decrement in the activity of oxidative marker enzymes for all fiber types except the fast-twitch glycolytic fiber. In contrast, the fast-twitch glycolytic fibers demonstrated the greatest decline in glycolytic enzymatic activity. Insulin-treated animals, either trained or untrained, exhibited enzyme activities similar to their normal counterparts. Exercise training of diabetic rats mimicked the effect of insulin treatment and caused a near normalization of the activity of the marker enzymes. These findings suggest that the enzymatic potential of all skeletal muscle fiber types of diabetic rats may be normalized by exercise training even in the absence of significant amounts of insulin.
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PMID:Influence of training on skeletal muscle enzymatic adaptations in normal and diabetic rats. 293 94

Hepatic glycogen metabolism was investigated in genetically diabetic C57BL/KsJ-db/db mice during their development. Initially, the development of obesity, hyperglycemia, hyperinsulinemia, and hyperglucagonemia in these mice was examined, which illustrated that the diabetes progressed normally. Little difference in hepatic glycogen concentrations was observed, averaging approximately 50 and 60 mg/g liver in diabetic (db/db) and control heterozygote (db/+) mice, respectively. Glycogen synthase activity (total and a-form) was significantly elevated by 5 wk in the diabetic mice relative to controls and reached maximum levels (two-fold higher than controls) around 8-9 wk. This activity then slowly declined during the rest of the 15-wk period examined. Both phosphorylase a and total phosphorylase activities were also elevated by 5 wk, reaching levels twofold higher than controls. These activities did not decline at the end of this 15-wk period, but instead continued to slowly increase. Glycogen synthase a activity showed a positive correlation (r = 0.54, N = 144) with circulating levels of insulin, and a similar correlation was seen for phosphorylase a activity and plasma glucagon levels (r = 0.64, N = 72). Protein kinase and phosphoprotein phosphatase activities were also measured, but no differences were detected between diabetic and control mice. This longitudinal study clarifies some of the changes in hepatic glycogen metabolism that occur during the progression of diabetes in the db/db mouse and indicates a role for circulating insulin and glucagon concentrations on the steady-state activities of glycogen synthase and phosphorylase, respectively.
Diabetes 1985 Apr
PMID:Age-related changes in hepatic glycogen metabolism in the genetically diabetic (db/db) mouse. 298 86

The distribution of the spontaneous and trypsin-stimulated phosphorylase phosphatase activities between glycogen particles and cytosol was examined in muscle extracts obtained from rats that had been fasted, made diabetic with streptozotocin or injected with adrenaline. In all conditions the particle-bound phosphatase activities decreased, glycogen was degraded and phosphorylase was released from the particles into the cytosol. However, in fasting and diabetes (but not after adrenaline) the combined glycogen particle + cytosolic phosphatase activities decreased, indicating that the activity lost from the particles was not simply shifted to the cytosol. Fasting and diabetes (but not adrenaline) also decreased the phosphatase-activating ability of the muscle extracts, which was, at least in part, attributable to the protein kinase FA. These data indicate the presence of at least two different mechanisms affecting the phosphatase system, one modified by fasting and diabetes, the other by adrenaline.
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PMID:Effects of streptozotocin-diabetes, fasting and adrenaline on phosphorylase phosphatase activities of rat skeletal muscle. 301 88

Investigations in our laboratory have shown that the activity of glycogen synthase phosphatase in the liver is shared by at least two functionally distinct proteins: a G-component, which is tightly associated with glycogen particles, and a soluble S-component. Most preparations of glycogen synthase-b that are isolated from the liver of fed glucagon-treated animals require the presence of both components in order to be converted to synthase-a. The G-component is subject to control mechanisms that do not affect the S-component. Its activity is strongly inhibited by phosphorylase-a. This feature explains why glycogen synthesis and glycogenolysis do not normally occur simultaneously, except in the glycogen-depleted liver, where a futile cycle may occur. Experiments in vitro have shown that a minimal glycogen concentration is required to ensure the interaction between the G-component and phosphorylase-a. The G-component is also selectively inhibited by Ca2+, and the magnitude of this inhibition depends markedly on the glycogen concentration. The latter inhibition is probably one of the mechanisms by which cyclic adenosine monophosphate (cAMP)-independent glycogenolytic agents achieve the inactivation of glycogen synthase in the liver. Glucocorticoid hormones and insulin are required for the induction and/or maintenance of the G-component in the liver. During the development of the fetal rat, glucocorticoids induce the G-component in the liver. This is an essential event in the glucocorticoid-triggered deposition of glycogen in the fetal liver. A functional adrenal cortex is also required in the adult animal to prevent a loss of the capacity for hepatic glycogen storage during starvation. The latter capacity depends on the concentration of functional G-component in the liver. Chronic diabetes causes a similar functional loss. However, the effect of glucocorticoids is not mediated by a putative secretion of insulin.
Diabetes Metab Rev 1987 Jan
PMID:Control of glycogen synthesis in health and disease. 303 40

Acute hormonal regulation of liver carbohydrate metabolism mainly involves changes in the cytosolic levels of cAMP and Ca2+. Epinephrine, acting through beta 2-adrenergic receptors, and glucagon activate adenylate cyclase in the liver plasma membrane through a mechanism involving a guanine nucleotide-binding protein that is stimulatory to the enzyme. The resulting accumulation of cAMP leads to activation of cAMP-dependent protein kinase, which, in turn, phosphorylates many intracellular enzymes involved in the regulation of glycogen metabolism, gluconeogenesis, and glycolysis. These are (1) phosphorylase b kinase, which is activated and, in turn, phosphorylates and activates phosphorylase, the rate-limiting enzyme for glycogen breakdown; (2) glycogen synthase, which is inactivated and is rate-controlling for glycogen synthesis; (3) pyruvate kinase, which is inactivated and is an important regulatory enzyme for glycolysis; and (4) the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase bifunctional enzyme, phosphorylation of which leads to decreased formation of fructose 2,6-P2, which is an activator of 6-phosphofructo-1-kinase and an inhibitor of fructose 1,6-bisphosphatase, both of which are important regulatory enzymes for glycolysis and gluconeogenesis. In addition to rapid effects of glucagon and beta-adrenergic agonists to increase hepatic glucose output by stimulating glycogenolysis and gluconeogenesis and inhibiting glycogen synthesis and glycolysis, these agents produce longer-term stimulatory effects on gluconeogenesis through altered synthesis of certain enzymes of gluconeogenesis/glycolysis and amino acid metabolism. For example, P-enolpyruvate carboxykinase is induced through an effect at the level of transcription mediated by cAMP-dependent protein kinase. Tyrosine amino-transferase, serine dehydratase, tryptophan oxygenase, and glucokinase are also regulated by cAMP, in part at the level of specific messenger RNA synthesis. The sympathetic nervous system and its neurohumoral agonists epinephrine and norepinephrine also rapidly alter hepatic glycogen metabolism and gluconeogenesis acting through alpha 1-adrenergic receptors. The primary response to these agonists is the phosphodiesterase-mediated breakdown of the plasma membrane polyphosphoinositide phosphatidylinositol 4,5-P2 to inositol 1,4,5-P3 and 1,2-diacylglycerol. This involves a guanine nucleotide-binding protein that is different from those involved in the regulation of adenylate cyclase. Inositol 1,4,5-P3 acts as an intracellular messenger for Ca2+ mobilization by releasing Ca2+ from the endoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes Metab Rev 1987 Jan
PMID:Mechanisms of hormonal regulation of hepatic glucose metabolism. 303 41


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