Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to determine whether altered glucose transporter expression is essential for the in vivo insulin-resistant glucose uptake characteristic of streptozocin-induced diabetes. Immunofluorescence in rat skeletal muscle colocalizes GLUT4 with dystrophin, both intrinsic to muscle fibers. In contrast, GLUT1 is extrinsic to muscle fibers, probably in perineurial sheath. Immunoblotting shows that levels of GLUT1 and GLUT4 protein per DNA in hindlimb muscle are unaltered from control levels at 7 d of diabetes but decrease to approximately 20% of control at 14 d of diabetes. This decrease is prevented by insulin treatment. In adipose cells of 7 d diabetic rats, GLUT4 levels are depressed. Thus, GLUT4 undergoes tissue-specific regulation in response to diabetes. GLUT4 and GLUT1 mRNA levels in muscle are decreased 62-70% at both 7 and 14 d of diabetes and are restored by insulin treatment. At 7 d of diabetes, when GLUT4 protein levels in muscle are unaltered, in vivo insulin-stimulated glucose uptake measured by euglycemic clamp is 54% of control. This reflects impairment in both glycogen synthesis and glycolysis and the substrate common to these two pathways, glucose-6-phosphate, is decreased approximately 30% in muscle of diabetic rats. These findings suggest a defect early in the pathway of glucose utilization, probably at the step of glucose transport. Because GLUT1 and GLUT4 levels are unaltered at 7 d of diabetes, reduced glucose uptake in muscle probably reflects impaired glucose transporter translocation or intrinsic activity. Later, at 14 d of diabetes, GLUT1 and GLUT4 protein levels are reduced, suggesting that sequential defects may contribute to the insulin-resistant glucose transport characteristic of diabetes.
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PMID:Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats. 204 Jul 1

We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant, whole-body and forearm glucose disposal, oxidative and nonoxidative glucose disposal (indirect calorimetry), and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal, pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis, because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where, by glucose mass action, whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis, but it did not result in accumulation of free intracellular glucose, glucose-6-phosphate, glucose-1-phosphate, fructose-6-phosphate, or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.
Diabetes 1990 Feb
PMID:Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. 212 71

Sulfonylureas are used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) largely because of their ability to enhance insulin secretion and possibly to potentiate insulin action. In this study, we investigated the effects of chronic glyburide treatment on glycogen synthase activity determined in skeletal muscle biopsies taken during euglycemic hyperinsulinemic clamps in nine Pima Indians with NIDDM. Insulin was infused at the rate of 40 mU/m2/min (low dose) followed by 400 mU/m2/min (high dose). Compared with the fasting value, the mean glycogen synthase activity assayed at low glucose-6-phosphate (G6P) concentration (active glycogen synthase) showed no significant changes during insulin infusion before glyburide treatment. After glyburide treatment, the mean active glycogen synthase increased by 39% (P less than .05) above the fasting value during the high-dose insulin infusion. Total glycogen synthase activity assayed at high G6P concentration did not change after glyburide treatment. Changes of insulin-stimulated active glycogen synthase associated with glyburide treatment correlated with changes in total body glucose disposal rates (r = .70, P less than .05) during euglycemic clamps. We conclude that glyburide treatment of subjects with NIDDM is associated with an increase in insulin action in vivo and concomitantly with improved insulin action on skeletal muscle glycogen synthase.
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PMID:Skeletal muscle glycogen synthase activity in subjects with non-insulin-dependent diabetes mellitus after glyburide therapy. 212 77

Erythrocyte membranes drawn from diabetic patients with poor metabolic control have increased protein glycosylation and decreased Ca2(+)-ATPase activity. A significant relationship was found between these two parameters. Similar results were obtained when protein glycosylation and Ca2(+)-ATPase activity were measured in membranes from normal erythrocytes preincubated with glucose. In this condition, both parameters showed a clear time and dose dependence. Incubation of erythrocyte membranes instead of intact erythrocytes with glucose and glucose-6-phosphate strongly suggests that only the glycosylation of the membrane inner-surface proteins can affect Ca2(+)-ATPase activity. The simultaneous presence of 10 mM glucose and 5 mM ATP in the incubation medium did not affect the degree of erythrocyte membrane protein glycosylation but significantly blocked the inhibitory effect of glucose on Ca2(+)-ATPase activity. However, 5 mM ATP only partially blocked the inhibitory effect of 100 mM glucose, suggesting a competitive mechanism of glucose and ATP for the enzyme active site. Our results show that glycosylation of erythrocyte membrane proteins significantly inhibits Ca2(+)-ATPase activity. This effect could contribute to the development of the capillary closure process observed in diabetic patients. Furthermore, it could represent an index of a general impairment of enzyme function arising in cells chronically exposed to high glucose levels.
Diabetes 1990 Jun
PMID:Decreased Ca2(+)-ATPase activity after glycosylation of erythrocyte membranes in vivo and in vitro. 214 Aug 3

Substrate cycles (SC) are formed by a 'forward pathway' (FP) and a 'backward pathway' (BP), the difference between FP and BP forming the 'metabolic flux' (MF) through the route of which the cycle is part. SC modulate regulatory effects, i.e. amplify or reduce the % change in MF compared to the % change in FP and BP, thus affecting the sensitivity to regulatory factors, including hormones. A formula is given to calculate (with an approximation of +/- 0.5) the 'flux response index' (FRI), i.e. the factor by which the % change in FP plus the % change in BP must be multiplied to obtain the % change in metabolic flux, when FP and BP undergo opposite, non-unidirectional changes (as is often the case in metabolic regulation). The formula is: FRI = [( FP + BP)/(FP-BP)]/2. By this formula we evaluated the hepatic activities of glucose-6-phosphatase and glucokinase (which roughly reflect hepatic glucose production and uptake, respectively), i.e. the two enzymes that catalyze the cycle between glucose-6-phosphate (glucose-6-P) and glucose. Based on data obtained in normal, nonobese diabetic and obese diabetic subjects as well as in normal, streptozotocin-diabetic, and obese diabetic (ob/ob) mice, we found that FRI was reduced in non-obese diabetic humans and animals whereas it was increased in obese-diabetic humans and mice, compared to normal controls. Thus, diabetes without obesity decreases, and obesity with diabetes increases, the sensitivity of the glucose-6-P/glucose cycle to regulatory agents.
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PMID:A formula for quantifying the effects of substrate cycles (futile cycles) on metabolic regulation. Its application to glucose futile cycle in liver as studied by glucose-6-phosphatase/glucokinase determinations. 215 82

To obtain insight regarding the mechanism(s) of response of the catalytic unit of glucose-6-phosphatase (D-glucose-6-P phosphohydrolase; EC 3.1.3.9) to glucocorticoid administration and insulin deprivation, the functional enzyme concentration E0 was estimated from presteady-state kinetics by the stopped-flow technique. The E0 values were compared with Vmax values determined by the steady-state kinetic approach. Studies were carried out with detergent-disrupted microsomes from livers of normal fed, 48-h fasted, streptozotocin-diabetic, and triamcinolone-treated rats. All of the treatments caused an increase in E0, but Vmax values were increased only in fasting and diabetes. Km values were unaffected by all the treatments. The increase in Vmax observed with fasted and diabetic rats was explained by an increase in E0 alone. These results showed that insulin deprivation resulted in an increased formation of fully active glucose-6-phosphatase catalytic unit. In contrast, administration of triamcinolone caused an increase in E0 but not in Vmax. It was concluded that glucocorticoid administration may promote formation of catalytic units of glucose-6-phosphatase which are less active than the enzyme normally present or formed in response to insulin deprivation.
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PMID:Hormonal responses of glucose-6-phosphatase catalytic unit studied by stopped-flow analysis. 216 Aug 32

Pancreatic islets from healthy (control) and neonatally streptozocin-induced diabetic (STZ-D) rats, a model for non-insulin-dependent diabetes mellitus, were incubated with 3H2O and 5.5 or 16.7 mM glucose. At 5.5 mM glucose, no detectable [3H]glucose was formed. At 16.7 mM, 2.2 patom.islet-1.h-1 of 3H was incorporated into glucose by the control islets and 5.4 patom.islet-1.h-1 by STZ-D islets. About 75% of the 3H was bound to carbon-2 of the glucose. Glucose utilization was 35.3 pmol.islet-1.h-1 by the control and 19.0 pmol.islet-1.h-1 by the STZ-D islets. Therefore, 4.5% of the glucose-6-phosphate formed by the control islets and 15.7% by the STZ-D islets was dephosphorylated. This presumably occurred in the beta-cells of the islets catalyzed by glucose-6-phosphatase. An increased glucose cycling, i.e., glucose----glucose-6-phosphate----glucose, in islets of STZ-D rats may contribute to the decreased insulin secretion found in these animals.
Diabetes 1990 Apr
PMID:Glucose cycling in islets from healthy and diabetic rats. 218 Jul 57

Because skeletal muscle plays a major role in glucose disposal, it may be the primary site of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM). Rates of glycogen synthesis (GS), glucose utilization via glycolysis, glycolytic utilization (GU), and glucose transport (GT) were studied in epitrochlearis muscles (EMs) obtained from 10-wk-old nonfasted Sprague-Dawley rats in which NIDDM was neonatally induced with streptozocin. Plasma glucose in NIDDM rats was elevated (P less than 0.001), whereas plasma insulin was similar in NIDDM and control rats. No differences in muscle weight, protein, glycogen, ATP, phosphocreatine, lactate, lactate-pyruvate ratios, or glucose-6-phosphate were noted in EMs of control and NIDDM rats. EMs were incubated in medium containing 5.6 or 11.2 mM glucose with tracer D-[5-3H]glucose and insulin from 0 to 7.18 x 10(-7) M for 1 or 2 h, and GS, GT, and GU were evaluated. Similar rates of basal (non-insulin-mediated) and insulin-stimulated GS, GU, and GT were observed in EMs of NIDDM and control rats incubated in 5.6 mM glucose for 2 h. Insulin dose-response curves revealed similar sensitivities and responsiveness. Increasing glucose concentration (from 5.6 to 11.2 mM) induced significant increases in basal rates of GS, GU, and GT in EMs of control but not NIDDM rats. Insulin dose-response curves for GS and GT revealed decreased sensitivity and no change in responsiveness in EMs of control and NIDDM rats, even though GU of EMs of NIDDM rats was significantly lower at basal and all other insulin concentrations. These data revealed that both insulin resistance and glucose resistance contribute to the impaired glucose metabolism in EMs of the NIDDM rat.
Diabetes 1990 Sep
PMID:Effect of insulin on glucose utilization in epitrochlearis muscle of rats with streptozocin-induced NIDDM. 220 Jul 30

This study was designed to examine the mechanisms causing peripheral insulin resistance in patients with insulin-dependent diabetes mellitus (IDDM) by studying insulin receptor function and glycogen synthase activity in biopsies of skeletal muscle. The results in seven such patients were compared with values obtained in a group of sedentary, age- and sex-matched normal subjects. In addition, since physical training appears to improve insulin sensitivity, the IDDM patients were reexamined after physical training for 6 weeks. The mean maximal glycogen synthase activity was lower in the diabetic than in the normal group [34.5 +/- 10.6 (+/- SD) vs. 45.7 +/- 8.6 nmol/mg protein.min; P less than 0.05], whereas there was no difference in the half-maximal activation constant (A0.5) for glucose-6-phosphate. Likewise, the mean yield of wheat germ agglutinin-purified insulin receptors recovered per mg muscle was 21% lower in the muscle biopsies from the diabetic patients (47 +/- 8 vs. 66 +/- 20 fmol/100 mg; P less than 0.05. However, basal and insulin-stimulated receptor kinase activities, expressed as phosphorylation of the synthetic peptide poly-Glu-Tyr(4:1), were identical in the two groups. After physical training in the diabetic patients the mean maximal oxygen uptake increased from 45.7 +/- 7.4 to 48.9 +/- 9.0 mL O2/kg.min (P less than 0.05), hemoglobin A1c decreased from 7.9 +/- 1.4% to 7.7 +/- 1.5% (P less than 0.05), and insulin requirements decreased from 43 +/- 9 to 38 +/- 8 U/day (P less than 0.05). The number of recovered insulin receptors did not increase, and the receptor kinase activity was similar to the pre-training value. Maximal glycogen synthase activity increased by 15% (P less than 0.02), whereas A0.5 for glucose-6-phosphate did not change. We conclude that insulin binding to muscle-derived insulin receptors is impaired in IDDM patients, whereas receptor kinase function appears to be normal. The capacity for glycogen storage in the diabetic skeletal muscle was reduced. Physical training tended to normalize glycogen synthase activity, but did not improve insulin receptor function significantly.
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PMID:Insulin receptor function and glycogen synthase activity in skeletal muscle biopsies from patients with insulin-dependent diabetes mellitus: effects of physical training. 249 87

Glucose turnover determined with tritiated isotopes of glucose is subject to potential error due to glucose/glucose-6-phosphate cycling and/or cycling through glycogen. To determine the extent to which these processes alter the apparent pattern of postprandial glucose metabolism, we measured glucose turnover simultaneously with [2(3)H] glucose (an isotope that minimally cycles through glycogen but is extensively detritiated during glucose/glucose-6-phosphate cycling) and [3(3)H] glucose (an isotope that is not detritiated during glucose/glucose-6-phosphate cycling but can cycle through glycogen). Glucose turnover was measured in patients with non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic subjects both before and after ingestion of a carbohydrate meal isotopically with labeled [6(14)C] glucose. In the postabsorptive state hepatic glucose appearance was higher (P less than .05) when determined with [2(3)H] glucose than with [3(3)H] glucose in the diabetic patients, but not in the nondiabetic subjects. After glucose ingestion the integrated responses of glucose appearance, systemic entry of ingested glucose, and hepatic glucose release all were higher (P less than .05) when determined with [2(3)H] glucose compared to [3(3)H] glucose in both the diabetic and nondiabetic subjects. However, the absolute difference between glucose turnover measured with [2(3)H] and [3(3)H] glucose were similar in the diabetic and nondiabetic subjects. Both isotopes provided a similar assessment of postprandial carbohydrate metabolism, indicating that either isotope can be used with equal efficacy to compare postprandial carbohydrate metabolism in patients with NIDDM and nondiabetic subjects.
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PMID:Assessment of the postprandial pattern of glucose metabolism in nondiabetic subjects and patients with non-insulin-dependent diabetes mellitus using a simultaneous infusion of [2(3)H] and [3(3)H] glucose. 235 58


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