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)

We studied the expression of the glucose transporter GLUT 4 in the soleus and red gastrocnemius muscles from obese, diabetic (fa/fa) Zucker rats compared to their lean littermates (Fa/-), with and without treatment with the antidiabetic drug metformin. In the untreated groups of rats, the GLUT 4 content in a crude membrane fraction of both the soleus and the red gastrocnemius muscles were significantly lower in the obese (fa/fa) rats (3.46 +/- 0.28 vs. 6.04 +/- 0.41, p < 0.001 and 6.0 +/- 0.24 vs. 9.1 +/- 0.48, p < 0.0001, respectively). Differences in GLUT 4 expression in soleus muscle from the same rats were confirmed by quantitative immunofluorescence microscopy, and the results were significantly correlated with the results obtained from quantitative immunoblotting (rho = 0.70, p < 0.0005). The decreased expression of GLUT 4 in fa/fa rats could contribute to the well-established insulin resistance in skeletal muscle of these animals. After 4 weeks of treatment with metformin, weight gain was not affected in either the diabetic (fa/fa) rats or the lean (Fa/-) rats. Improvement of glucose homeostasis by metformin was not associated with normalization of the GLUT 4 expression in the skeletal muscles studied, indicating (1) that the decreased GLUT 4 expression is not directly related to hyperinsulinaemia and diabetes mellitus and (2) that metformin does not normalize the expression of GLUT 4 in skeletal muscle of the diabetic (fa/fa) Zucker rats.
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PMID:Metformin ameliorates diabetes but does not normalize the decreased GLUT 4 content in skeletal muscle of obese (fa/fa) Zucker rats. 833 68

Previous studies have shown that the principal glucose transporter isoform within the blood-brain barrier (BBB) is GLUT1, and that GLUT1 mRNA is upregulated and immunoreactive GLUT1 protein is downregulated in rats with streptozocin (STZ)-induced experimental diabetes. The present studies investigate effects of insulin therapy on both GLUT1 mRNA and immunoreactive GLUT1 protein in brain capillaries isolated from control (CO), diabetic (DM), and insulin-treated diabetic (IRx) rats. The following variables were measured: serum glucose levels, rat brain capillary immunoreactive GLUT1 level by quantitative Western blotting, and rat brain capillary GLUT1 and actin mRNA levels by quantitative Northern blotting. Serum glucose levels were 6.4 +/- 1.2, 30.3 +/- 3.2, and 3.7 +/- 1.7 mmol/L in CO, DM, and IRx rats, respectively. Brain capillary immunoreactive GLUT1 transporter protein level was 53% +/- 13% of CO values in DM rats, and this value was unchanged with insulin treatment. GLUT1 mRNA level in rat brain was increased to 131% +/- 8% of CO values in DM rats and was 80% +/- 5% of CO values in IRx rats. In conclusion, short-term insulin therapy in rats with STZ-induced diabetes normalizes BBB GLUT1 mRNA level, but does not normalize depressed immunoreactive GLUT1 protein level.
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PMID:Insulin therapy normalizes GLUT1 glucose transporter mRNA but not immunoreactive transporter protein in streptozocin-diabetic rats. 834 16

Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed alpha-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.
Diabetes 1993 Sep
PMID:Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. 834 45

Diabetes alters adult brain glucose uptake and glucose transporter 1 gene expression. To investigate the effect of diabetes on genes regulating fetal brain glucose uptake, we examined the effect of moderate (blood glucose 10-16.7 mM, normoinsulinemia) and severe (blood glucose > 16.8 mM, hypoinsulinemia) maternal diabetes on the expression of genes regulating fetal brain glucose uptake in the genetically nonobese diabetic mouse. In the moderately diabetic state, a 50% decline in fetal brain GLUT1 mRNA levels was associated with a 20% increase in the corresponding GLUT1 protein levels. Simultaneously, although fetal brain GLUT3 mRNA and protein levels were barely detectable, no change in hexokinase I enzyme mRNA, protein (115,000 and 100,000 M(r)) or activity, was noted. In the severe form of maternal diabetes GLUT1 protein was unchanged, GLUT3 protein levels remained low, and a 2- to 3-fold increase in the lower molecular form of the hexokinase I protein (100,000 M(r)) and enzyme activity occurred. These observations suggest that moderate and severe forms of maternal diabetes do not affect the fetal brain glucose transporter levels to a physiologically significant extent. The severe form of maternal diabetes, however, enhances 1.5- to 3-fold the expression and activity of hexokinase I. This enzyme mediates the rate-limiting step in brain glucose metabolism, namely the intracellular conversion of glucose to glucose-6-phosphate.
Diabetes 1993 Oct
PMID:Effect of maternal diabetes on the expression of genes regulating fetal brain glucose uptake. 837 89

Insulin resistance in diabetic rats involves pretranslational suppression of the GLUT 4 glucose transporter in muscle. Because the capacity for insulin-mediated glucose transport varies as a function of muscle group, we hypothesized that GLUT 4 was differentially expressed and regulated by diabetes in a muscle-specific manner. We studied control (C), streptozocin (STZ)-induced diabetic (D), and insulin-treated diabetic (Tx) rats and examined the following muscles that vary in fiber composition: soleus (type I fibers), gastrocnemius (mixed type IIa > IIb), vastus lateralis and rectus abdominis (type IIb > IIa), and cardiac muscle. In C animals, these muscles exhibited significant differences in the baseline expression of GLUT 4. Relative GLUT 4 content was highest in cardiac muscle, intermediate in soleus, and significantly lower in gastrocnemius, rectus abdominis, and vastus lateralis (1.8:1.0:0.6). The impact of diabetes and insulin therapy on GLUT 4 expression also varied as a function of muscle group. After four weeks of diabetes, GLUT 4 levels were reduced by approximately 50% in cardiac muscle, soleus, and gastrocnemius. In contrast, GLUT 4 content in rectus abdominis and vastus lateralis was similar to that in control rats. Exogenous insulin treatment of diabetic rats increased GLUT 4 content in soleus, cardiac muscle, and gastrocnemius, but had no effect in either vastus lateralis or rectus abdominis. Temporal effects of diabetes and insulin treatment were also examined in different skeletal muscle. Soleus showed a significant decrease in GLUT 4 content as early as 2 days with a further decrease at 4 weeks; rectus abdominis showed little change at either time point.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Muscle group-specific regulation of GLUT 4 glucose transporters in control, diabetic, and insulin-treated diabetic rats. 841 43

Liver insulin resistance and glucagon-stimulated hepatic glucose production are characteristics of the diabetic state. To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism. By inhibiting renal tubular glucose reabsorption, phlorizin infusion to diabetic rats induced normoglycaemia, did not significantly alter low circulating insulinaemia, but caused a marked decrease in hyperglucagonaemia. Glucokinase and L-type pyruvate kinase mRNA levels were reduced respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of phlorizin infusion partially restored glucokinase mRNA and activity (40% of control levels), but had no effect on L-type pyruvate kinase mRNA and activity. In contrast to the glycolytic enzymes, mRNA and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase were increased (10- and 2.2-fold, respectively) in fed diabetic rats. Phlorizin administration decreased phosphoenolpyruvate carboxykinase mRNA to values not different from those in control rats, while phosphoenolpyruvate carboxykinase activity remained 50% higher than that in control rats. The 50% rise in liver glucose transporter (GLUT 2) mRNA and protein, produced by diabetes, was also corrected by phlorizin treatment. In conclusion, we propose that phlorizin treatment of diabetic rats may induce a partial shift of the predominating gluconeogenesis, associated with hepatic glucose overproduction, into glycolysis, by correction of impaired pre-translational regulatory mechanisms. This could be essentially mediated through improved pancreatic alpha-cell function and subsequent lowering of hyperglucagonaemia. These observations suggest that glucagon-stimulated hepatic glucose production may result, in part, from glucose toxicity.
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PMID:Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism. 847 72

The structure of the glucose transporter and the characteristics of the identified members of the facilitative glucose transporter gene family (GLUT1-5) are reviewed. The role of glucose transport in insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) is discussed. The potential contributions of genetic mutation and disruption of short- or long-term regulation of glucose transporters, particularly GLUT4, in insulin-sensitive tissues to the etiology of NIDDM are examined.
J Diabetes Complications
PMID:The molecular biology of glucose transport: relevance to insulin resistance and non-insulin-dependent diabetes mellitus. 851 55

The effects of englitazone in male Wistar rats fed a high-fat diet (59% of calories as fat) were compared with control rats fed a high-carbohydrate diet (69% of calories as carbohydrate) (5-15 animals per group). Insulin-stimulated (17 nmol/l) 2-deoxy-D-glucose (2-DG) uptake was inhibited 31% in adipocytes isolated from rats on the high-fat diet for 3 weeks, but englitazone (50 mg/kg for the last 7 days) normalized the response. There was a selective decrease in GLUT4 (54 +/- 5% of high-carbohydrate) in epididymal fat from rats on the high-fat diet for 3 weeks, but englitazone treatment did not reverse the defect in GLUT4 (43 +/- 8% of high-carbohydrate) or increase GLUT1 (81 +/- 12% of high-carbohydrate). Englitazone normalized oral glucose (1 g/kg body wt) intolerance and excessive (210% of high-carbohydrate) liver glycogen deposition (from [14C]glucose) caused by the high-fat diet. The high-fat diet tended to decrease insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3'-kinase (PI-3-kinase) expression in epididymal fat (26% decrease; P < 0.1). Englitazone did not reverse this decrease in IRS-1 and PI-3-kinase levels in fat from high-fat-fed rats (there was a further 25-30% decrease, P < 0.05), nor did it increase PI-3-kinase activity in 3T3-L1 adipocytes under conditions (48 h incubation) where it stimulated 2-DG uptake sixfold or enhanced insulin-stimulated 2-DG uptake. In summary, englitazone prevented the insulin resistance associated with a high-fat diet, but the mechanism of action does not involve changes in fat or muscle glucose transporter content and may not involve activation of the insulin signaling pathway via PI-3-kinase.
Diabetes 1996 Jan
PMID:The antihyperglycemic agent englitazone prevents the defect in glucose transport in rats fed a high-fat diet. 852 61

The effect of bradykinin on glucose transporter translocation in isolated rat heart was compared with the effect of insulin. Hearts from male obese (fa/fa) Zucker rats were perfused under normoxic conditions and constant pressure in a classic Langendorff preparation with 12 mmol/l glucose as substrate, and a set of functional parameters was measured simultaneously. Bradykinin was administered at a concentration (10(-11) mmol/l) that did not increase coronary flow. Insulin was used at a concentration (8 x 10(-8) mmol/l) known to maximally stimulate glucose transport in this model. After 15 min of perfusion with insulin or bradykinin, subcellular membrane fractions of the heart were prepared, and distribution of glucose transporter protein (GLUT1 and GLUT4) in fractions enriched with surface membranes (transverse tubules [TTs] and sarcolemmal membranes [PMs]) and with low-density microsomal membranes (LDMs) were determined by immunoblotting with the respective antibodies. Both glucose transporter isoforms were translocated after stimulation with insulin (increased transporter protein content in the PM+TT-enriched fraction with a concomitant decrease in the LDM-enriched fraction) and, to a smaller extent, also with bradykinin. These data suggest that in hearts of insulin-resistant obese (fa/fa) Zucker rats, bradykinin interacts with or facilitates the translocation process of both GLUT1 and GLUT4.
Diabetes 1996 Jan
PMID:Insulin-induced glucose transporter (GLUT1 and GLUT4) translocation in cardiac muscle tissue is mimicked by bradykinin. 852 3

Insulin rapidly stimulates glucose transport in muscle fiber. This process controls the utilization of glucose in skeletal muscle, and it is deficient in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. The effect of insulin on muscle glucose transport is mainly due to the recruitment of GLUT4 glucose carriers to the cell surface of the muscle fiber. There is increasing evidence that the recruitment of GLUT4 carriers triggered by insulin affects selective domains of sarcolemma and transverse tubules. In contrast, GLUT1 is located mainly in sarcolemma and is absent in transverse tubules, and insulin does not alter its cellular distribution in muscle fiber. The differential distribution of GLUT1 and GLUT4 in the cell surface raises new questions regarding the precise endocytic and exocytic pathways that are functional in the muscle fiber. The current view of insulin-induced GLUT4 translocation is based mainly on studies performed in adipocytes. These studies have proposed the existence of intracellular compartments of GLUT4 that respond to insulin in a highly homogeneous manner. However, studies performed in skeletal muscle have identified insulin-sensitive as well as insulin-insensitive intracellular GLUT4-containing membranes. These data open a new perspective on the dynamics of intracellular GLUT4 compartments in insulin-sensitive cells.
Diabetes 1996 Jan
PMID:Insulin-induced redistribution of GLUT4 glucose carriers in the muscle fiber. In search of GLUT4 trafficking pathways. 852 4


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