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)

Increased oxidant stress has been suggested to occur in diabetes and to contribute to the development of late diabetic complications. Whether oxidant stress plays a role in the development or progression of insulin resistance is not known. In this study we hypothesized that exposing 3T3-L1 adipocytes to prolonged micromolar concentrations of H2O2 would reduce their acute metabolic responses to insulin stimulation. 3T3-L1 adipocytes exposed to 25 mU/ml glucose oxidase (GO) for 18 h exhibited a threefold increase in basal 2-deoxyglucose (2-DG) uptake activity. However, net increase in 2-DG uptake activity after acute insulin (100 nM) stimulation was 355 +/- 56 pmol.mg protein-1.min-1 in control vs. 198 +/- 41 pmol.mg protein-1.min-1 in GO-pretreated cells (P < 0.05). Basal lipogenesis activity was significantly enhanced by GO, but acute insulin stimulation resulted in significantly reduced lipogenesis activity (29 +/- 4 vs. 11 +/- 1 nmol glucose/well for control and 50 mU/ml GO, respectively, P = 0.001). Glycogen synthase alpha activity was reduced by GO (78 +/- 1 vs. 43 +/- 2 pmol UDP-glucose.mg protein-1.min-1, P = 0.03), whereas insulin stimulation of glycogen synthase was reduced, exhibiting a right shift in the insulin dose-response curve. These effects of GO were associated with increased GLUT-1 and reduced GLUT-4 protein and mRNA content. In conclusion, our data suggest that oxidant stress alters glucose transporters expression and insulin-stimulated metabolism in 3T3-L1 adipocytes.
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PMID:Oxidant stress reduces insulin responsiveness in 3T3-L1 adipocytes. 917 96

By immunocytochemistry we have studied the effect of recombinant human insulin-like growth factor I (rhIGF-I) on expression of renal GLUT-1, -2, and -5 in rats with streptozotocin (STZ)-induced diabetes. In the renal tubules of these rats, expression of GLUT-1 was reduced and that of GLUT-2 was increased. GLUT-1 expression was restored, and GLUT-2 expression was normalized by 2-wk administration of rhIGF-I. We have shown that GLUT-5 was expressed at the brush-border membrane of the proximal convoluted tubules (PCT) of the cortex and at the glomerular mesangial cells (GMC) in normal rat kidney. In the diabetic rats, GLUT-5 expression was increased at both sites, along with an increase of GLUT-2 expression at the basolateral membrane of PCT, and was decreased to normal level at both sites by treatment with rhIGF-I. Thus, like GLUT-2, GLUT-5 is suggested to regulate glucose reabsorption in PCT. The relationship between overexpression of GLUT-5 in GMC and accumulation of sorbitol and advanced glycosylation end products are discussed. Regulation of GLUT expression may play an important role on renal glucose homeostasis.
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PMID:Recombinant insulin-like growth factor I normalizes expression of renal glucose transporters in diabetic rats. 924 89

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 +/- 19 vs. 185-209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 +/- 13 vs. 166-194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 +/- 4 mg. kg-1. min-1 in wild-type vs. 61 +/- 4, 67 +/- 5, and 63 +/- 6 mg. kg-1. min-1 in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU. kg-1. min-1 insulin, and 54 +/- 7, 85 +/- 4, and 98 +/- 11 in wild-type, GLUT-1, and GLUT-4 mice given 60-80 mU. kg-1. min-1 insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 +/- 3.4 vs. 42.4 +/- 5.9, 51.2 +/- 8.1, and 55.9 +/- 4. 9 mg. kg-1. min-1 in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.
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PMID:GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance. 995 Aug 1

Prompted by our recent observations that GLUT-1 is expressed in fetal muscles, but not in adult muscle fibers, we decided to investigate whether GLUT-1 expression could be reactivated. We studied different stimuli concerning their ability to induce GLUT-1 expression in mature human skeletal muscle fibers. Metabolic stress (obesity, non-insulin-dependent diabetes mellitus), contractile activity (training), and conditions of de- and reinnervation (amyotrophic lateral sclerosis) could not induce GLUT-1 expression in human muscle fibers. However, regenerating muscle fibers in polymyositis expressed GLUT-1. In contrast to GLUT-1, GLUT-4 was expressed in all investigated muscle fibers. Although the significance of GLUT-1 in adult human muscle fibers appears limited, GLUT-1 may be of importance for the glucose supplies in immature and regenerating muscle.
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PMID:Induction of GLUT-1 protein in adult human skeletal muscle fibers. 1105 76

A stable clone of rat mesangial cells expressing antisense GLUT-1 (i.e., MCGT1AS cells) was developed to protect them from high glucose exposure. GLUT-1 protein was reduced 50%, and the 2-deoxy-[(3)H]glucose uptake rate was reduced 33% in MCGT1AS. MCLacZ control cells and MCGT1 GLUT-1-overexpressing cells were used for comparisons. In MCLacZ, 20 mM D-glucose increased GLUT-1 transcription 90% vs. no increase in MCGT1AS. Glucose (8 mM) and 12 mM xylitol [a hexose monophosphate (HMP) shunt substrate] did not stimulate GLUT-1 transcription. An 87% replacement of the standard 8 mM D-glucose with 3-O-methylglucose reduced GLUT-1 transcription 80%. D-Glucose (20 mM) increased fibronectin mRNA and protein by 47 and 100%, respectively, in MCLacZ vs. no increases in MCGT1AS. Fibronectin synthesis was elevated 48% in MCGT1 and reduced 44% in MCGT1AS. We conclude that 1) transcription of GLUT-1 in response to D-glucose depends on glucose metabolism, although not through the HMP shunt, and 2) antisense GLUT-1 treatment of mesangial cells blocks D-glucose-induced GLUT-1 and fibronectin expression, thereby demonstrating a protective effect that could be beneficial in the setting of diabetes.
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PMID:Antisense GLUT-1 protects mesangial cells from glucose induction of GLUT-1 and fibronectin expression. 1124 57

Microangiopathy is a systemic complication of diabetes that is especially severe in the retinal microcirculation. The objective of this study was to compare glucose uptake and glucose transporter expression between retinal endothelial cells and the closely related endothelial cells derived from the cerebral microcirculation. Endothelial cells isolated from bovine brain, bovine retinal, and rat heart microvessels were cultured in the presence of control (5 mM) and high levels of (30 mM) d-glucose for 1-5 days. Glucose uptake by cultured endothelial cells was determined by measuring the uptake of [(3)H]deoxy-d-glucose and glucose transporter protein expression was assessed by Western blot. Our results showed that glucose uptake was significantly (P < 0.001) higher in brain- and heart-derived endothelial cells than in retinal endothelial cells at both physiologic and high concentrations of glucose. High levels of glucose caused a significant (P < 0.05) decrease in glucose uptake in brain-derived and heart endothelial cells but had no effect on retinal endothelial cells. Similarly, in response to high glucose levels there was a significant (P < 0.01) down regulation of GLUT-1 in brain-derived endothelial cells but not in retinal endothelial cells. These results suggest that despite a low basal level of glucose uptake the inability of retinal endothelial cells to down regulate glucose uptake in the presence of high glucose levels could make them especially sensitive to the deleterious effects of hyperglycemia in diabetes.
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PMID:Differential glucose uptake in retina- and brain-derived endothelial cells. 1167 26

Abnormal embryonic development is a complication of the diabetic pregnancy, and heart defects are among the most common and detrimental congenital malformations of the diabetic embryopathy. Hypoglycemia is a common side effect of diabetes therapy and is a potential teratogen. An association between hypoglycemia and congenital defects has been difficult to demonstrate in humans, but in vivo and in vitro animal studies have illustrated the importance of glucose as a substrate for normal development. Hypoglycemia alters embryonic heart morphology, producing abnormal looping and chamber expansion, decreased myocardial thickness, disorganized layers, and decreased overall size. Hypoglycemia decreases embryonic heart rate and vascularity, and it alters embryonic heart metabolism by increasing glucose uptake and glycolysis. Hypoglycemia also affects protein expression in the embryonic heart, increasing the expression of glucose regulated proteins, hexokinase, and glucose transport protein. Thus, hypoglycemia interferes with normal cardiogenesis and alters morphology, function, metabolism, and expression of certain proteins in the developing heart. It is likely that these factors contribute to heart defects observed in the diabetic embryopathy, but the definitive link has yet to be made. Future studies are expected to further elucidate mechanisms mediating hypoglycemia-induced cardiac dysmorphogenesis.
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PMID:Hypoglycemia and embryonic heart development. 1177 16

Diabetes is associated with extensive microvascular pathology and decreased expression of the glucose transporter (GLUT-1) in retina, but not brain. To explore the basis of these differences, the authors simultaneously measured glucose influx (micromol x g(-1) x min(-1)) and blood flow (mL x g(-1) x min(-1)) in retina and brain cortex of nondiabetic control rats (normoglycemic and acute-hyperglycemic) and in rats with streptozotocin-induced diabetes (with or without aminoguanidine (AMG) treatment) using a single-pass, dual-label indicator method. In addition, tissue glucose and adenosine triphosphate (nmol/mg dry weight) levels were measured. Glucose influx in retina exceeded that of cortex by about threefold for both the nondiabetic and diabetic groups. In contrast, blood flow in retina was significantly lower than in cortex by about threefold for each group. Retinal and cortical glucose influx in the diabetic rats was lower than in the nondiabetic acute-hyperglycemic group, but not in the normoglycemic group. Blood flow in these tissues remained relatively unchanged with glycemic conditions. The glucose levels in the diabetic retina (aminoguanidine untreated and aminoguanidine treated) were fourfold to sixfold greater than the nondiabetic retina. The cortical glucose levels remained unchanged in all groups. These data suggest that the accumulation of glucose in the diabetic retina cannot be explained by increased endothelial-glucose uptake or increased vascular membrane permeability.
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PMID:Comparison of glucose influx and blood flow in retina and brain of diabetic rats. 1508 14

In this study, we clarify that high glucose inhibits albumin uptake in cultured LLC-PK1 cells. LLC-PK1 cells cultured for 6 days with 5.5-27.8 mM D-glucose were challenged by fluorescein isothiocyanate (FITC)-conjugated human albumin (HA). FITC-HA binding and uptake were inhibited by >5.5mM glucose (5.5 mM > (P < 0.01) 11.0 mM > (P < 0.05) 16.7 mM approximately= 27.8 mM). Analysis of FITC-HA binding and uptake at 5.5 and 16.7 mM D-glucose (high glucose, HG) showed decreased affinity (K(m) for binding: 35.5 mg/l versus 52.6 mg/l, K(m) for uptake; 41.3 mg/l versus 55.6 mg/l) and maximal velocity (B(max)--0.33 microg versus 0.27 microg/30 min/mg protein; U(max)--4.40 microg versus 3.48 microg/60 min/mg protein) at HG. A comparison of the time courses of FITC-HA binding and uptake at 5.5 mM glucose and at HG showed that HG suppressed them beyond 15 min (P < 0.005-0.001). Phlorizin (>0.25 mM) completely reversed the HG-induced inhibition of FITC-HA binding and uptake. High glucose decreased mRNA of GLUT-1 and SGLT-1, but did not influence that of SGLT-2. The simultaneous presence of Vitamin E (10(-6)M), Vitamin C (10(-6)M) and reduced glutathione (0.25 mM) reversed the suppressed FITC-HA binding and uptake by HG, while any one or two of these molecules, and various inhibitors of advanced glycation end products, failed to do so. In conclusion, a high glucose milieu causes inhibition of albumin binding and uptake in proximal tubular cells by increasing metabolic oxidative stress through excessive glucose flux via the sodium glucose transporter.
Diabetes Res Clin Pract 2004 Sep
PMID:High glucose reduces albumin uptake in cultured proximal tubular cells (LLC-PK1). 1533 Dec 1

The direct effects of prolonged exposure to sulphonylureas on the function and survival of human islets are unknown. This study assessed the insulin content, glucose-stimulated insulin release, islet cell apoptosis, and mRNA expression of insulin and GLUT-1 in isolated human islets cultured in the presence of therapeutical concentrations of glimepiride (10 microM), glibenclamide (10 microM), or chlorpropamide (600 microM). Islets were prepared by collagenase digestion and density gradient purification from 18 multiorgan donors and were then exposed for 24 h to the different sulphonylureas. Insulin content decreased significantly following culture with any sulphonylurea compound. In response to an acute challenge with 3.3 and 16.7 mM glucose, insulin release from the control islets accounted for 1.9 +/- 0.5% and 4.9 +/- 1.7% of total insulin content (P<.01), respectively. Glucose responsiveness was preserved in islets precultured in the presence of glimepiride, whereas high glucose level did not elicit any significant increase of insulin secretion from islets preincubated with glibenclamide or chlorpropamide. These alterations were reverted by an additional 48-h incubation in drug-free conditions. The amount of apoptotic cells did not differ significantly among the experimental groups. Quantitative RT-PCR studies showed that, compared with the control islets, cells preincubated with glibenclamide or chlorpropamide had an increased expression of insulin mRNA, with no change in the expression of GLUT-1. In conclusion, prolonged exposure of human islets to different sulphonylureas causes different disturbances of islet cell function, with glimepiride showing milder effects, as compared with chlorpropamide and glibenclamide.
J Diabetes Complications
PMID:Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets. 1564 92


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