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)

Brain maturation is characterized by a peak of cerebral energy metabolism and blood flow occurring between 3 and 8 years of age in humans and around 14-17 days of postnatal life in rats. This high activity coincides with the period of active brain growth. The human brain is dependent on glucose alone during that period, whereas rat brain uses both glucose and ketone bodies to cover its energetic and biosynthetic needs. The maturation of the density of glucose transporter sites-GLUT1 located at the blood-brain barrier and GLUT3 at the neuronal membrane-parallels the development of cerebral glucose utilization. During moderate acute hypoglycaemia, there are no changes in cerebral functional activity; cerebral glucose utilization decreases and blood flow increases only when hypoglycaemia is severe (lower than 2 mumol/ml). During chronic hypoglycaemia, the brain adapts to the low circulating levels of glucose: the number of glucose transporter sites is increased, and cerebral glucose utilization and function are maintained at normal levels while cerebral blood flow is more moderately increased than during acute hypoglycaemia. Neuronal damage consecutive to severe and prolonged hypoglycaemia occurs mainly in the cerebral cortex, hippocampus and caudate-putamen as a result of active release of excitatory amino acids.
Diabetes Metab 1997 Feb
PMID:Cerebral energy metabolism, glucose transport and blood flow: changes with maturation and adaptation to hypoglycaemia. 905 63

Glucose transport and GLUT1 expression were studied in fibroblasts from 7 lean and 5 obese non-insulin-dependent diabetic (NIDDM) subjects with at least 2 NIDDM first-degree relatives and from 12 lean and 5 obese non-diabetic subjects with no family history of diabetes. The obese individuals also had a strong family history of obesity. Fibroblasts from all of the subjects exhibited no difference in insulin receptor binding, autophosphorylation, and kinase and hexokinase activity. At variance, basal 2-deoxyglucose (2-DG) uptake and 3H-cytochalasin B binding were 50% increased in cells from individuals with NIDDM (p < 0.001) and/or obesity (p < 0.01) as compared to the lean non-diabetic subjects. Insulin-dependent (maximally stimulated-basal) 2-DG uptake and cytochalasin B binding were decreased three-fold in cells from the diabetic and/or obese subjects (p < 0.01). GLUT1 mRNA and total protein levels were comparable in fibroblasts from all the groups. However, basal GLUT1 cell-surface content was 50% greater in fibroblasts from the NIDDM and/or obese subjects as compared to the lean non-diabetic individuals while insulin-dependent GLUT1 recruitment at the cell surface was diminished three-fold. Increased basal GLUT1 content in the plasma membrane was also observed in skeletal muscle of 4 NIDDM and 3 non-diabetic obese individuals (p < 0.05 vs the lean non diabetic subjects). Basal 2-DG uptake in fibroblasts from diabetic/obese individuals and lean control subjects strongly correlated with the in vivo fasting plasma insulin concentration of the donor. A negative correlation was demonstrated between the magnitude of insulin-dependent glucose uptake by the fibroblasts and plasma insulin levels in vivo. We conclude that a primary abnormality in glucose transport and GLUT1 cell-surface content is present in fibroblasts from NIDDM and obese individuals. The abnormal GLUT1 content is also present in skeletal muscle plasma membranes from NIDDM and obese individuals.
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PMID:Abnormal glucose transport and GLUT1 cell-surface content in fibroblasts and skeletal muscle from NIDDM and obese subjects. 911 19

Impaired glucose-stimulated insulin secretion and impaired insulin-mediated glucose uptake are both prominent phenotypic features of non-insulin-dependent diabetes mellitus (NIDDM). Membrane proteins GLUT1 (HepG2), GLUT2 (liver/islet), and GLUT4 (muscle/adipose tissue) facilitate glucose uptake into cells, and their genes are candidates for NIDDM. To assess their role in primary defects of diabetes, we performed linkage analyses between NIDDM and 10 polymorphic markers near GLUT1, GLUT2 and GLUT4 genes in 79 multiplex French NIDDM families. Linkage analyses were performed using both parametric (lodscore) and non-parametric (allele sharing among affected sib pairs) methods. No evidence was found for linkage between NIDDM and GLUT1, GLUT2 and GLUT4 regions, regardless of the methods or models used for analyses. Thus, these familial linkage studies demonstrate that GLUT1, GLUT2 and GLUT4 loci did not contribute significantly to NIDDM in this cohort. The decreased expression of glucose transporters observed in some NIDDM patients may be secondary to other genetic or environmental defects.
Diabetes Metab 1997 Apr
PMID:Genetic analyses of glucose transporter genes in French non-insulin-dependent diabetic families. 913 2

The complications of diabetes arise in part from abnormally high cellular glucose uptake and metabolism. To determine whether altered glucose transporter expression may be involved in the pathogenesis of diabetic nephropathy, we investigated the effects of elevated extracellular glucose concentrations on facilitative glucose transporter (GLUT) expression in rat mesangial cells. GLUT1 was the only transporter isoform detected. Cells exposed to 20 mmol/l glucose medium for 3 days demonstrated increases in GLUT1 mRNA (134%, P < 0.002), GLUT1 protein (68%, P < 0.02), and V(max) (50%, P < 0.05) for uptake of the glucose analog [3H]2-deoxyglucose (3H2-DOG), when compared to cells chronically adapted to physiologic glucose concentrations (8 mmol/l). The increase in GLUT1 protein was sustained at 3 months, the latest time point tested (77% above control, P < 0.01). In contrast, hypertonic mannitol had no effect on GLUT1 protein levels. Insulin-like growth factor I (IGF-I; 30 ng/ml) increased the uptake of 3H2-DOG by 28% in 8 mmol/l glucose-treated cells (P < 0.05) and by 75% in cells switched to 20 mmol/l glucose for 3 days (P < 0.005). These increases in 3H2-DOG uptake occurred despite a lack of effect of IGF-I on GLUT1 protein levels (P > 0.5 vs. control). Therefore, hyperglycemia and IGF-I treatment both lead to increases in mesangial cell glucose uptake, and hyperglycemia induces increased GLUT1 expression, which can directly lead to the pathological changes of diabetic nephropathy. The effects of high glucose and of IGF-I to stimulate 3H2-DOG uptake also appear to be additive.
Diabetes 1997 Jun
PMID:D-glucose stimulates mesangial cell GLUT1 expression and basal and IGF-I-sensitive glucose uptake in rat mesangial cells: implications for diabetic nephropathy. 916 76

Renal tubular reabsorption of glucose is substantially increased in humans and rats with diabetes mellitus. The influx of luminal glucose is mediated by Na+/glucose cotransporter system and glucose efflux from tubules to interstitium by facilitative glucose transporters (GLUT). In Zucker diabetic rats, GLUT2 protein levels of renal proximal tubules were higher than in control litter mates: 9.67 +/- 1.95 versus 4.72 +/- 1.55 (P = 0.0073). In the same proximal tubules, diabetes was associated with minor decreases in GLUT1 protein levels: 1.96 +/- 0.37 for diabetics and 2.37 +/- 0.34 for controls (P = 0.12). Na+/glucose cotransporter system protein levels were similar in both groups, whereas Na+/K+ ATPase levels were slightly decreased in diabetic rats, but the difference was not statistically significant. In this report, it is suggested that in long-term uncontrolled diabetes, GLUT2 transporters are overexpressed in renal tubules. This adaptation promotes low-affinity, high-capacity glucose efflux. The higher number of high K(m) GLUT2 ensures that glucose reabsorption is increased by promoting glucose efflux, which could be rate-limiting in the face of hyperglycemia.
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PMID:Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. 918 62

GLUT2 may play an important role in pancreatic beta-cell glucose metabolism. A decrease in glucose uptake due to underexpression of GLUT2 has been considered as the cause of beta-cell dysfunction in diabetes with different pathogenesis. However, this view has been challenged by recent studies, in which the underexpression of GLUT2 was not accompanied by a decrease in glucose uptake. Our present aim is to evaluate the presumed importance of GLUT2 in maintaining the efficiency of beta-cell glucose uptake. We studied the kinetic characteristics of 3-O-methylglucose uptake in two beta-cell lines. One of these is the beta TC3 cell line which expresses GLUT1 and the other is the beta HC9 cell line which expresses both GLUT1 and GLUT2. Under equilibrium exchange conditions, 3-O-methylglucose transport in these two cell lines showed similar values of K(m) and V(max). The apparent IC50 of cytochalasin B for inhibiting 3-O-methylglucose transport in beta HC9 cells was nine times as high as in beta TC3 cells, indicating that GLUT1 is the critically important glucose transporter in the beta TC3 cell line and GLUT2 in the beta HC9 cell line. In both cell lines, the rates of glucose uptake were at least three times as fast as that of glucose phosphorylation. Our results suggest that GLUT1 is able to compensate for GLUT2 loss as it occurs in beta TC3 and maintains a commensurately high capacity of glucose uptake to sustain glucose metabolism in pancreatic beta-cells.
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PMID:GLUT1 is adequate for glucose uptake in GLUT2-deficient insulin-releasing beta-cells. 923 Mar 44

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

Several glucose transporters have recently been identified in glomeruli, and in cultured glomerular cells. These include the facilitative glucose transporter isoforms GLUTs 1, 3 and 4, and sodium-glucose cotransport activity with characteristics of SGLT1. GLUTs 1, 3 and 4 are all high affinity, low capacity, facilitative glucose transporters which typically would be saturated at or near physiologic glucose concentrations. The SGLT transporter of mesangial cells is also a high affinity transporter which similarly could be saturated under normal glucose conditions. This suggests that in order for mesangial cells to take up excessive quantities of glucose in diabetes, changes in glucose transporter expression, translocation or activity may be required. Accordingly, recent investigations discovered positive-feedback regulation of the mesangial cell GLUT1 transporter by glucose, and a regulatory role for GLUT1 in glucose metabolism and extracellular matrix synthesis. Future investigations of glucose transporters in the pathogenesis of diabetic renal disease will now likely proceed in multiple directions, including but not limited to: (1) examination of their regulation by growth factors implicated in diabetic nephropathy, and the resultant effects on ECM synthesis; (2) determination of the mechanisms by which GLUT1 regulates the expression of aldose reductase, PKC, GLUT1, and other genes in the mesangial cell; and (3) Suppression of glucose transporters in attempts to prevent high glucose-induced diabetic glomerulosclerosis.
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PMID:Glucose transporters of the glomerulus and the implications for diabetic nephropathy. 928 9

Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-gamma, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulin-responsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.
Diabetes 1997 Sep
PMID:Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. 928 37

It is becoming well established that poor fetal and early postnatal growth can have long-term effects on adult health, including susceptibility to non-insulin-dependent diabetes mellitus, cardiovascular disease and hypertension. It is suggested that this results from poor nutrition during early life having permanent effects on the structure and metabolism of certain organs and tissues. In the present study we investigated the effect of a low-protein diet during pregnancy and lactation on adipocyte properties and glucose tolerance. Rat dams were fed on a diet containing either 200 (control) or 80 (low protein) g protein/kg during pregnancy and lactation. In addition cross-fostering techniques were employed to enable a separate evaluation of the prenatal and postnatal periods. All offspring were weaned onto a 200 g protein/kg diet at 21 d of age and then studied at 6 weeks of age. The mothers' protein supply during lactation appeared to be the most critical time window for long-term growth. In contrast, the offspring of mothers fed on a low-protein diet during pregnancy or lactation were significantly more glucose tolerant than controls, suggesting that both time windows can have long-term effects on glucose tolerance. In addition offspring of mothers fed on a low-protein diet during pregnancy or lactation had significantly smaller adipocytes than controls. However the largest reduction in adipocyte size was observed when there was a low-protein diet during both pregnancy and lactation. The amount of insulin receptor present in adipocyte membranes was increased in the three animal groups that had been exposed to the low-protein diets while levels of the insulin responsive glucose transporter (GLUT 4) were similar in adipocyte membranes from all groups.
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PMID:Altered adipocyte properties in the offspring of protein malnourished rats. 929 65


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