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)

Glucose is reabsorbed from the glomerular filtrate in the proximal segment of the renal tubule in two stages. The first stage is uphill transport across the brush border membrane by Na(+)-glucose cotransport and the second stage is downhill transport across the basolateral membrane by facilitated diffusion. Genes for both a renal Na(+)-glucose cotransporter (SGLT1) and a renal facilitated glucose transporter (GLUT2) have been cloned and sequenced. To examine whether SGLT1 and GLUT2 colocalize to the same tubular epithelial cells in rat kidney, double-immunoperoxidase studies with dual chromogens and paraformaldehyde perfusion-fixed frozen sections of rat kidney were performed. Antipeptide antisera were prepared against rat GLUT2 (amino acids 510-522) and rabbit SGLT1 (amino acids 402-420). Proximal tubules were identified immunocytochemically with an antiserum raised against a synthetic peptide corresponding to the 21 amino acids at the COOH-terminal of the heavy chain of rat gamma-glutamyl transpeptidase, which is a proximal tubule-specific enzyme. The anti-GLUT2 antiserum strongly stained the basolateral membrane of 46% of cortical tubules, whereas the SGLT1 antiserum stained the brush border of 56% of the cortical tubules. The gamma-glutamyl transpeptidase antiserum also stained the brush border of 51% of the cortical tubules. GLUT2 and SGLT1 colocalized to 40% of cortical epithelium, but 16% of cortical epithelial cells were immunopositive for brush border SGLT1 and immunonegative for basolateral GLUT2. These gamma-glutamyl transpeptidase staining results suggest that at least 50% of the tubules in the cortex are proximal tubules and that SGLT1 and GLUT2 colocalize to most proximal tubules. The fact that SGLT1 antiserum immunoreacted with tubules unreactive to the GLUT2 antiserum suggests that either the SGLT1 epitope is conserved on a related brush border protein or that there is another GLUT transporter responsible for the exit of sugar from these proximal tubule cells.
Diabetes 1992 Jun
PMID:Colocalization of GLUT2 glucose transporter, sodium/glucose cotransporter, and gamma-glutamyl transpeptidase in rat kidney with double-peroxidase immunocytochemistry. 135 Feb 59

The precise genetic defects underlying the etiology of non-insulin-dependent diabetes mellitus (NIDDM) have yet to be identified. The beta-cell/liver glucose transporter gene GLUT2 represents a good candidate for the etiology of the disease, being involved in the glucose signalling for beta-cell insulin release. Population association studies of the GLUT2 gene in NIDDM have so far yielded controversial results. In order to determine the possible contribution of this gene to the inheritance of NIDDM, we have employed a new approach, where two polymorphic markers of the GLUT2 locus, detected with the restriction enzyme Taq-1, were examined for linkage with the disease in a group of 22 Italian pedigrees with affected members (n = 50). Departure from independent segregation between markers and disease was analyzed by the Affected-Pedigree-Members (APM) statistical method. Furthermore, association analysis between the Taq-1 RFLPs at the GLUT2 locus and NIDDM was performed in a group of diabetics with a strong family history, comprising the 22 probands and 23 other diabetics with an affected first-degree relative. The results indicate that there was no segregation distortion between the Taq-1 markers of the GLUT2 gene and the disease in the pedigrees examined. Also, no significant difference in genotype distribution, haplotype and allele frequencies was found between diabetics and controls for the two Taq-1 RFLPs. We conclude that genetic variation at the GLUT2 transporter gene is unlikely to contribute in a major way to the inheritance for NIDDM in this Italian population.
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PMID:Polymorphisms at the GLUT2 (beta-cell/liver) glucose transporter gene and non-insulin-dependent diabetes mellitus (NIDDM): analysis in affected pedigree members. 135 29

Familial NIDDM probably results from combined inherited defects of insulin secretion and action. Members of the facilitative glucose transporter family are strong candidates for both defects, and RFLPs for both GLUT1 (erythrocyte) and GLUT2 (liver/islet) genes have been associated with NIDDM in some populations. To test the hypothesis that GLUT1 and GLUT2 mutations contribute to the inherited predisposition to NIDDM, we examined linkage of these loci with NIDDM in 18 large Utah white pedigrees (two and three generation) ascertained for > or = 2 NIDDM siblings. We used two RFLPs detected with Xba1 and Stu1 for the GLUT1 transporter. For the GLUT2 (liver/beta-cell) transporter gene, we used an RFLP detected with EcoR1 and a highly polymorphic (6-allele) dinucleotide (microsatellite) repeat. Analysis was performed with the MLINK program of the LINKAGE package. We tested four models for each locus: dominant and recessive, with IGT alternately considered as unknown affection status, or affected if IGT was diagnosed < or = 45 yr of age and unknown if > 45 yr. Disease gene frequencies were chosen to give approximate disease prevalence in American whites (q = 0.03, dominant; q = 0.25, recessive). Linkage of GLUT1 and NIDDM was strongly and significantly rejected under all models, with total (pooled) LOD scores of -5.7 to -8.9, indicating > 500,000:1 odds against linkage. Pooled LOD scores were significantly negative (< -2.0, or 100:1 odds against linkage) to a recombination fraction of > 5%. No heterogeneity was apparent. Analysis of GLUT2 gave similar results, with LOD scores of < -4.0 under each model, indicating at least 10,000:1 odds against linkage.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Dec
PMID:Linkage analysis of GLUT1 (HepG2) and GLUT2 (liver/islet) genes in familial NIDDM. 135 87

Previous studies revealed that rat islets express the GLUT2-liver facilitative glucose transporter isoform, a glucose carrier with a low affinity for glucose but a high capacity for glucose transport. These studies indicated the presence of a second glucose transporter in rat islets; however, they did not indicate to which of the five known facilitative glucose transporters it corresponded. In this study, we isolated RNA from rat islets of Langerhans and confirmed the presence of GLUT2 mRNA. In addition, we present data indicating that the second isoform expressed in islets is the GLUT1-erythrocyte isoform. The effect of culturing islets in 5.5, 8.3, or 11.1 mM glucose on the levels of GLUT1 and GLUT2 mRNA also was examined. The levels of GLUT1 and GLUT2 mRNA were two- and threefold higher, respectively, in islets cultured for 24 h in 11.1 mM glucose compared with those incubated in the presence of 5.5 mM glucose. Therefore, the previously observed increase in GLUT2 mRNA levels in the islets of rats made hyperglycemic by chronic infusion of glucose can be mimicked in vitro, implying that glucose regulates GLUT2 mRNA expression.
Diabetes 1992 Jan
PMID:Expression of GLUT1 and GLUT2 glucose transporter isoforms in rat islets of Langerhans and their regulation by glucose. 137 Jan 54

The NSTZ rat model combines loss of glucose-induced insulin secretion with a reduced amount of the high Km B-cell glucose transporter, GLUT2. The purpose of this study was to determine whether the restoration of glucose-induced insulin secretion was paralleled by an increase of GLUT2. Rats injected at 2 days of age with 90 mg/kg STZ were studied at 8-13 wk of age. Insulin secretion was assessed in the isolated perfused pancreas with 16.7 mM glucose preceded by 40 min of 0 or 5.5 mM glucose. In control rats, 16.7 mM glucose caused the same large biphasic insulin response whether preceded by 0 or 5.5 mM glucose. In NSTZ rats, after 5.5 mM glucose, 16.7 mM glucose elicited virtually no rise in insulin release. In contrast, after 0 mM glucose, a large insulin response to the glucose challenge occurred that was equal to that of the control groups when the differences in B-cell mass were taken into account. However, the dose-response curve for glucose-induced insulin secretion was shifted to the left, and no second phase of insulin secretion was observed. GLUT2 was assessed after the perfusions by indirect immunofluorescence with anti-GLUT2 antisera. Both control groups showed homogenous staining in all B-cells. NSTZ rats perfused with 5.5 mM glucose had a marked diminution in GLUT2 staining. We observed no increase in GLUT2 staining in the NSTZ rats perfused with 0 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Oct
PMID:Recovery of glucose-induced insulin secretion in a rat model of NIDDM is not accompanied by return of the B-cell GLUT2 glucose transporter. 139 6

Expression of GLUTs in rat peripheral nerve was first studied at the mRNA level with Northern transfer analysis with cDNAs specific for GLUT1, GLUT2, GLUT3, and GLUT4. GLUT1 mRNA was the only GLUT mRNA detectable in rat sciatic nerve. In situ hybridization localized this mRNA to the perineurium and to some endo- and epineurial capillaries. Indirect immunofluorescence stainings demonstrated that GLUT1 protein epitopes were concentrated primarily in the perineurium and endoneurial capillaries. Also, some Schwann cells, a few epineurial capillaries, and medium-sized blood vessels showed a faintly positive immunoreaction. All cell types present in primary cultures initiated from rat sciatic nerve (perineurial cells, Schwann cells, and fibroblasts) expressed GLUT1 protein in vitro. Thus, Schwann cells, which expressed GLUT1 only occasionally at a low level in vivo, have the potential to express GLUT1 at a markedly higher level under cell culture conditions. Incubation of the cultures in 25 mM D-glucose for 7 days caused a 39% reduction in the amount of immunodetectable GLUT1 protein, and a marked (34%) decrease of GLUT1 mRNA compared with cultures incubated in 5.5 mM D-glucose. Interestingly, the reduction of [3H]-2-DG uptake in the same cultures exceeded 70%, suggesting that the reduced amount of GLUT1 protein alone did not explain the marked reduction in glucose uptake in these cultures. Immunostaining of the cell cultures suggested that perineurial cells were the main target for the glucose-induced decrease of GLUT1 protein.
Diabetes 1992 Dec
PMID:Glucose transporters of rat peripheral nerve. Differential expression of GLUT1 gene by Schwann cells and perineural cells in vivo and in vitro. 144

To obtain information on the regulation of glucose transport across the basolateral membrane (BLM) of intestinal epithelial cells, we measured the number of [3H]cytochalasin B binding sites and the level of liver-type glucose transporter (GLUT2) protein in the BLM in the jejunum of rats (i) with diabetes (ii) given a high-carbohydrate diet or (iii) with experimental hyperglycemia (12 h infusion of a high-glucose solution). A glucose uptake and the number of D-glucose inhibitable [3H]cytochalasin B binding sites in BLM vesicles were significantly increased in all three conditions. Western blot analysis showed that the amount of GLUT2 protein in BLM vesicles was increased in rats with diabetes and those given a high-carbohydrate diet, but not in those with experimental hyperglycemia. These results suggest that there is a mechanism for rapid regulation of glucose transport in the BLM that does not depend on change in the amount of GLUT2.
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PMID:Role of liver-type glucose transporter (GLUT2) in transport across the basolateral membrane in rat jejunum. 146 87

Three major metabolic abnormalities contribute to hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) including defective glucose-induced insulin secretion, elevated rates of hepatic glucose output, and insulin's impaired ability to stimulate glucose uptake in peripheral target tissues (insulin resistance). These functions involve cellular glucose transport in beta-cells, liver, adipose tissue, and skeletal muscle; and, in some instances, abnormalities in glucose transporter isoforms (GLUT) specifically expressed in these tissues may constitute key biochemical lesions underlying defective glucose homeostasis. In animal models of NIDDM, suppression of GLUT2 in beta-cells is correlated with loss of high-Km glucose transport and glucose-sensitive insulin secretion. Although there are no data on humans with NIDDM, GLUT2 loss would constitute an attractive mechanism for defective glucose sensing in beta-cells if it can be shown that transport then becomes rate limiting for glucose metabolism. In the liver, however, hepatocyte glucose transport via GLUT2 probably plays only a permissive role in sustaining increased glucose efflux. Peripheral insulin resistance is associated with decreased glucose transport activity, the likely rate-limiting step for glucose uptake in fat and muscle. Accordingly, the insulin-responsive GLUT4 isoform expressed exclusively in insulin target tissues has been studied intensively in NIDDM. In these studies, pretranslational suppression of GLUT4 appears to be the key mechanism of insulin resistance in adipocytes. However, levels of GLUT4 protein and mRNA are normal in vastus lateralis and rectus abdominis, inferring that defects in GLUT4 functional activity or insulin-mediated translocation cause insulin resistance in muscle. Thus, the intensified study of glucose transport has provided important new insights into NIDDM pathogenesis over the past 5 yr and has presented investigators with additional intriguing hypotheses.
Diabetes Care 1992 Mar
PMID:Glucose transport and NIDDM. 155 8

To investigate the role of glucose in regulating glucose transporters in pancreatic beta-cells, we studied the hamster clonal beta-cell line HIT-T15, which retains responsiveness to glucose. Northern blot analysis demonstrates that GLUT2 and GLUT1 mRNA are abundant in HIT cells. After a 24-h culture with various concentrations of glucose (0-22.2 mM [0-400 mg/dl]), the GLUT2 mRNA level in HIT cells increased by 40% at 22.2 mM (400 mg/dl) glucose compared with 11.1 mM (200 mg/dl) without a change in mRNA stability. It also decreased proportionally to the reduction of glucose concentration. Glucose deprivation resulted in a decrease of GLUT2 mRNA to an almost undetectable level, with a marked increase in the degradation rate of mRNA. In contrast, the GLUT1 mRNA was not affected by glucose. We show that glucose uptake is highest in HIT cells incubated at 2.8-5.5 mM (50-99 mg/dl) glucose for 24 h, and that levels in cells cultured at 0 mM (0 mg/dl) and 22.2 mM (400 mg/dl) glucose decrease to approximately 20% of the maximum level. This decrease is consistent with the effects of glucose on glucose-stimulated insulin secretion in HIT cells. Our results indicate that glucose is involved in regulating GLUT2 mRNA and glucose uptake activity and that the glucose responsiveness of the insulin secretion correlates with the glucose-induced change in glucose uptake activity in HIT cells.
Diabetes 1992 May
PMID:Glucose as regulator of glucose transport activity and glucose-transporter mRNA in hamster beta-cell line. 156 28

In order to determine the role of insulin and glucose transporter gene expression in the development of diabetes in obesity, we examined insulin and GLUT2-liver type and GLUT4-muscle-fat type glucose transporter mRNA levels in obese and diabetic rats. Ventromedial hypothalamus-lesioned (VMH), Zucker fatty (ZF), and Wistar fatty (WF) rats were used as models. VMH and ZF rats are most frequently used as models for simple obesity. In contrast, WF rats, which have been established by transferring the fa gene of ZF rats to Wistar Kyoto rats, develop both obesity and diabetes. Pancreatic insulin content of VMH rats at 10 weeks after the operation and of ZF rats at 5 and 14 weeks of age was significantly higher than that of controls. On the other hand, insulin content of WF rats at 5 and 14 weeks of age was not significantly different from that of lean littermates. The insulin mRNA levels of VMH rats were increased progressively and were significantly higher than those in sham-operated animals at 4 and 10 weeks after the operation. In ZF rats, the insulin mRNA levels at 5 and 14 weeks of age were significantly higher than those of their lean littermates. In WF rats, by contrast, the insulin mRNA levels were similar to those of lean littermates at 5 and 14 weeks of age. The insulin mRNA levels of WF rats were about 40% of that of ZF rats at 14 weeks of age. On the other hand, at 14 weeks of age, the GLUT2 mRNA levels of liver were significantly higher in ZF and WF rats than those in their respective littermates, but not at 5 weeks of age. The GLUT4 mRNA levels of skeletal muscle in both ZF and WF rats were not significantly different from those of controls. It is suggested that the inability of WF rats to augment insulin gene expression in response to a large demand for insulin is associated with the occurrence of diabetes, and that the activation of GLUT2 mRNA without the activation of GLUT4 mRNA is common to obesity with and without diabetes.
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PMID:Insulin and glucose transporter gene expression in obesity and diabetes. 157 85


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