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)

GLUT2 disappearance is a marker of the beta cell glucose-unresponsiveness associated with diabetes. Understanding the factor(s) leading to this dysfunction may shed light on pathogenesis of diabetes. Since the regulation of GLUT2 expression in diabetes can so far only be studied in in vivo experiments, we developed a novel experimental approach to study the genetic regulation of GLUT2 in diabetes. By encapsulating islets or cell lines in semi-permeable membranes, these cells can be exposed to the diabetic environment of rats or mice and can be retrieved for analysis of GLUT2 expression and for the change in the secretory response to glucose. Immunocytochemical analysis of transporter expression reveals changes in protein expression while transcriptional analysis of GLUT2 gene expression could be performed in cells transfected with promoter-reporter gene constructs. Using this last approach we hope to be able to characterize the promoter regions involved in the beta cell- and diabetes-specific regulation of GLUT2 expression and possibly to determine which factors are responsible for this regulation.
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PMID:Regulated expression of GLUT2 in diabetes studied in transplanted pancreatic beta cells. 782 64

Pancreatic beta cells secrete insulin in response to an increase in the level of blood glucose above 5 mM, which is characteristic of the fasting state. Glucose metabolism is essential for glucose sensing, and both the high-Km glucose transporter GLUT2 and the high-Km glucose phosphorylating enzyme glucokinase have been implicated in coupling insulin secretion to extracellular glucose levels. Experiments in isolated islets, immortalized beta-cell lines and transgenic animals, together with findings in humans with maturity-onset diabetes of the young, indicate that the primary beta-cell glucose sensor is glucokinase. Although the level of GLUT2 is frequently reduced in animal models of type II diabetes, GLUT2 does not limit glucose metabolism in beta cells and does not appear to regulate glucose induction of insulin secretion.
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PMID:The pancreatic beta-cell glucose sensor. 784 65

The functions of absorption of dietary glucose by the small intestine and reabsorption of filtered glucose by the renal proximal tubule are strikingly similar in their organization and in the way they adapt to uncontrolled diabetes mellitus. In both cases, transepithelial glucose and Na+ fluxes are augmented. The epithelial adaptations to hyperglycemia of uncontrolled diabetes are accomplished by increasing the glucose transport surface area and the number of the efflux glucose transporter GLUT2 located in the basolateral membrane. The signals that modify the size of the epithelium and the overexpression of basolateral GLUT2 are not known. It was speculated that high glucose levels and enhanced Na+ flux may be important factors in the signaling event that culminates in a renal and intestinal epithelium that is modified to transport higher rates of glucose against a higher extracellular level of glucose.
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PMID:Gene expression of epithelial glucose transporters: the role of diabetes mellitus. 787 42

Loss of GLUT 2, the glucose transporter isoform of pancreatic beta cells, has been reported to accompany the onset and perhaps contribute to the pathogenesis, of insulin-dependent and non-insulin-dependent diabetes mellitus in BB/Wor and Zucker fatty rats. In this study we investigated the effect of Kilham Rat Virus infection on GLUT2 expression in diabetes-resistant BB/Wor rats. Viral antibody-free diabetes-resistant rats do not develop spontaneous diabetes, but inoculation with Kilham Rat Virus induces autoimmune beta-cell destruction and hyperglycaemia. Pancreas sections from normoglycaemic diabetes-resistant BB/Wor rats were obtained 5, 7 and 25 days after inoculation with Kilham Rat Virus and stained for GLUT2 using a rabbit polyclonal antibody. At all time points, beta cells displayed GLUT2 expression comparable to uninfected diabetes-resistant controls. Immunostained insulin content of the beta cells also remained unchanged. Sections were also examined from Kilham Rat Virus inoculated diabetes-resistant rats with lymphocytic insulitis or diabetes. GLUT2 and insulin immunostaining were unchanged in non-diabetic rats with early insulitis. GLUT2 beta-cell staining was variably reduced in diabetic rats with established insulitis and reduced beta-cell insulin immunostaining. Hence, the initial stages of Kilham Rat Virus-induced diabetes in diabetes-resistant rats are not accompanied by a significant reduction in GLUT2 expression. These results suggest that the loss of GLUT2 does not play a significant role in the aetiology of diabetes in the Kilham Rat Virus-infected diabetes-resistant BB/Wor rat.
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PMID:Preservation of GLUT 2 expression in islet beta cells of Kilham rat virus (KRV)-infected diabetes-resistant BB/Wor rats. 789 47

The glucose analog streptozotocin (STZ) has long been used as a tool for creating experimental diabetes because of its relatively specific beta-cell cytotoxic effect, but the mechanism by which systemic injection of STZ causes beta-cell destruction is not well understood. In the current study, we have used insulinoma (RIN) and AtT-20ins cell lines engineered for overexpression of GLUT2 or GLUT1 to investigate the role of glucose transporter isoforms in mediating STZ cytotoxicity. The in vivo effects of STZ were evaluated by implantation of RIN cells expressing or lacking GLUT2 into athymic nude rats. The drug had a potent cytotoxic effect on RIN cells expressing GLUT2, but had no effect on cells lacking GLUT2 expression, as indicated by histological analysis and measurement of the blood glucose levels of treated animals. The preferential cytotoxic effect of STZ on GLUT2-expressing cell lines was confirmed by in vitro analysis of GLUT2-expressing and untransfected RIN cells, as well as GLUT2- and GLUT1-overexpressing AtT-20ins cells. Consistent with these data, only GLUT2-expressing RIN or AtT-20ins cells transported STZ efficiently. We conclude that expression of GLUT2 is required for efficient killing of neuroendocrine cells by STZ, and this effect is related to specific recognition of the drug as a transported substrate by GLUT2 but not GLUT1.
Diabetes 1994 Nov
PMID:STZ transport and cytotoxicity. Specific enhancement in GLUT2-expressing cells. 792 7

A number of pancreatic beta-tumor cell (beta TC) lines have been derived from insulinomas arising in transgenic mice expressing the SV40 T antigen gene under control of the insulin promoter. Some of these lines secrete insulin in response to physiological glucose concentrations. However, this phenotype is unstable. After propagation in culture, these nonclonal lines become responsive to subphysiological glucose levels and/or manifest reduced insulin release. Here we report the use of soft-agar cloning to isolate single-cell clones from a beta TC line, which give rise to sublines that maintain correct glucose responsiveness and high insulin production and secretion for > 55 passages (over a year) in culture. One of these clonal lines, denoted beta TC6-F7, was characterized in detail. beta TC6-F7 cells expressed high glucokinase and low hexokinase activity, similarly to normal islets. In addition, they expressed mRNA for the GLUT2 glucose transporter isotype and no detectable GLUT1 mRNA, as is characteristic of normal beta-cells. These results demonstrate that transformed beta-cells can maintain a highly differentiated phenotype during prolonged propagation in culture, which has implications for the development of continuous beta-cell lines for transplantation therapy of diabetes.
Diabetes 1994 Dec
PMID:Clonal insulinoma cell line that stably maintains correct glucose responsiveness. 795 92

The polymerase chain reaction-single stranded conformation Polymorphism (PCR-SSCP) procedure was applied to examine whether the mutation in the liver/islet glucose transporter (GLUT2) gene could be associated with non-insulin-dependent diabetes mellitus (NIDDM) in Japanese. Samples were processed through 30-40 cycles of 1 min denaturation at 94 degrees C, 1 min annealing at 55-68 degrees C for 1-2 min, extention at 72 degrees C for 1 min, and denaturation at 94 degrees C for 1 min. We identified a silent mutation in codon 479 for PheTTT/TTC.
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PMID:[The detection of GLUT2 gene mutation by polymerase-chain reaction single stranded conformation polymorphism (PCR-SSCP) method]. 798 79

The liver/pancreatic beta cell type glucose transporter (GLUT2) is expressed in the pancreatic beta cell, a glucose carrier with a low affinity for glucose but a high capacity for glucose transport. The expression of GLUT2 in the normal pancreatic islet is increased after exposure to high glucose, while it is decreased in model animal with non-insulin-dependent diabetes mellitus (NIDDM). In Pima Indians, to assess the genetic components of the acute insulin response (AIR) and NIDDM, polymorphic dinucleotide repeat regions in the GLUT2 gene were evaluated. Robust sib-pair linkage analyses suggest linkage between GLUT2 and AIR, but no linkage was observed with NIDDM. The coding region of the GLUT2 gene was screened for mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. A single base change was identified in exon 3 in -5% of the study population. Although this base change resulted in an amino acid substitution (Thr110-Ile110), no significant association was noted between AIR and the mutation. We also screened for mutations using PCR-SSCP analysis in Japanese subjects. A single base silent polymorphism (Phe497, TTT-TTC) was identified in exon 10. Significant association was noted between TTC type and NIDDM (N = 78), compared to normal controls (N = 80). These data suggest the possibility that GLUT2 is one of the candidate genes for NIDDM.
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PMID:[Candidate gene approach in Japanese NIDDM: liver/pancreatic beta cell type glucose transporter (GLUT2)]. 798 99

The effect of insulinopenic diabetes on the expression of glucose transporters in the small intestine was investigated. Enterocytes were sequentially isolated from jejunum and ileum of normal fed rats, streptozotocin-diabetic rats, and diabetic rats treated with insulin. Facilitative glucose transporter (GLUT) 2, GLUT5, and sodium-dependent glucose transporter 1 protein content was increased from 1.5- to 6-fold in enterocytes isolated from diabetic animals in both jejunum and ileum. Insulin was able to reverse the increase in transporter protein expression seen after induction of diabetes. There was a four- to eightfold increase in the amount of enterocyte glucose transporter mRNA after diabetes with greater changes in sodium-dependent glucose transporter 1 and GLUT2 than in GLUT5 levels. In situ hybridization showed that after the induction of diabetes there was new hybridization in lower villus and crypt enterocytes that was reversed by insulin treatment. Thus, the increase in total hexose transport caused by diabetes is due to a premature expression of hexose transporters by enterocytes along the crypt-villus axis, causing a cumulative increase in enterocyte transporter protein during maturation. These changes are likely to represent an adaptive response by the organism to increase nutrient absorption in a perceived state of tissue starvation. These adaptive changes may lead to exacerbation of hyperglycemia in uncontrolled diabetes.
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PMID:Small intestine hexose transport in experimental diabetes. Increased transporter mRNA and protein expression in enterocytes. 811 95

The acute insulin response (AIR), a measure of pancreatic beta-cell function, aggregates in families and is a predictor for the development of non-insulin-dependent diabetes mellitus (NIDDM) in insulin-resistant Pima Indians. To assess the genetic components of AIR and NIDDM, polymorphic dinucleotide repeat regions in two candidate genes, the liver/islet glucose transporter gene (GLUT2) and the glucokinase gene, were evaluated. Sib-pair linkage analyses were performed to determine if linkage exists between these marker loci and measurements of AIR and NIDDM. No linkage was found between glucokinase and either AIR or NIDDM. Robust sib-pair linkage analyses suggest linkage between GLUT2 and acute insulin response (P = 0.04), but no linkage was observed with NIDDM. The coding region of the GLUT2 gene was screened for mutations using polymerase chain reaction-single-strand conformation polymorphism analysis. A single base change was identified in exon 3 in approximately 5% of the study population, and it constitutes the first reported mutation in the human GLUT2 gene. This base change resulted in an amino acid substitution (Thr110-->Ile110) in the second membrane-spanning region of the GLUT2 protein. No significant association was noted between AIR and the presence or absence of the mutation. Thus, this mutation in GLUT2 is unlikely the cause of a low AIR in Pima Indians.
Diabetes 1994 Apr
PMID:Linkage analysis of acute insulin secretion with GLUT2 and glucokinase in Pima Indians and the identification of a missense mutation in GLUT2. 813 61


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