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)

The renal reabsorption of glucose is mediated by two major classes of transporters. Initially, luminal glucose is concentrated in tubules by Na(+)-glucose cotransporters (Na(+)-GLUT). Afterwards, glucose reaches the blood space through facilitative glucose transporters, low-Michaelis constant (Km) GLUT1 and high-Km GLUT2. Hence, the transtubular flux of glucose could be impaired in hyperglycemia because the outwardly directed glucose gradient, from tubule to blood, is potentially lowered. However, in diabetic rats, transtubular glucose flux is not reduced but increased. In this work the molecular mechanism underlying this adaptation was examined. We tested the hypothesis that upregulation of renal tubular high-Km GLUT2 gene may compensate for the decrease in the tubule to blood glucose gradient. In rat tubules, GLUT1 protein and mRNA steady-state levels were reduced, and GLUT2 protein and mRNA levels were increased in rats after 2, 3, and 4 wk of uncontrolled streptozotocin-induced diabetes. These molecular adaptations were associated with augmented facilitative glucose flux. In summary, changes in GLUT1 and GLUT2 gene expression are important to the preservation of renal glucose reabsorption in hyperglycemia.
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PMID:Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. 814 29

Pancreatic islet GLUT2 mRNA is known to be regulated in vitro and in vivo by glucose. We have investigated several potential mechanisms mediating the response of islet GLUT2 to glucose. GLUT2 mRNA and protein were measured from isolated rat islets cultured for up to 24 h under selected conditions. Glucose at 11 mM stimulated GLUT2 mRNA 10-fold compared with 2 mM glucose, with no additional increase at 16.7 mM glucose, whereas maximal 4-fold induction of the protein was attained with 16 mM glucose. Time course studies showed a 2.5-fold induction of GLUT2 mRNA apparent after only 8 h of culture at 16.7 mM glucose. Glycolysis inhibitor mannoheptulose suppressed the stimulatory effect of 16.7 mM glucose on GLUT2 mRNA and protein. Metabolizable sugars mannose and glyceraldehyde enhanced transporter mRNA levels, in contrast with the lack of stimulation by nonmetabolizable 2-deoxy-D-glucose. Stimulation by different sugars and glycolysis inhibition led to analogous changes of proinsulin mRNA, suggesting that common signaling mechanisms are shared in glucose regulation of proinsulin and GLUT2 gene expression. Preexposure to mannoheptulose, however, failed to suppress glucose-stimulated insulin release. Tunicamycin, a glycoprotein synthesis inhibitor, did not block the effect of 16 mM glucose on GLUT2 mRNA levels. RNA and protein synthesis inhibitors actinomycin and cycloheximide abolished the enhancing effects of high glucose on GLUT2 mRNA. These findings indicate that glucose metabolism, but not glycoprotein synthesis or substrate interaction with the transporter protein, is instrumental in the stimulatory effects of glucose on beta-cell GLUT2 mRNA accumulation. In addition, ongoing RNA and protein synthesis are required for this effect.
Diabetes 1993 Sep
PMID:Signals derived from glucose metabolism are required for glucose regulation of pancreatic islet GLUT2 mRNA and protein. 834 38

Pancreatic islets were cultured for 24 h in medium containing either low (1.4), normal (5.5), or high (16.7 mM) glucose, and then insulin secretion was measured at the end of 1 h incubation at 37 degrees C. Insulin release in the absence of glucose was 64 +/- 20, 152 +/- 11, and 284 +/- 30 pg.islet-1.h-1 (mean +/- SE, n = 6, G1.4 and G16.7 vs. G.5.5, P < 0.05) and the response to 22 mM glucose stimulation was 640 +/- 136, 2460 +/- 276, and 1890 +/- 172 pg.islet-1.h-1, respectively (n = 6, G1.4 vs. G5.5, P < 0.01, G16.7 vs. G5.5, P = 0.065). The 50% maximal response of insulin secretion (increment over baseline) was reached at an average glucose concentration of 9.9 +/- 0.7 mM in islets preexposed to G5.5, and at glucose 13.3 +/- 0.9 and 4.8 +/- 0.4 mM (P < 0.05 in respect to G5.5) in islets preexposed to G1.4 and G16.7, respectively. To investigate the molecular mechanism responsible for this altered glucose sensitivity, we measured, in parallel experiments, the kinetic characteristics of glucose transport, glucokinase, and glucose utilization. Glucose transport was measured by evaluating 3-O-methylglucose uptake. The apparent Km of the low-affinity transporter (GLUT2) was 16.6 +/- 2.4 mM in isolated pancreatic cells cultured at 5.5 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Jan
PMID:Glucose modulates glucose transporter affinity, glucokinase activity, and secretory response in rat pancreatic beta-cells. 842 Aug 17

The application of molecular biology to the study of membrane transport proteins has led to a rapid advance in our understanding of the mechanisms behind the regulation of blood glucose levels. Moreover the demonstration of lesions in the expression of GLUT2 in the islets from diabetic models has provided a focus for research efforts aimed at addressing the defects responsible for the development and onset of both type I and perhaps type II diabetes. The recent demonstration that an 'artificial beta-cell' can be engineered from anterior pituitary-derived cell lines by transfection with both the insulin cDNA and the cDNA encoding GLUT2 represents a significant advance in the development of potential therapies for type I diabetes [24].
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PMID:Pancreatic beta-cells express a low affinity glucose transporter: functional consequences in normal and diabetic states. 844 85

The trace element vanadium is a potent insulinomimetic agent in vitro. Oral administration of vanadate to rats made diabetic by streptozotocin (45 mg/kg i.v.) caused a 65% fall in plasma glucose levels without modifying low insulinemia. We studied whether the hypoglycemic effect of vanadate was associated with altered expression of genes involved in key steps of hepatic glucose metabolism. Glucokinase (GK) and L-type pyruvate kinase (L-PK) mRNA levels were decreased respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of vanadate treatment partially restored GK mRNA and activity (40% of control levels), and totally restored L-PK parameters. In contrast to the glycolytic enzymes, mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were increased (15- and 2-fold, respectively) in fed diabetic rats. Vanadate treatment normalized both PEPCK mRNA and activity in diabetic rat liver. The 2-fold increase in liver glucose transporter (GLUT2) mRNA and protein, produced by diabetes, was also corrected by this treatment. In conclusion, oral vanadate given to diabetic rats induces a shift of the predominating gluconeogenic flux, with subsequent high hepatic glucose production, into a glycolytic flux by pretranslational regulatory mechanisms.
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PMID:Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2. 847 58

The gene encoding the predominant facilitative glucose transporter expressed in pancreatic beta-cells and hepatocytes, termed GLUT2, has been cloned and characterized. The human GLUT2 gene is composed of 11 exons spanning approximately 30 kilobases. The sequence of the promoter region and all exons and adjacent intron regions has been determined and deposited in the GenBank database. Two highly polymorphic simple tandem repeat DNA polymorphisms useful for linkage studies were localized in introns 1 and 4a. In addition, a 168-base pair insertion/deletion polymorphism was identified in intron 3. The characterization of the human GLUT2 gene will facilitate studies of its role in the development of diabetes mellitus.
Diabetes 1993 May
PMID:Organization of the human GLUT2 (pancreatic beta-cell and hepatocyte) glucose transporter gene. 848 35

Pancreatic beta TC lines derived from insulinomas arising in transgenic mice expressing SV40 Tag under control of the insulin promoter manifest a differentiated beta-cell phenotype and secrete insulin in response to glucose. Previously reported beta TC lines respond to subphysiological extracellular glucose levels compared with normal beta-cells. Recently, several beta TC lines were developed with normal glucose-regulated insulin secretion from insulinomas obtained by breeding of the RIP-Tag transgene from the original C57BI/6 mouse strain into the C3HeB/FeJ strain. One of these beta TC lines, beta TC7, was characterized in detail. Beta TC7 cells express GLUT2 and have levels of glucokinase and hexokinase activity similar to those of normal islets. As a result these cells exhibit a normal glucose concentration dependency for glycolysis and insulin secretion, thus representing an accurate model of beta-cell function. On continuous propagation in culture, beta TC7 cells acquired a response to lower extracellular glucose levels. This change was associated with a fourfold increase in hexokinase activity, without significant changes in glucokinase activity and glucose uptake rates. These findings suggest an important role for glucose phosphorylation rates in regulation of the beta-cell insulin secretory response to glucose.
Diabetes 1993 Jun
PMID:Murine insulinoma cell line with normal glucose-regulated insulin secretion. 849 13

GLUT2 underexpression has been reported in the beta-cells of Zucker diabetic fatty rats and db/db mice, models of spontaneously occurring NIDDM with antecedent obesity. To determine whether the beta-cells of a nonobese rodent model of NIDDM exhibit the same abnormalities in GLUT2, we studied Goto-Kakizaki rats. In these mildly diabetic animals glucose-stimulated insulin secretion was reduced at all ages examined from 8 to 48 wk. In normal control Wistar rats, immunostainable GLUT2 was present on all insulin-positive cells in the pancreatic islets. Only 85% of beta-cells were GLUT2-positive in GK rats at 12 wk of age, and only 34% were positive at 48 wk of age. GLUT2 mRNA was 50% of normal in 12-wk-old GK rats. In the latter age-group, glucose-stimulated insulin secretion was only 28% of normal at a time when 85% of beta-cells were GLUT2-positive and initial 3-O-methyl-D-glucose transport rate was 77% of the control value. We conclude that although GLUT2 is underexpressed, neither the magnitude of the underexpression of GLUT2 nor of the reduction in GLUT2 transport function in islets of GK rats is sufficient by itself to explain the profound reduction in glucose-stimulated insulin secretion.
Diabetes 1993 Jul
PMID:GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. 851 73

Diabetes in humans and experimental animals invariably is associated with a loss of glucose-induced insulin secretion. It has been hypothesized that this reversible defect is an adaptation of beta cells to chronic hyperglycemia, a hypothesis that has been strengthened by studies in experimental models of diabetes. Recently, a marked underexpression of the beta-cell glucose transporter GLUT2 has been found in diabetic rodents. Although this finding provides an attractive potential explanation for the abnormal insulin secretion of diabetes, some problems with the hypothesis have emerged. Additional studies must be carried out to define the potentially pathogenic role of GLUT2.
J Diabetes Complications
PMID:The relationship of diabetes, loss of glucose-induced insulin secretion, and GLUT2. 851 54

A defect in glucose sensing of the pancreatic beta-cells has been observed in several animal models of type II diabetes and has been correlated with a reduced gene expression of the glucose transporter type 2 (Glut2). In a transgenic mouse model, expression of Glut2 antisense RNA in pancreatic beta-cells has recently been shown to be associated with an impaired glucose-induced insulin secretion and the development of diabetes. To identify factors that may be involved in the specific decrease of Glut2 in the beta-cells of the diabetic animal, an attempt was made to localize the cis-elements and trans-acting factors involved in the control of Glut2 expression in the endocrine pancreas. It was demonstrated by transient transfection studies that only 338 base pairs (bp) of the murine Glut2 proximal promoter are needed for reporter gene expression in pancreatic islet-derived cell lines, whereas no activity was detected in nonpancreatic cells. Three cis-elements, GTI, GTII, and GTIII, have been identified by DNAse I footprinting and gel retardation experiments within these 338 bp. GTI and GTIII bind distinct but ubiquitously expressed trans-acting factors. On the other hand, nuclear proteins specifically expressed in pancreatic cell lines interact with GTII, and their relative abundance correlates with endogenous Glut2 expression. These GTII-binding factors correspond to nuclear proteins of 180 and 90 kilodaltons as defined by Southwestern analysis. The 180-kilodalton factor is present in pancreatic beta-cell lines but not in an alpha-cell line. Mutation of the GTI or GTIII cis-elements decreases transcriptional activity directed by the 338-bp promoter, whereas mutation of GTII increases gene transcription. Thus negative and positive regulatory sequences are identified within the proximal 338 bp of the GLUT2 promoter and may participate in the islet-specific expression of the gene by binding beta-cell specific trans-acting factors.
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PMID:Pancreatic-specific expression of the glucose transporter type 2 gene: identification of cis-elements and islet-specific trans-acting factors. 854 49


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