Expression of GLUT-2 antisense RNA in beta cells of transgenic mice leads to diabetes.

Valera, Alfons; Solanes, Gemma; Fernández-Álvarez, Josefa; Pujol, Anna; Ferrer, Jorge; Asins, Guillermina; Gomis, R; Bosch, Fátima

doi:10.1016/s0021-9258(19)61937-x

Cited by 78 publications

(5 citation statements)

References 21 publications

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“…However, the rate of glucose transport in ␤-cells is 50-to 100-fold greater than the rate of GLUT2 phosphorylation. Moreover, a 70-80% reduction of GLUT2 expression is needed to impair GSIS (40). Thus, GLUT2 has mainly a permissive role allowing glucose unrestricted access to GK, which is the rate-limiting step of glucose metabolism in ␤-cells and may be an important target protein of GLP-1 signaling.…”

Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide-1 Enhances Glucokinase Activity in Pancreatic β-Cells through the Association of Epac2 with Rim2 and Rab3A

et al. 2012

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Glucokinase (GK), which phosphorylates D-glucose, is a major glucose sensor in β-cells for glucose-stimulated insulin secretion (GSIS) and is a promising new drug target for type 2 diabetes (T2D). In T2D, pancreatic β-cells exhibit defective glucose sensitivity, which leads to impaired GSIS. Although glucagon-like peptide-1-(7-36)-amide (GLP-1) is known to enhance β-cell glucose sensitivity, the effect of GLP-1 on GK activity is still unknown. The present study demonstrated that GLP-1 pretreatment for 30 min significantly enhanced GK activity in a glucose-dependent manner, with a lower Michaelis-Menten constant (K(m)) but unchanged maximal velocity (V(max)). Thus, GLP-1 acutely enhanced cellular glucose uptake, mitochondrial membrane potential, and cellular ATP levels in response to glucose in rat INS-1 and native β-cells. This effect of GLP-1 occurred via its G protein-coupled receptor pathway in a cAMP-dependent but protein kinase A-independent manner with evidence of exchange protein activated by cAMP (Epac) involvement. Silencing Epac2, interacting molecule of the small G protein Rab3 (Rim2), or Ras-associated protein Rab3A (Rab3A) significantly blocked the effect of GLP-1. These results suggested that GLP-1 can further potentiate GSIS by enhancing GK activity through the signaling of Epac2 to Rim2 and Rab3A, which is the similar pathway for GLP-1 to potentiate Ca(2+)-dependent insulin granule exocytosis. The present finding may also be an important mechanism of GLP-1 for recovery of GSIS in T2D.

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Section: Discussionmentioning

confidence: 99%

Glucagon-Like Peptide-1 Enhances Glucokinase Activity in Pancreatic β-Cells through the Association of Epac2 with Rim2 and Rab3A

et al. 2012

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“…Under these conditions, glucose transport, having a capacity that is largely in excess of glucose phosphorylation and metabolism, does not play a pivotal role in determining the secretory response (Efrat et al, 1994). However, when the expression or function of the glucose transporter is significantly reduced, it may limit the access of glucose to glucokinase, thus preventing a normal glucose sensing and appropriate insulin secretion (Orci et al, 1990;Thorens et al, 1990;Valera et al, 1994). Here, in order to test whether the decrease in glucose uptake could be responsible for the impairment of insulin secretion, we measured both GLUT-2 protein levels in isolated islets by Western blotting and pancreatic glucose uptake by using its nonmetabolizable 3H-labeled analog 2-deoxyglucose.…”

Section: Discussionmentioning

confidence: 99%

2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced impairment of glucose-stimulated insulin secretion in isolated rat pancreatic islets

2005

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“…Loss of pancreatic b cell Glut expression in humans and rodents is associated with hyperglycemia and diminished glucosestimulated insulin secretion (GSIS), which are early markers in the pathogenesis of diabetes and precede the development of insulin resistance (Johnson et al, 1990;Orci et al, 1990a;Thorens et al, 1990;Unger, 1991;Guerra et al, 2005). Glut-2 is essential for the primary GSIS response of mouse b cells, and reduced Glut-2 expression abolishes this role of the pancreas coincident with the onset of type 2 diabetes (Valera et al, 1994;Guillam et al, 1997Guillam et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

Dietary and Genetic Control of Glucose Transporter 2 Glycosylation Promotes Insulin Secretion in Suppressing Diabetes

Ohtsubo

Takamatsu

Minowa

et al. 2005

Cell

397

317

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Pancreatic beta cell-surface expression of glucose transporter 2 (Glut-2) is essential for glucose-stimulated insulin secretion, thereby controlling blood glucose homeostasis in response to dietary intake. We show that the murine GlcNAcT-IVa glycosyltransferase is required for Glut-2 residency on the beta cell surface by constructing a cell-type- and glycoprotein-specific N-glycan ligand for pancreatic lectin receptors. Loss of GlcNAcT-IVa, or the addition of glycan-ligand mimetics, attenuates Glut-2 cell-surface half-life, provoking endocytosis with redistribution into endosomes and lysosomes. The ensuing impairment of glucose-stimulated insulin secretion leads to metabolic dysfunction diagnostic of type 2 diabetes. Remarkably, the induction of diabetes by chronic ingestion of a high-fat diet is associated with reduced GlcNAcT-IV expression and attenuated Glut-2 glycosylation coincident with Glut-2 endocytosis. We infer that beta cell glucose-transporter glycosylation mediates a link between diet and insulin production that typically suppresses the pathogenesis of type 2 diabetes.

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Expression of GLUT-2 antisense RNA in beta cells of transgenic mice leads to diabetes.

Cited by 78 publications

References 21 publications

Glucagon-Like Peptide-1 Enhances Glucokinase Activity in Pancreatic β-Cells through the Association of Epac2 with Rim2 and Rab3A

Glucagon-Like Peptide-1 Enhances Glucokinase Activity in Pancreatic β-Cells through the Association of Epac2 with Rim2 and Rab3A

2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced impairment of glucose-stimulated insulin secretion in isolated rat pancreatic islets

Dietary and Genetic Control of Glucose Transporter 2 Glycosylation Promotes Insulin Secretion in Suppressing Diabetes

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