Pancreatic b-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, b-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial elevations in blood glucose facilitate glucose uptake into b-cells by diffusion through glucose transporters residing at the plasma membrane. Glucose transport is essential for glycolysis and glucose-stimulated insulin secretion. In human Type 2 diabetes and in the mouse model of obesity-associated diabetes, a marked deficiency of b-cell glucose transporters and glucose uptake occurs with the loss of glucose-stimulated insulin secretion. Recent studies have shown that the preservation of glucose transport in b-cells maintains normal insulin secretion and blocks the development of obesity-associated diabetes. To further elucidate the underlying mechanisms, we have constructed a computational model of human b-cell glucose transport in health and in Type 2 diabetes, and present a systems analysis based on experimental results from human and animal studies. Our findings identify a metabolic threshold or ‘‘tipping point’’ whereby diminished glucose transport across the plasma membrane of b-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in b-cell dysfunction including the loss of glucose stimulated insulin secretion. Our model further discriminates among molecular control points in this pathway wherein maximal therapeutic intervention is achieved.

C. Luni, J. D. Marth, F. J. Doyle (2012). Computational Modeling of Glucose Transport in Pancreatic beta-Cells Identifies Metabolic Thresholds and Therapeutic Targets in Diabetes. PLOS ONE, 7(e53130), 1-8 [10.1371/journal.pone.0053130].

Computational Modeling of Glucose Transport in Pancreatic beta-Cells Identifies Metabolic Thresholds and Therapeutic Targets in Diabetes

C. Luni;
2012

Abstract

Pancreatic b-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, b-cells maintain plasma glucose concentrations within a narrow range in concert with insulin action among multiple tissues. Postprandial elevations in blood glucose facilitate glucose uptake into b-cells by diffusion through glucose transporters residing at the plasma membrane. Glucose transport is essential for glycolysis and glucose-stimulated insulin secretion. In human Type 2 diabetes and in the mouse model of obesity-associated diabetes, a marked deficiency of b-cell glucose transporters and glucose uptake occurs with the loss of glucose-stimulated insulin secretion. Recent studies have shown that the preservation of glucose transport in b-cells maintains normal insulin secretion and blocks the development of obesity-associated diabetes. To further elucidate the underlying mechanisms, we have constructed a computational model of human b-cell glucose transport in health and in Type 2 diabetes, and present a systems analysis based on experimental results from human and animal studies. Our findings identify a metabolic threshold or ‘‘tipping point’’ whereby diminished glucose transport across the plasma membrane of b-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in b-cell dysfunction including the loss of glucose stimulated insulin secretion. Our model further discriminates among molecular control points in this pathway wherein maximal therapeutic intervention is achieved.
2012
C. Luni, J. D. Marth, F. J. Doyle (2012). Computational Modeling of Glucose Transport in Pancreatic beta-Cells Identifies Metabolic Thresholds and Therapeutic Targets in Diabetes. PLOS ONE, 7(e53130), 1-8 [10.1371/journal.pone.0053130].
C. Luni; J. D. Marth; F. J. Doyle
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/776262
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