Abstract
Pancreatic β-cell dysfunction is a diagnostic criterion of Type 2 diabetes and includes defects in glucose transport and insulin secretion. In healthy individuals, β-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 β-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 β-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 β-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 β-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 β-cells limits intracellular glucose-6-phosphate production by glucokinase. This metabolic threshold is crossed in Type 2 diabetes and results in β-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.
Highlights
Glucose transport across the plasma membrane is an essential process among cells and organisms [1,2,3]
In understanding how the acquisition of deficient b-cell glucose transport may contribute to the pathogenesis of Type 2 diabetes, we have developed a mathematical model of glucose transport that integrates experimental findings that include human data from bcells of normal and T2D donors [7], with supporting data from rodent studies
We have developed a computational model for b-cell glucose transport and the alterations that occur in health and diabetes from the published findings of multiple laboratories
Summary
Glucose transport across the plasma membrane is an essential process among cells and organisms [1,2,3]. Pancreatic b-cells sense a postprandial rise in blood glucose and secrete insulin into circulation by a process termed glucose-stimulated insulin secretion (GSIS). The resulting activation of insulin receptors among peripheral tissues increases glucose uptake in normalizing blood glucose levels [4]. In this way, the pancreatic b-cell acts in concert with peripheral insulin action to regulate glucose homeostasis in the organism. The ability of the b-cell to transport glucose across the plasma membrane and thereby sense changes in blood glucose concentration is an essential component of normal b-cell function and the maintenance of glucose homeostasis
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