Pancreatic B-cell dysfunction and glucose toxicity in non-insulin-dependent diabetes.

Abstract

Regulation of insulin secretion in response to feeding is determined by the direct actions of glucose and amino acids on the pancreatic B-cell together with indirect effects mediated by activation of hormonal and neural arms of the entero-insular axis (Berggren et al. 1992; Morgan, 1992; Have1 et al. 1994; Flatt, 1996). These signals are integrated at the level of the pancreatic B-cell such that insulin is secreted to regulate nutrient metabolism and glucose homeostasis appropriately. In non-insulin-dependent diabetes mellitus (NIDDM), defects in insulin action and the mechanisms that regulate insulin secretion are key to the glucose intolerance and metabolic disarray associated with the disease (Kahn & Porte, 1990; Leahy, 1990 Flatt et al. 1992). Possible molecular mechanisms underlying pancreatic B-cell dysfunction in NIDDM include site-specific defects in the stimulus-secretion coupling pathway and alterations in B-cell responsiveness consequent to environmental changes in diabetes. Deleterious effects of hyperglycaemia, so-called glucose toxicity (Unger & Grundy, 1985), represent an important means through which changes in internal environment impair B-cell function and both the secretion and action of insulin. The participation and interaction of site-specific defects and environmental factors in pancreatic B-cell dysfunction of NIDDM are considered in the framework of our current understanding of the regulation of B-cell function and stimulus-secretion coupling (matt, 1992; Flatt & Lenzen, 1994). Particular attention is drawn to the results of our recent and ongoing studies indicating an important role for glycation of functionally-important B-cell proteins in the glucose toxicity and functional demise of insulin-secreting cells.