The key role of islet dysfunction in Type II diabetes mellitus

Daniel Porte, Jr.
Steven E. Kahn

Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine and VA Medical Center, Seattle, Washington, USA

Abstract

Fasting plasma glucose levels are constant from day to day in normal individuals. This constancy is due to a close coordination between glucose production by the liver and glucose uptake in peripheral tissues. This review focusses on the key role of the endocrine pancreas alpha and beta cells to provide this coordination. Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia. The degree of fasting hyperglycemia, in turn is correlated with the basal rate of hepatic glucose production. This increased rate of glucose release by the liver results in part from impaired hepatic sensitivity to insulin, but is largely due to reduced insulin secretion and increased glucagon secretion. Though basal immunoreactive insulin and glucagon levels in patients with NIDDM may appear normal when compared to those of healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin and glucagon secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon release. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia, but in a curvilinear fashion. Thus, islet alpha- and beta-cell function is reduced by more than 50% in NIDDM by the time that clinical fasting hyperglycemia develops (140 mg/dL). The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. The nature of this interaction is such that defective insulin action becomes more important to the hyperglycemia as islet alpha- and beta-cell function declines. Therapeutic interventions, to be effective, must reduce hepatic glucose production either by improving islet dysfunction and raising plasma insulin and reducing plasma glucagon levels, or by improving the effectiveness of insulin on the liver and the periphery. Both result in a decline in the fasting glucose levels regardless of the cause of hyperglycemia. We conclude that NIDDM is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a key role. Treatment should be based upon this pathophysiologic understanding.

Clin Invest Med 1995; 18 (4): 247-254

Table of contents: CIM vol. 18, no. 4