Islet dysfunction in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus is characterized by fasting hyperglycemia associated with defects in the pancreatic islet, the liver, and the peripheral tissues, which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas A and B cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with non-insulin-dependent diabetes mellitus and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin and reduced insulin secretion. Though basal insulin levels in patients with non-insulin-dependent diabetes mellitus may appear normal when compared with those of healthy persons, islet function testing at matched glucose levels reveals impairments of basal and stimulated insulin secretion due to a reduction in B cell secretory capacity. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. 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. This impairment becomes more important to the hyperglycemia as the islet dysfunction declines. Therapeutic interventions either improve islet dysfunction and raise plasma insulin levels, reduce hepatic glucose production, or improve the efficiency of tissue glucose uptake. All result in a decline in the fasting glucose level regardless of the cause of hyperglycemia. It is concluded that non-insulin-dependent diabetes mellitus is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role.