PATHOGENESIS OF TYPE-2 (NON-INSULIN-DEPENDENT) DIABETES-MELLITUS - A BALANCED OVERVIEW

Following an overnight fast the majority of glucose disposal occurs in insulin-independent tissues, the brain (approximately 50%) and splanchnic organs (approximately 25%), while only 25% occurs in insulin-dependent tissues, primarily muscle [1-4]. Basal glucose utilization (approximately 2 mg.kg-1.min-1) is precisely matched by glucose production by the liver [1-4]. Following glucose ingestion, the balance between uptake and output is disrupted and maintenance of glucose homeostasis depends upon three processes that must occur in a co-ordinated fashion: (1) insulin secretion; (2) stimulation of glucose uptake by splanchnic (liver and gut) and peripheral (primarily muscle) tissues in response to hyperinsulinaemia plus hyperglycaemia; (3) suppression of hepatic glucose production. It logically follows that abnormalities at the level of the Beta cell, muscle, and/or liver can lead to the development of glucose intolerance. The full blown syndrome of Type 2 (non-insulin-dependent) diabetes mellitus requires the simultaneous presence of two defects, insulin resistance and impaired Beta-cell function. In Type 2 diabetes the primary or inherited defect most likely represents impaired tissue (muscle and/or liver) sensitivity to insulin. Eventually, however, the Beta cell fails to maintain a sufficiently high rate of insulin secretion to compensate for the insulin resistance, and overt diabetes mellitus ensues.