Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

Subjects who develop type 2 diabetes have a complex phenotype with defects in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin, all of which contribute to the development of overt hyperglycemia. Although the precise mechanisms whereby these three factors interact to produce glucose intolerance and diabetes are uncertain, it has been suggested that the final common pathway responsible for the development of type 2 diabetes is the failure of the pancreatic β cell to compensate for insulin resistance (1). Here, we review evidence for this model from both human and animal studies, and we consider the effects of specific drug treatments and of heightened FFA levels on insulin sensitivity and insulin secretion in individuals at risk for type 2 diabetes. Coleman and coworkers (2), drawing on their work with the ob/ob mouse, first proposed that a failure of β-cell compensation for insulin resistance is responsible for the development of type 2 diabetes. When insulin-resistant ob/ob mice, which provide a genetic model of obesity, were bred with mice of different strains, the phenotypes of the progeny differed depending on their genetic background. Mice carrying the ob mutation in the C57BL/6 background had relatively normal blood glucose levels, whereas in the C57Ks background the animals developed overt hyperglycemia. The major difference between these two mouse strains lay in their β-cell responses. The nondiabetic C57BL/6 mice underwent a marked expansion of β-cell mass, whereas C57Ks animals showed histologic evidence of islet degeneration, degranulation, and progressive atrophy. The C57Ks animals accordingly had insulin levels about one-tenth those of the C57BL/6 animals, and these levels declined progressively with age. These data indicated that the genetic background on which insulin resistance develops influences the adequacy of pancreatic β-cell compensation for insulin resistance, and hence the predisposition to diabetes.