ROLE OF INSULIN-RESISTANCE IN TYPE-2 DIAB ETES

Type 2, non-insulin-dependent, diabetes is a disease of glucose homeos tasis involving up to 5 % of the adult population. The percentage of t he population with glucose intolerance is even greater, 10 %. These la ter patients are not diagnosed as ''diabetics'', but 50 % of them have non-insulin-dependent diabetes. Globally, 10 % of the adult populatio n has or will have Type 2 diabetes, a major health care problem. Chara cteristically, in patients with Type 2 diabetes, pancreatic insulin se cretion is deficient, liver glucose production is increased during the post-absorption period and peripheral glucose consumption, particular ly in striated muscles, is decreased due to insulin resistance. There has been much progress in our understanding of the pathogenic mechanis ms involved. When clinical manifestations have become apparent, the re lative roles of defective insulin secretion and insulin resistance are difficult to distinguish. However, in persons with oral glucose intol erance or in persons with a high risk of developing Type 2 diabetes, t hese two mechanisms are more easily differentiated. High risk patients can be identified on the basis of our knowledge of genetic factors in Type 2 diabetes. The incidence of Type 2 diabetes is considerably inc reased in subjects with two diabetic parents. In addition to genetic f actors, environmental factors also influence the development of non-in sulin-dependent diabetes, contributing to the multifactorial nature of type 2 diabetes. In order to establish the relative importance of the se different factors, it is useful to define the different stages with characteristic degrees of metabolic disorder, insulin secretion abnor malities and insulin secretion. Different causes which may lead to Typ e 2 diabetes could thus be determined together with their chronology, making it possible to define a strategy for identifying responsible ge nes. Using this method, three stages between normal glucose tolerance to Type 2 diabetes could be defined. Clinically, the first stage prese nts as a slight increase in insulin secretion and a minimal decrease i n the peripheral effect of insulin on glucose uptake. Fasting glucose levels, liver glucose production and oral glucose tolerance are normal . The biochemical disorder concerns insulin resistance in muscles. In the second stage, insulin secretion rises sharply and the peripheral e ffect of insulin on glucose uptake decreases greatly. Fasting glucose level is normal, but liver production rises and oral glucose tolerance decreases. These biochemical disorders concern muscle insulin resista nce and increased hepatic neoglucogenesis. There is a progressive decl ine in insulin secretion during the third stage, together with a major decrease in effects of insulin on peripheral glucose uptake. Fasting glucose and liver glucose production are both increased and oral gluco se tolerance is greatly diminished. These biochemical disorders concer n muscle insulin resistance, increased hepatic neoglucogenesis and def ective insulin secretion. The biochemical mechanisms implicated in the passage from normal glucose tolerance to frank diabetes are discussed here. We attempt to define the genes which might play a role in the p athogenesis of Type 2 diabetes.