Evolution from obesity to diabetes.

The relationship between obesity and Type 2 diabetes mellitus is so closely related that it is worth questioning the possibility of obesity being more than just one diabetes risk factor among others but a factor which participates causally to the development of Type 2 Diabetes on a genetic background. In this review, the evolution of normal glucose tolerance towards impaired glucose tolerance corresponds to the development of compensatory metabolic changes. These compensatory mechanisms are hyperinsulinaemia and postprandial hyperglycaemia which prevents a defect in glucose uptake and especially glucose storage. These compensatory responses are overcome with time and diabetes develops in spite of the hyperinsulinaemia and the hyperglycaemia. The capacity for glucose storage is decreased and cannot be overcome at this stage by increases of both glucose and insulinemic responses. Inhibition of glycogen synthase activity by an increased muscle glycogen concentration is probably more powerful than its stimulation by insulin and glucose and the capacity for glucose storage remains decreased. Finally with time insulin secretion gradually decreases as a consequence of chronic hyperglycaemia and results in full pancreatic decompensation. At this stage hepatic glucose production is increased. The most important factor in the evolution from obesity to diabetes reside in the permanence of the increase in lipid oxidation and mainly in the duration of obesity. An important consequence of permanently high lipid oxidation is the chronic resistance to glucose uptake, initially compensated for by increased plasma insulin and glucose concentrations. A vicious circle starts after insulin resistance to glucose uptake appears, followed by hyperglycaemia blocking the glucose storage system and by the lack of storing capacity leading to a rise in glycaemia. In conclusion, all these metabolic phenomena are appearing in a sequential way, progressively adapting to the deteriorating situation, through the stages of normal glucose tolerance, impaired glucose tolerance, hyperinsulinaemic and finally hypoinsulinemic diabetes.