The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus

Type 2 diabetes is a heterogeneous disorder characterized by defects in insulin secretion and action. Insulin resistance is a key feature of type 2 diabetes. However, insulin resistance alone does not appear to be sufficient to cause diabetes. Longitudinal studies have shown that the development of overt hyperglycemia is associated with a decline in beta -cell secretion. In patients with impaired glucose tolerance or in the early stages of type 2 diabetes, first-phase insulin release is almost invariably lost despite the enhancement of second-phase secretion. Both animal and human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. This effect is primarily mediated at the level of the liver, allowing prompt inhibition of endogenous glucose production (EGP) and thereby restraining the mealtime rise in plasma glucose. In type 2 diabetes, the loss of the early surge of insulin release is a precocious and quite common defect that plays a pathogenic role in postmeal hyperglycemia and one that may require specific therapeutic intervention. This becomes even more apparent if the negative impact of prandial glucose spikes is taken into consideration. Epidemiological evidence exists to indicate that 2-h postload plasma glucose levels are strongly associated with all-cause and cardiovascular mortality relative risk. Indeed the acute elevation of plasma glucose concentration triggers an array of tissue responses that may contribute to the development of diabetic complications. Considering that type 2 diabetes begins with meal-related hyperglycemia in many patients, it becomes apparent that normalization of postmeal plasma glucose levels should be the target for rational therapy and the goal in the early stages of the disease. If a primary goal of diabetes therapy is control of postmeal glucose excursion, then the regulation of glucose absorption from the gut and entry into the circulation is an important mechanism to consider. The restoration of the rapid increase in plasma insulin concentration may be quite an efficient therapeutic approach. Copyright (C) 2001 John Wiley & Sons, Ltd.