WHAT THERAPY DO OUR NIDDM PATIENTS NEED - INSULIN RELEASERS

NIDDM is the result of concomitant defects in both insulin secretion and insulin action. Although plasma insulin concentration in NIDDM patients may be normal or even increased as compared to normal individuals, insulin secretion is always impaired when related to ambient hyperglycemia. Moreover, the loss of first-phase insulin secretion is always present and it occurs at the very early stage of the disease. The defect in the early release of insulin may have quite an impact in post-prandial glucose homeostasis, due to inadequate suppression of hepatic glucose production. Therefore, insulin releasers should be able; 1. to increase total insulin secretory capacity, and 2. to restore physiologic profile of insulin secretion. However, this is rarely achieved with the current therapeutical tools. Sulfonylureas may exert some suppressive action on the liver and may maintain a portal-peripheral venous insulin gradient. Metformin may improve insulin sensitivity but has no effect on the p-cell. Exogenous insulin exerts an inhibitory effect on hepatic glucose production but it does not maintain the physiologic gradient, neither can it mimic first-phase insulin secretion. Therefore, more appropriate tools must be sought. Prompt stimulation of insulin secretion can be elicited by alpha(2)-adrenoreceptor antagonists, but their clinical use is still under evaluation. New sulfonylureas are under development, though some of them may exert a better peripheral action than more potent stimulation of the beta-cell. Special interest has been focused on incretin peptides. Infusion of glucagon-like peptide 1 (GLP-1) in NIDDM patients improves glucose tolerance through enhancement of acute release of insulin, suppression of glucagon secretion, and improvement of peripheral glucose utilization. Finally, the possibility should be considered to reproduce rather than stimulate first-phase insulin secretion by s.c. injection of fast-acting insulin analogs. Whatever the mean will be used, restoration of first-phase insulin secretion may be expected to improve post-prandial glucose profile as a consequence of better modulation of hepatic glucose production. The reduced rise in post-prandial plasma glucose level is likely to relieve the challenge on the beta-cell so that a smoother second phase insulin secretion is obtained. In the long run, this may translate in an overall amelioration of glucose control while avoiding chronic hyperinsulinemia.