NORMALIZATION OF INSULIN RESPONSES TO GLUCOSE BY OVERNIGHT INFUSION OF GLUCAGON-LIKE PEPTIDE-1(7-36) AMIDE IN PATIENTS WITH NIDDM

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans . Its effects on overnight glucose concentrations and the specific pha ses of insulin response to glucose and nonglucose secretogogues in sub jects with NIDDM are not known. We compared the effects of overnight i ntravenous infusion of GLP-1 (7-36) amide with saline infusion, on ove rnight plasma concentrations of glucose, insulin, and glucagon in eigh t subjects with NIDDM. The effects on basal (fasting) beta-cell functi on and insulin sensitivity were assessed using homeostasis model asses sment (HOMA) and compared with seven age- and weight-matched nondiabet ic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic cl amp and the insulin response to a subsequent bolus of tile nonglucose secretogogue, arginine, were measured. These were compared with simila r measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimula ted beta-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of whic h was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasm a concentrations compared with saline, with postabsorptive glucose con centrations (2400-0800) of 5.6 +/- 0.8 and 7.8 +/- 1.4 mmol/l, respect ively (P < 0.0002). Basal beta-cell function assessed by HOMA was impr oved from geometric mean (1 SD range), 45% beta (24-85) to 91% beta (5 5-151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-8-33) to 116 pmol/l (12-438) (P < 0.005), second-phase insulin response to glucose from 13 6 pmol/l (53-352) to 1,156 pmol/l (357-3,748) (P < 0.0002), and increm ental insulin response to arginine from 443 pmol/l (172-1,144) to 811 pmol/l (272-2,417) (P < 0.002). All responses on GLP-1 were not signif icantly different from nondiabetic control subjects. Reduction of over night glucose by exogenous insulin did not improve any of the phases o f stimulated beta-cell function. Prolonged intravenous infusion of GLP -1 thus significantly lowered overnight glucose concentrations in subj ects with NIDDM and improved both basal and stimulated beta-cell funct ion to nondiabetic levels. It may prove to be a useful agent in the re duction of hyperglycemia in NIDDM.