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 phases of
insulin response to
glucose and nonglucose
secretogogues in subjects with
NIDDM are not known. We compared the effects of overnight
intravenous infusion of
GLP-1 (7-36)
amide with saline infusion, on overnight plasma concentrations of
glucose,
insulin, and
glucagon in eight subjects with
NIDDM. The effects on basal (fasting) beta-cell function and
insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The
GLP-1 infusion was continued, and the first- and second-phase
insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the
insulin response to a subsequent bolus of the nonglucose
secretogogue,
arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving
GLP-1. The effects on stimulated beta-cell function of lowering plasma
glucose per se were assessed by a separate overnight infusion of
soluble insulin, the rate of which was adjusted to mimic the
blood glucose profile achieved with
GLP-1. Infusion of
GLP-1 resulted in significant lowering of overnight plasma
glucose concentrations compared with saline, with mean postabsorptive
glucose concentrations (2400-0800) of 5.6 +/- 0.8 and 7.8 +/- 1.4 mmol/l, respectively (P < 0.0002). Basal beta-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% beta (24-85) to 91% beta (55-151) 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 136 pmol/l (53-352) to 1,156 pmol/l (357-3,748) (P < 0.0002), and incremental
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 significantly different from nondiabetic control subjects. Reduction of overnight
glucose by exogenous
insulin did not improve any of the phases of stimulated beta-cell function. Prolonged
intravenous infusion of
GLP-1 thus significantly lowered overnight
glucose concentrations in subjects with
NIDDM and improved both basal and stimulated beta-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of
hyperglycemia in
NIDDM.