GLUCAGON-LIKE PEPTIDE-1 IMPROVES THE ABILITY OF THE BETA-CELL TO SENSE AND RESPOND TO GLUCOSE IN SUBJECTS WITH IMPAIRED GLUCOSE-TOLERANCE

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the P-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establi sh if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and p otent insulin secretagogue, improves this defect. Two weight-matched g roups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 m mol/l) and another with seven subjects with diet-treated NIDDM (2-h gl ucose, 14.5 +/- 0.9 mmol/l), mere studied on two occasions during a 12 -h oscillatory glucose infusion, a sensitive test of the ability of th e beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg . kg(-l). min(-1), amplitude 33% above and below t he mean rate, and periodicity of 144 min, with infusion of saline or G LP-1 at 0.4 pmol . kg(-1). min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in pla sma glucose concentration, insulin secretion rates (ISRs) increased si gnificantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/m in; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were c ompatible with enhanced insulin secretion in the presence of GLP-1. Sp ectral power was used as a measure of the ability of the P-cell to sec rete insulin in response to small changes in the plasma glucose concen tration during the oscillatory infusion. Spectral power for ISR increa sed from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP- 1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM sub jects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dos age GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. beta-Cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may p reserve beta-cell function in subjects with IGT or mild NIDDM.