Impaired glucose tolerance (IGT) and
NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma
glucose concentrations. The aim of this study was to establish if
glucagon-like peptide 1 (GLP-1), a natural enteric
peptide and potent
insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h
glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated
NIDDM (2-h
glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory
glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to
glucose.
Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or
GLP-1 at 0.4 pmol x kg(-1) x 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 plasma
glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; 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 compatible with enhanced insulin secretion in the presence of
GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete
insulin in response to small changes in the plasma
glucose concentration during the oscillatory infusion. Spectral power for ISR increased 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 subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage
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 preserve beta-cell function in subjects with IGT or mild
NIDDM.