Glucagon-like peptide-1 (7-36) amide (GLP-1) is released from the gut into the circulation after meals and is the most potent physiological insulinotropic hormone in man. In contrast to presently available therapeutic agents for non-insulin-dependent diabetes mellitus (NIDDM), GLP-1 has the advantages of both suppressing glucagon secretion and delaying gastric emptying. We report the first chronic study of subcutaneous (s/c) GLP-1 treatment in NIDDM. Five patients with poorly controlled NIDDM were entered into a six-week, double-blind crossover trial. Each received three weeks treatment with s/c GLP-1 40 nmol or saline, given three times a day immediately before meals. A standardized test meal was given at the beginning and end of each treatment period. GLP-1 reduced plasma glucose area under the curve (AUC) following the standard test meal by 25% (AUC, 0-180 mins, GLP-1 start of treatment 482.2 +/- 38.2 vs. saline start of treatment 635.7 +/- 45.4 mmol min L-1, F = 16.4, P < 0.02). The beneficial effect of GLP-1 on plasma glucose concentration was fully maintained for the three-week treatment period. Plasma glucagon levels were significantly lower for 60 min postprandially after GLP-1 treatment. In this group of patients there was no significant increase in postprandial insulin levels with GLP-1. We have demonstrated a significant improvement in postprandial glycaemic control with s/c GLP-1 treatment that was fully maintained over a three-week treatment period. GLP-1 improves glycaemic control even in the absence of an insulinotropic effect and is a potential treatment for NIDDM.