This study was designed to investigate the effect of glucogon-like peptide-1 (GLP-1) on pancreatic beta-cell function in normal, Zucker diabetic fatty (ZDF) rats, a model for non-insulin-dependent diabetes mellitus (NIDDM or type II diabetes) and their heterozygous siblings. Pancreas perfusion and enzyme-linked immunosorbent assay (ELISA) were used to detect the changes in insulin release under fasting and hyperglycemic conditions and following stimulation with GLP-1. Animals from the ZDF/Gmi-fa rats (ZDF) were grouped according to age, sex, and phenotype (obese or lean), and compared with LA lean rats. Glucose stimulation (10 mmol/L) in obese rats showed repressed response in insulin release. Glucose plus GLP-1 stimulation caused increased insulin release in all groups. The degree of this response differed between groups: lean > obese; young > adult; female > male. The LA lean control group was most sensitive, while the ZDF overtly diabetic group had the lowest response. In addition, the pulsatile pattern of insulin secretion was suppressed in ZDF rats, especially in obese groups. These results support the hypothesis that GLP-1 can effectively stimulate insulin secretion. Insulin release was defective in ZDF obese rats and could be partially restored with GLP-1. ZDF lean rats also showed suppression of beta-cell function and there was a difference in beta-cell function related to sex in ZDF strain. This study documents the efficacy of GLP-1 to stimulate insulin release and contributes to our understanding of the pathophysiological mechanisms underlying NIDDM.