In the present series of experiments, the ability of the postulated incretin factor, glucagon-like peptide 1 (GLP-1), to stimulate insulin release from desensitized islets was determined. Compared with responses observed from control islets incubated for 3.5 hours with 5.6 mmol/L glucose alone, prior exposure to 10 mmol/L glucose, 20 mmol/L glucose, or 10 mu mol/L carbachol reduced peak second-phase insulin release rates to a subsequent 20-mmol/L glucose stimulus by 63%, 81%, or 70%, respectively. Efflux of H-3-inositol from prior high-glucose- or carbachol-exposed islets was abolished and accumulation of inositol phosphates (IPs) in response to 20 mmol/L glucose was reduced. Further addition of 10 nmol/L GLP-1 together with 20 mmol/L glucose significantly increased insulin output from desensitized islets. Carbachol (10 mu mol/L) preexposure also abolished the subsequent insulin secretory and H-3-inositol efflux responses to 8 mmol/L glucose plus 10 mu mol/L carbachol. Inclusion of 10 nmol/L GLP-1 together with 8 mmol/L glucose plus 10 mu mol/L carbachol improved but did not normalize secretion from these islets. These improvements in secretory responsiveness from high-glucose- or carbachol-desensitized islets occurred despite the lack of any apparent restorative effect of GLP-1 on agonist-induced increases in phosphoinositide (PI) hydrolysis. Finally, unlike the situation observed with carbachol or high glucose preexposure, chronic exposure of islets to GLP-1 (100 nmol/L) did not desensitize islets to a subsequent 20-mmol/L glucose stimulus. We conclude from these studies that the incretin factor GLP-1 may play an important role in maintaining insulin output from islets in which phospholipase C (PLC) mediated hydrolysis of islet PI pools is impaired. GLP-1 may prevent a further decline in beta cell function and the associated deterioration in glucose tolerance that accompanies chronic exposure of islets to one of several agonists, including high glucose. (C) 1996 by W.B. Saunders Company