GLUCAGON-LIKE PEPTIDE-1 STIMULATES INSULIN-SECRETION BUT NOT PHOSPHOINOSITIDE HYDROLYSIS FROM ISLETS DESENSITIZED BY PRIOR EXPOSURE TO HIGHGLUCOSE OR THE MUSCARINIC AGONIST CARBACHOL

In the present series of experiments, the ability of the postulated in cretin factor, glucagon-like peptide 1 (GLP-1), to stimulate insulin r elease from desensitized islets was determined. Compared with response s 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 r ates to a subsequent 20-mmol/L glucose stimulus by 63%, 81%, or 70%, r espectively. Efflux of H-3-inositol from prior high-glucose- or carbac hol-exposed islets was abolished and accumulation of inositol phosphat es (IPs) in response to 20 mmol/L glucose was reduced. Further additio n of 10 nmol/L GLP-1 together with 20 mmol/L glucose significantly inc reased 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 carbach ol. Inclusion of 10 nmol/L GLP-1 together with 8 mmol/L glucose plus 1 0 mu mol/L carbachol improved but did not normalize secretion from the se islets. These improvements in secretory responsiveness from high-gl ucose- or carbachol-desensitized islets occurred despite the lack of a ny apparent restorative effect of GLP-1 on agonist-induced increases i n phosphoinositide (PI) hydrolysis. Finally, unlike the situation obse rved with carbachol or high glucose preexposure, chronic exposure of i slets 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 i ncretin 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 tolera nce that accompanies chronic exposure of islets to one of several agon ists, including high glucose. (C) 1996 by W.B. Saunders Company