title: Glucagon-like peptide-1 stimulates insulin secretion but not phosphoinositide hydrolysis from islets desensitized by prior exposure to high glucose or the muscarinic agonist carbachol.
abstract: 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 micromol/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 3H-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 micromol/L) preexposure also abolished the subsequent insulin secretory and 3H-inositol efflux responses to 8 mmol/L glucose plus 10 micromol/L carbachol. Inclusion of 10 nmol/L GLP-1 together with 8 mmol/L glucose plus 10 micromol/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 desensitized 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 in 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.
authors.affiliation: Yale University School of Nursing, New Haven, CT, USA.
authors.forename: W S
authors.initials: WS
authors.lastname: Zawalich
authors.forename: K C
authors.initials: KC
authors.lastname: Zawalich
mesh_terms: D000818:Animals; D002217:Carbachol / Q000008:administration & dosage* / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018721:Muscarinic Agonists / Q000008:administration & dosage* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D002217:Carbachol; D005934:Glucagon; D005947:Glucose