The role of the free cytosolic calcium level in beta-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7-37).
Using the glucose-responsive hamster beta-cell line (hamster insulin tumor cells), we examined the cellular mechanisms by which gastric inhibitory polypeptide (GIP) and glucagon-like peptide I(7-37) (GLP-I) potentiate glucose-stimulated insulin secretion. Glucose alone increased insulin secretion and increased the free cytosolic calcium levels ([Ca2+]i) without altering cAMP content. When added to glucose-stimulated cells, GIP and GLP-I increased cAMP levels and further increased insulin secretion. At 4 mM but not 0.4 mM glucose, both peptides triggered a dose-dependent rise in [Ca2+]i with ED50s of 0.4 and 0.2 nM for GIP and GLP-I, respectively. The increase in [Ca2+]i was blocked by either chelation of extracellular Ca2+ with EGTA or nimodipine, the voltage-dependent Ca2+ channel blocker. Nimodipine also inhibited the potentiation of glucose-stimulated insulin secretion by GIP and GLP-I without inhibition of the stimulatory effect of these two peptides on cAMP accumulation. Neither peptide altered phosphoinositide metabolism, further underlining that the mobilization of intracellular Ca2+ from endoplasmic reticulum is not involved in the GIP and GLP-I signal transduction pathways. This study establishes that GIP and GLP-I potentiate glucose-stimulated insulin secretion by increasing extracellular Ca2+ influx through voltage-dependent Ca2+ channels.
Lu
M
M
Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center, Boston, Massachusetts 02111.
Wheeler
M B
MB
Leng
X H
XH
Boyd
A E
AE
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D009553:Nimodipine / Q000494:pharmacology; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D010716:Phosphatidylinositols; D004533:Egtazic Acid; D009553:Nimodipine; D005749:Gastric Inhibitory Polypeptide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; C051322:glucagon-like peptide 1 (7-37); D002118:Calcium