Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells.
Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal peptide with potent insulinotropic activities on pancreatic beta-cells in vivo and in vitro. In earlier studies elevated concentrations GLP-I(7-37) inhibited insulin release and cAMP generation in beta-cells. We now show that the GLP-I(7-37) receptor in the glucose-responsive B-cell line HIT-T15 undergoes rapid and reversible homologous desensitization in response to supraphysiological concentrations of GLP-I(7-37). GLP-I(7-37) stimulated insulin release and cAMP generation in a glucose-dependent biphasic manner with a maximum stimulation at 10 nmol/liter. The first-phase insulin secretory response was reduced by 41% at doses of GLP-I(7-37) of 100 nmol/liter and higher. Preperifusion of B-cells with 100 nmol/liter GLP-I(7-37) for 5 or 10 min reduced a subsequent insulin secretory response to 10 nmol/liter GLP-I(7-37) after hormone washout and recovery periods of 10 min (52% and 55% reduction) or 30 min (33% reduction or full recovery). Preperifusion of HIT-T15 cells with 100 nmol/liter glucagon (10 min) or 100 nmol/liter gastric inhibitory peptide (GIP) (10 min) had no effect on the insulin secretory response to 10 nmol/liter GLP-(7-37). Prior exposure of cells to 100 nmol/liter GLP-(7-37) (10 min) did not alter the GIP-induced (10 nmol/liter) insulin release, but 100 nmol/liter GIP (10 min) reduced the insulin secretion during stimulation with 10 nmol/liter GIP by 56%. These data indicate that: 1) the GLP-I(7-37) receptor is subject to rapid and reversible homologous desensitization and, 2) the GLP-I(7-37) receptor on beta-cells is distinct from that of GIP. The recent finding of elevated GLP-I(7-36)amide levels in subjects with noninsulin-dependent diabetes suggest the possibility that a homologous desensitization of the GLP-I(7-37) receptor might contribute to the impaired insulin secretion in this disorder.
Fehmann
H C
HC
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston 02114.
Habener
J F
JF
D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D018027:Receptors, Glucagon; D014407:Tumor Cells, Cultured
D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D000242:Cyclic AMP; D005947:Glucose