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.