ENHANCED GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE SECRETION AND INSULINOTROPIC ACTION IN GLUCAGON-LIKE PEPTIDE-1 RECEPTOR (- -)-MICE/

Incretins are gastrointestinal hormones that act on the pancreas to po tentiate glucose-stimulated insulin secretion. Despite the physiologic al importance of the enteroinsular axis, disruption of glucagon-like p eptide (GLP)-1 action is associated with only modest glucose intoleran ce in GLP-1 receptor -/- (GLP-1R -/-) mice. me show here that GLP-1R - /- mice exhibit compensatory changes in the enteroinsular axis via inc reased glucose-dependent insulinotropic polypeptide (GIP) secretion an d enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were signif icantly elevated versus those in +/+ control mice after an oral glucos e tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P less than or equ al to 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a s ignificantly greater insulin response in GLP-1R -/- than in +/+ mice ( P less than or equal to 0.02-0.05). In contrast, no significant pertur bation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1 R -/- mice. Total pancreatic insulin but not glucagon content was sign ificantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs . 121 +/- 10 pmol/mg protein; P less than or equal to 0.005). These ob servations suggest that upregulation of the GIP component of the enter oinsular axis, at the levels of GLP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.