Glucose-dependent insulinotropic
polypeptide (GIP) is an
incretin hormone secreted by endocrine K-cells in response to nutrient absorption. In this study we have utilized a specific and enzymatically stable
GIP receptor antagonist, (
Pro3)GIP, to evaluate the contribution of endogenous GIP to insulin secretion and
glucose homeostasis in mice. Daily injection of (
Pro3)GIP (25 nmol/kg
body weight) for 11 days had no effect on food intake or
body weight. Non-fasting plasma
glucose concentrations were significantly raised (p<0.05) by day 11, while plasma
insulin concentrations were not significantly different from saline treated controls. After 11 days, intraperitoneal
glucose tolerance was significantly impaired in the (
Pro3)GIP treated mice compared to control (p<0.01).
Glucose-mediated insulin secretion was not significantly different between the two groups.
Insulin sensitivity of 11-day (
Pro3)GIP treated mice was slightly impaired 60 min post injection compared with controls. Following a 15 min refeeding period in 18 h fasted mice, food intake was not significantly different in (
Pro3)GIP treated mice and controls. However, (
Pro3)GIP treated mice displayed significantly elevated plasma
glucose levels 30 and 60 min post feeding (p<0.05, in both cases). Postprandial insulin secretion was not significantly different and no changes in pancreatic
insulin content or islet morphology were observed in (
Pro3)GIP treated mice. The observed
biological effects of (
Pro3)GIP were reversed following
cessation of treatment for 9 days. These data indicate that ablation of GIP signaling causes a readily reversible
glucose intolerance without appreciable change of insulin secretion.