Effects of short-term chemical ablation of the GIP receptor on insulin secretion, islet morphology and glucose homeostasis in mice.
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.
Irwin
Nigel
N
Diabetes Research Group, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. n.irwin@ulster.ac.uk
Gault
Victor A
VA
Green
Brian D
BD
Greer
Brett
B
McCluskey
Jane T
JT
Harriott
Patrick
P
O'Harte
Finbarr P M
FP
Flatt
Peter R
PR
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors* / Q000502:physiology
D001786:Blood Glucose; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor