Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro3)GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes.
Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide [GIP]) is an important incretin hormone secreted by endocrine K-cells in response to nutrient ingestion. In this study, we investigated the effects of chemical ablation of GIP receptor (GIP-R) action on aspects of obesity-related diabetes using a stable and specific GIP-R antagonist, (Pro3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro3)GIP over an 11-day period. Nonfasting plasma glucose levels and the overall glycemic excursion (area under the curve) to a glucose load were significantly reduced (1.6-fold; P < 0.05) in (Pro3)GIP-treated mice compared with controls. GIP-R ablation also significantly lowered overall plasma glucose (1.4-fold; P < 0.05) and insulin (1.5-fold; P < 0.05) responses to feeding. These changes were associated with significantly enhanced (1.6-fold; P < 0.05) insulin sensitivity in the (Pro3)GIP-treated group. Daily injection of (Pro3)GIP reduced pancreatic insulin content (1.3-fold; P < 0.05) and partially corrected the obesity-related islet hypertrophy and beta-cell hyperplasia of ob/ob mice. These comprehensive beneficial effects of (Pro3)GIP were reversed 9 days after cessation of treatment and were independent of food intake and body weight, which were unchanged. These studies highlight a role for GIP in obesity-related glucose intolerance and emphasize the potential of specific GIP-R antagonists as a new class of drugs for the alleviation of insulin resistance and treatment of type 2 diabetes.
Gault
Victor A
VA
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland BT52 1SA, UK. va.gault@ulster.ac.uk
Irwin
Nigel
N
Green
Brian D
BD
McCluskey
Jane T
JT
Greer
Brett
B
Bailey
Clifford J
CJ
Harriott
Patrick
P
O'harte
Finbarr P M
FP
Flatt
Peter R
PR
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000209:etiology; D004435:Eating / Q000187:drug effects; D005502:Food; D005749:Gastric Inhibitory Polypeptide / Q000008:administration & dosage*; D018149:Glucose Intolerance / Q000188:drug therapy; D006442:Glycated Hemoglobin / Q000032:analysis; D006965:Hyperplasia; D007328:Insulin / Q000032:analysis / Q000097:blood; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000737:chemistry / Q000473:pathology*; D007700:Kinetics; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors* / Q000187:drug effects
D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide; D006442:Glycated Hemoglobin; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; C041086:gastric inhibitory polypeptide receptor