Daily administration of the GIP-R antagonist (Pro³)GIP in streptozotocin-induced diabetes suggests that insulin-dependent mechanisms are critical to anti-obesity-diabetes actions of (Pro³)GIP

Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro³)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in...

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Published in:Diabetes, obesity & metabolism obesity & metabolism, 2008-04, Vol.10 (4), p.336-342
Main Authors: McClean, P.L, Gault, V.A, Irwin, N, McCluskey, J.T, Flatt, P.R
Format: Article
Language:English
Subjects:
(Pro3)GIP
(Pro³)GIP
Animals
Anti-Obesity Agents - therapeutic use
beta-cells
Blood Glucose - analysis
diabetes
Diabetes Mellitus, Experimental - blood
Diabetes Mellitus, Experimental - drug therapy
Diabetes Mellitus, Experimental - pathology
Gastric Inhibitory Polypeptide - therapeutic use
GIP-R antagonist
Glucagon - therapeutic use
glucose homeostasis
glucose-dependent insulinotropic polypeptide
Glycated Hemoglobin A - analysis
Insulin - blood
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - pathology
Male
Mice
Mice, Inbred Strains
Models, Animal
Random Allocation
Receptors, Gastrointestinal Hormone - antagonists & inhibitors
Somatostatin - therapeutic use
streptozotocin
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Summary:Glucose-dependent insulinotropic polypeptide-receptor (GIP-R) antagonism using (Pro³)GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure and function in a commonly used model of obesity-diabetes, namely ob/ob mice. The effect of GIP-R antagonism in a streptozotocin (STZ)-induced model of insulin deficiency has not been evaluated. The present study has investigated the effects of daily administration of (Pro³)GIP to STZ-treated mice. Swiss TO mice received once-daily injection of (Pro³)GIP (25 nmol/kg body weight) or saline 4 days prior to and 16 days after injection of STZ, and effects on metabolic parameters and islet architecture were assessed. (Pro³)GIP treatment had no significant effect on hyperphagia or body weight loss. However, hyperglycaemia and glycated haemoglobin were worsened, glucose tolerance further decreased and insulin sensitivity was impaired by (Pro³)GIP. These effects were observed on an STZ-induced background characterized by severe reductions of circulating insulin, beta-cell mass and pancreatic insulin stores. These data indicate that the beneficial actions of the GIP-R antagonist, (Pro³)GIP, in obesity-diabetes appear to be largely mediated through insulin-dependent mechanisms that merit further investigation.
ISSN:1462-8902
1463-1326
DOI:10.1111/j.1463-1326.2007.00712.x