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.
OBJECTIVE
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 (Pro(3))GIP to STZ-treated mice.


METHODS
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.


RESULTS
(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.


CONCLUSIONS
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.
McClean
P L
PL
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
Gault
V A
VA
Irwin
N
N
McCluskey
J T
JT
Flatt
P R
PR
D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005749:Gastric Inhibitory Polypeptide / Q000627:therapeutic use*; D005934:Glucagon / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D007328:Insulin / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D011897:Random Allocation; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000627:therapeutic use
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D005749:Gastric Inhibitory Polypeptide; D005934:Glucagon; D006442:Glycated Hemoglobin; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D013004:Somatostatin; C479120:glucose-dependent insulinotropic polypeptide, Pro(3)-; C041086:gastric inhibitory polypeptide receptor