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-diabetes.

P.R. Flatt, Brian Green, Patrick Harriott, V.A. Gault, N. Irwin, J.T. McCluskey, Brett Greer, C.J. Bailey, F.P.M. O'Harte

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Abstract

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 ß-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.
Original languageEnglish
Pages (from-to)2436-2446
Number of pages11
JournalDiabetes
Volume54(8)
Issue number8
DOIs
Publication statusPublished - Aug 2005

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Gastric Inhibitory Polypeptide
Insulin Resistance
Obesity
Glucose
gastric inhibitory polypeptide receptor
Eating
Insulin
Incretins
Withholding Treatment
Glucose Intolerance
Endocrine Cells
Intraperitoneal Injections
Islets of Langerhans
Type 2 Diabetes Mellitus
Hypertrophy
Area Under Curve
Hyperplasia
Young Adult

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title = "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-diabetes.",
abstract = "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 {\ss}-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.",
author = "P.R. Flatt and Brian Green and Patrick Harriott and V.A. Gault and N. Irwin and J.T. McCluskey and Brett Greer and C.J. Bailey and F.P.M. O'Harte",
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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-diabetes. / Flatt, P.R.; Green, Brian; Harriott, Patrick; Gault, V.A.; Irwin, N.; McCluskey, J.T.; Greer, Brett; Bailey, C.J.; O'Harte, F.P.M.

In: Diabetes, Vol. 54(8), No. 8, 08.2005, p. 2436-2446.

Research output: Contribution to journalArticle

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AU - Green, Brian

AU - Harriott, Patrick

AU - Gault, V.A.

AU - Irwin, N.

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AU - Bailey, C.J.

AU - O'Harte, F.P.M.

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