Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro(3))GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes

Victor Gault, Nigel Irwin, BD Green, Janie McCluskey, B Greer, CJ Bailey, P Harriott, Finbarr O'Harte, Peter Flatt

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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, (Pro 3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro(3))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 (Pro 3)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.
LanguageEnglish
Pages2436-2446
JournalDiabetes
Volume54
Issue number8
Publication statusPublished - Aug 2005

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Gastric Inhibitory Polypeptide
Insulin Resistance
Obesity
Glucose
Eating
Insulin
Incretins
Withholding Treatment
Glucose Intolerance
Endocrine Cells
gastric inhibitory polypeptide receptor
pro-glucose-dependent insulinotropic polypeptide
Intraperitoneal Injections
Type 2 Diabetes Mellitus
Hypertrophy
Area Under Curve
Hyperplasia
Young Adult
Body Weight
Hormones

Cite this

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title = "Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro(3))GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related 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, (Pro 3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro(3))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 (Pro 3)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.",
author = "Victor Gault and Nigel Irwin and BD Green and Janie McCluskey and B Greer and CJ Bailey and P Harriott and Finbarr O'Harte and Peter Flatt",
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T1 - Chemical ablation of gastric inhibitory polypeptide receptor action by daily (Pro(3))GIP administration improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure in obesity-related diabetes

AU - Gault, Victor

AU - Irwin, Nigel

AU - Green, BD

AU - McCluskey, Janie

AU - Greer, B

AU - Bailey, CJ

AU - Harriott, P

AU - O'Harte, Finbarr

AU - Flatt, Peter

PY - 2005/8

Y1 - 2005/8

N2 - 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, (Pro 3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro(3))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 (Pro 3)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.

AB - 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, (Pro 3)GIP. Young adult ob/ob mice received once-daily intraperitoneal injections of saline vehicle or (Pro(3))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 (Pro 3)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.

M3 - Article

VL - 54

SP - 2436

EP - 2446

JO - Diabetes

T2 - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 8

ER -