Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice

Miyawaki, Kazumasa; Yamada, Yoshio; Yano, Hideki; Niwa, Hitoshi; Ban, Nobuhiro; Ihara, Yu; Kubota, Akira; Fujimoto, Sakae; Kajikawa, Mariko; Kuroe, Akira; Tsuda, Kinsuke; Hashimoto, Hiroyuki; Yamashita, Tetsuo; Jomori, Takahito; Tashiro, Fumi; Miyazaki, Jun‐ichi; Seino, Yutaka

doi:10.1073/pnas.96.26.14843

Cited by 414 publications

(300 citation statements)

References 37 publications

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“…In normal mice, genetic knockout or chemical antagonism of the GIP receptor clearly results in mild impairments of glucose homeostasis and insulin secretion [34,45]. Similar effects were produced by acute as opposed to longer-term administration of (Pro 3 )GIP to adult ob/ob mice [36].…”

Section: Discussionmentioning

confidence: 94%

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

et al. 2007

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Aims/hypothesis Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro 3 )GIP is able to counter the development of genetic obesityrelated diabetes. Materials and methods Young (5-7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro 3 )GIP (25 nmol kg −1 day −1 ) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA 1c , circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro 3 )GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p< 0.001), HbA 1c (p<0.05), glucose tolerance (p<0.001), meal tolerance (p<0.001) and insulin sensitivity (p<0.05). Remarkably, (Pro 3 )GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro 3 )GIP, while levels of triacylglycerol, LDLcholesterol and resistin were decreased (p<0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro 3 )GIP treatment than in control ob/ob mice (p<0.01), but plasma insulin levels remained substantially raised (p<0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

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Section: Discussionmentioning

confidence: 94%

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

et al. 2007

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“…KO mice lacking the GIP receptor showed impaired tolerance to oral glucose load but not to intraperitoneal glucose injection (22). High-fat feeding for 3 weeks induced a marked increase in the glycemic excursions after meal absorption.…”

Section: Gluco-incretins Control Insulin Secretion At Multiple Levelsmentioning

confidence: 95%

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

Preitner¹,

Ibberson²,

Franklin³

et al. 2004

J. Clin. Invest.

115

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The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double-as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R -/-but not in Gipr -/-mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.

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“…These mice exhibit reduced glucosestimulated insulin secretion after oral administration of glucose, which results in mild glucose intolerance (Miyawaki et al, 1999). However, the islet response to intraperitoneal glucose was normal, demonstrating that the GIP receptor is primarily involved in the incretin action.…”

Section: Gip Receptorsmentioning

confidence: 97%

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell

Åhrén

2007

Pharmacology & Therapeutics

159

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Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G-protein) coupled receptors (GPCRs). Examples of islet GPCRs are GPR40 and GPR119, which are GPCRs with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors

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Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice

Cited by 414 publications

References 37 publications

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

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