Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure
Tanya Hansotia, … , Yutaka Seino, Daniel. J. Drucker
Tanya Hansotia, … , Yutaka Seino, Daniel. J. Drucker
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):143-152. https://doi.org/10.1172/JCI25483.
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Research Article Metabolism

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure

Abstract

The incretin hormones glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r–/–, Gipr–/–, and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor–1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala2]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the β cell via control of adipokine secretion and energy expenditure.

Authors

Tanya Hansotia, Adriano Maida, Grace Flock, Yuichiro Yamada, Katsushi Tsukiyama, Yutaka Seino, Daniel. J. Drucker

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Figure 1

DIRKO mice exhibit reduced weight gain and impaired glucose tolerance on HF diet.

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DIRKO mice exhibit reduced weight gain and impaired glucose tolerance on...
(A) Body weight gain in WT and DIRKO mice on RC or HF diet (n = 8–13 per group). (B and C) Oral glucose tolerance in WT (B) and DIRKO mice (C) fed RC or HF diet for 12 weeks (n = 6–8 per group). At right, plasma insulin concentrations obtained 10 minutes after glucose administration (top; n = 6–8 per group) and quantification of AUC for the total glycemic excursions (bottom; n = 6–8 per group). (D) Plasma insulin/glucose ratios (ng/ml to mmol/l) at the 10–20 minute time point following glucose administration (n = 6–8 per group). *P < 0.05, ***P < 0.001 versus WT-RC; ###P < 0.001 versus WT-HF; ΧΧP < 0.01 versus DIRKO-RC.