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.
View: Text | PDF
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

×

Figure 2

Analyses of the endocrine pancreas in WT and DIRKO mice.

Options: View larger image (or click on image) Download as PowerPoint
Analyses of the endocrine pancreas in WT and DIRKO mice. Following 20 we...
Following 20 weeks on RC or HF diet, nonfasted WT and DIRKO mice were euthanized, and pancreata were harvested for assessment of insulin mRNA and insulin content as well as for histological and morphometric analyses. Blood was also obtained by cardiac puncture for measurement of ambient levels of circulating insulin. (A) Pancreatic histology and immunohistochemical staining for insulin in sections from WT and DIRKO mice. Original magnification, ×100. (B) Percent total β cell area per total pancreatic area (n = 5–9 per group). (C) Total islet number per total pancreatic area in μm2 (n = 6–9 per group). (D) Number of BrdU+ β cells per islet (n = 4–7 per group). (E) Insulin mRNA levels in pancreata from mice (n = 7–8 per group). (F) Pancreatic insulin content in WT and DIRKO mice (n = 7–10 per group). (G) Ambient levels of plasma insulin (n = 8–12 per group). *P < 0.05, **P < 0.01, ***P < 0.001 versus WT-RC; #P < 0.05, ###P < 0.001 versus WT-HF; ΧP < 0.05 versus DIRKO-RC.