Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Xueying Lin, … , Yedan Li, Morris F. White
Xueying Lin, … , Yedan Li, Morris F. White
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):908-916. https://doi.org/10.1172/JCI22217.
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Article Metabolism

Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes

Abstract

The molecular link between obesity and β cell failure that causes diabetes is difficult to establish. Here we show that a conditional knockout of insulin receptor substrate 2 (Irs2) in mouse pancreas β cells and parts of the brain — including the hypothalamus —increased appetite, lean and fat body mass, linear growth, and insulin resistance that progressed to diabetes. Diabetes resolved when the mice were between 6 and 10 months of age: functional β cells expressing Irs2 repopulated the pancreas, restoring sufficient β cell function to compensate for insulin resistance in the obese mice. Thus, Irs2 signaling promotes regeneration of adult β cells and central control of nutrient homeostasis, which can prevent obesity and diabetes in mice.

Authors

Xueying Lin, Akiko Taguchi, Sunmin Park, Jake A. Kushner, Fan Li, Yedan Li, Morris F. White

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Pancreas β cell function in aged fIrs2:cr2 and fIrs2:cr2:Irs1+/_ mice.(A...
Pancreas β cell function in aged fIrs2:cr2 and fIrs2:cr2:Irs1+/_ mice.(A) Random-fed blood glucose levels were determined at the indicated ages. Averages ± SE were determined from at least 5 male mice per genotype. (B) Random insulin levels were determined in male mice of the indicated genotypes and ages. Averages ± SE were determined from at least 5 mice per genotype. (C) Cre-mediated recombination/deletion of fIrs2 alleles was determined by real-time PCR analysis in single islets isolated from male fIrs2:cr2 mice at the indicated ages; or determined in hypothalamus from 10-month-old fIrs2 or fIrs2:cr2 mice. (D) Real-time PCR analysis of cr2 expression in isolated fIrs2:cr2 islets at the indicated ages; mRNA levels were normalized against cyclophilin expression, and the averages ± SE were determined for 2 male mice at each age. (E) Body weight of male littermates of the indicated genotypes that were fed regular chow and weighed weekly from postnatal day 21 until 16 weeks of age; each point represents the average ± SE of at least 6 mice. (F) Three representative pancreatic sections obtained from 6-month-old mice of the indicated genotypes immunostained with antibodies against insulin (green) or glucagon (red).