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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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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Growth and nutrient homeostasis of the fIrs2:cr2 mice. (A) Male litterma...
Growth and nutrient homeostasis of the fIrs2:cr2 mice. (A) Male littermates fed regular or low-fat chow were weighed weekly from postnatal day 21 until 32 weeks of age; each point represents the average ± SE of at least 6 mice. Omitted error bars are smaller than the symbol. (B) Food intake was determined with 8-week-old male mice over 24 hours using a Comprehensive Lab Animal Monitoring System; average ± SE for 4 animals per genotype is reported. (C) Cumulative water intake was determined with 8-week-old male mice over 24 hours using a Comprehensive Lab Animal Monitoring System; average ± SE for 3 animals per genotype is reported. (D) Average lean and fat body mass ± SE was determined on three 8-week-old male of the indicated genotypes using a dual energy X-ray absorptiometry (DEXA) scanner (GE Medical Systems Lunar) according to the manufacturer’s instructions. (E) Average ± SE plasma insulin and leptin levels were determined on at least fifteen 8-week-old random fed male mice of each genotype using a rat insulin or mouse leptin ELISA Kit. *P < 0.05; **P < 0.01.