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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 Article has an altmetric score of 3

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

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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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Figure 3

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Glucose homeostasis in the fIrs2:cr2 mice. (A) Average ± SE random-fed b...
Glucose homeostasis in the fIrs2:cr2 mice. (A) Average ± SE random-fed blood glucose levels were determined using a Glucometer Elite in at least fifteen 8-week-old male mice of the indicated genotypes. (B and C) Glucose-disposal rates and hepatic glucose output before and during hyperinsulinemia (average ± SE) were determined on 6_10 fasted and conscious 10-week-old male mice of the indicated genotypes. (D) Pancreas insulin content was determined using rat insulin ELISA Kit following acid-ethanol extraction. Results are average ± SE for five 8-week-old mice per genotype. (E) After a 16-hour overnight fast, blood glucose (average ± SE) was determined on at least fifteen 8-week-old male mice of the indicated genotypes following intraperitoneal injection of 2 g D-glucose/kg body weight. (F) The integrated glucose tolerance (GTT, t = 0 Ø 120 min) for the 8-week old male mice fed the ordinary diet (data in E) was compared with that for 16-week-old male mice fed a low-fat diet (LFD, 5%); these ages were selected for comparison to match the body weights. The glucose tolerance curves were integrated using the trapezoid rule implemented in Sigmaplot 8.0 (Systat Software Inc.). *P < 0.05; **P < 0.01.

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