Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes
Anita M. Hennige, Deborah J. Burks, Umut Ozcan, Rohit N. Kulkarni, Jing Ye, Sunmin Park, Markus Schubert, Tracey L. Fisher, Matt A. Dow, Rebecca Leshan, Mark Zakaria, Mahmud Mossa-Basha, Morris F. White
Anita M. Hennige, Deborah J. Burks, Umut Ozcan, Rohit N. Kulkarni, Jing Ye, Sunmin Park, Markus Schubert, Tracey L. Fisher, Matt A. Dow, Rebecca Leshan, Mark Zakaria, Mahmud Mossa-Basha, Morris F. White
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Article Metabolism

Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes

Abstract

The insulin receptor substrate-2 (Irs2) branch of the insulin/IGF signaling system coordinates peripheral insulin action and pancreatic β cell function, so mice lacking Irs2 display similarities to humans with type 2 diabetes. Here we show that β cell–specific expression of Irs2 at a low or a high level delivered a graded physiologic response that promoted β cell growth, survival, and insulin secretion that prevented diabetes in Irs2–/– mice, obese mice, and streptozotocin-treated mice; and that upon transplantation, the transgenic islets cured diabetes more effectively than WT islets. Thus, pharmacological approaches that promote Irs2 expression in β cells, especially specific cAMP agonists, could be rational treatments for β cell failure and diabetes.

Authors

Anita M. Hennige, Deborah J. Burks, Umut Ozcan, Rohit N. Kulkarni, Jing Ye, Sunmin Park, Markus Schubert, Tracey L. Fisher, Matt A. Dow, Rebecca Leshan, Mark Zakaria, Mahmud Mossa-Basha, Morris F. White

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Irs2 protein expression and β cell function. (a) Irs2 protein levels mea...
Irs2 protein expression and β cell function. (a) Irs2 protein levels measured by specific immunoblotting in Irs2 immunoprecipitates of 200 μg total protein from islet extracts of 4-week-old WT mice, Irs2–/– mice, or two lines of transgenic mice (rip9→Irs2 and rip13→Irs2). (b) Irs2 protein levels measured by specific immunoblotting in Irs2 immunoprecipitates of 200 μg total protein from Min6 cells treated for 8 hours with the indicated concentrations of exendin-4 or dibutyl-cAMP (diB-cAMP) (c) Representative WT, rip9→Irs2, or rip13→Irs2 pancreas sections immunostained with anti-insulin antibodies (left panel) or anti-FLAG antibodies (right panel) that were detected by cyanine (Irs2) or fluorescein (Insulin) conjugated secondary antibodies, respectively. Original magnification, ×100. (d) Pancreatic insulin content per mg total pancreas was measured in acid/ethanol extracts of total pancreas from 6-month-old WT, rip9→Irs2, and rip13→Irs2 mice. Data are the mean values ± SEM of five mice per genotype. *P < 0.05, **P < 0.01. (e) Glucose-stimulated insulin release measured in 6-week-old WT and rip13→Irs2 mice. D-glucose (3 g/kg body wt) was injected intraperitoneally into 16-hour-fasted mice and blood samples were collected at the indicated timepoints. Results are expressed as mean values ± SEM of six WT and six rip→Irs2 mice (*P < 0.05). (f) Irs2 protein levels measured by specific immunoblotting in Irs2 immunoprecipitates from hypothalamic extracts of 4-week-old WT, rip9→Irs2, rip13→Irs2, Irs2–/–, or Irs2–/–:rip13→Irs2 mice. rip9, rip9→Irs2; rip13, rip13→Irs2.