Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes
Anita M. Hennige, … , Mahmud Mossa-Basha, Morris F. White
Anita M. Hennige, … , Mahmud Mossa-Basha, Morris F. White
Published November 15, 2003
Citation Information: J Clin Invest. 2003;112(10):1521-1532. https://doi.org/10.1172/JCI18581.
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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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Figure 6

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IGF1 and insulin signaling in isolated islets. (a) Islets were isolated ...
IGF1 and insulin signaling in isolated islets. (a) Islets were isolated from WT or Irs2–/– C57BL/6 mice and incubated overnight before stimulation with insulin or IGF1 for 20 minutes as described in Methods. Each lane was loaded with 100 μg of total islet protein. The results are representative of at least three independent experiments. (b) Islets were isolated from WT, Irs2–/–:rip13→Irs2, and rip13→Irs2 mice and incubated overnight before stimulation with IGF1 for 20 minutes as described in Methods. The same amount of total protein (300 μg) was loaded onto the gel and transferred to a nitrocellulose membrane. Membranes were analyzed for the presence of Erk1/2 and phosphorylated Erk (pErk1/2); Akt1/2 and phosphorylated Akt (pAkt1/2); Foxo1 and phosphorylated Foxo1 (pFoxo1); and cleaved caspase-3 (Casp3).