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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Survival and function of rip13→Irs2 mice during streptozotocin-induced d...
Survival and function of rip13→Irs2 mice during streptozotocin-induced diabetes. (a) Representative H&E-stained pancreas sections from untreated WT or rip13Irs2 islets compared with pancreas sections obtained 15 days after one injection per day for 5 days of low-dose (40 mg/kg) streptozotocin (strep; original magnification, ×200). (b) Blood glucose levels in WT or rip13→Irs2 mice were measured before and after five (daily) injections of low-dose (40 mg/kg) streptozotocin. Results are expressed as mean ± SEM of eight WT and eight rip13→Irs2 mice (**P < 0.01); (c) Glucose levels (mg/dl) divided by serum insulin levels (ng/dl) are shown for experimental days 0, 6, and 15 (***P < 0.001). (d) Apoptotic cells were detected in deparaffinized sections using a rhodamine DNA fragmentation detection assay. The number of apoptotic nuclei per β cell is shown for day 15. Values are expressed as mean ± SEM of eight WT and eight transgenic mice (***P < 0.001). (e) Transplantation of WT islets into streptozotocin-diabetic mice. C57BL/6 mice were treated with 100 mg/kg streptozotocin for 3 consecutive days. Blood glucose levels were measured in samples obtained through tail bleeds of fed mice before transplantation (shaded area) and at the indicated ages after transplantation of 300 (filled circles) or 150 (open circles) WT islets. (f) Transplantation of rip13→Irs2 islets into streptozotocin-diabetic mice was conducted in identical fashion with 250 (filled circles), 120 (open circles), or 50 (inverted triangles) islets. Values are mean ± SEM of at least three mice per experiment.