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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Figure 4

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Gene expression in WT tissues and rip13→Irs2 islets. (a) Affymetrix MG-U...
Gene expression in WT tissues and rip13→Irs2 islets. (a) Affymetrix MG-U74v2 arrays (A, B, and C arrays) were used to estimate the relative mRNA levels for Glut1 (93738_at), Glut2 (103357_at), Glut3 (93804_at), and Glut4 (102314_at) in 6-week-old WT brain (B), adipose (F), rip13→Irs2 islets (I), liver (L), and muscle (M); the Affymetrix probe set is indicated in parentheses. Genes called present (Pr) or absent (A) by GeneChip (version 5) are indicated on the figure. The bars show averages of normalized expression measurements obtained from samples of two mice. (b) The fold change for mRNA in rip13→Irs2 islets normalized against WT islets is shown for Glut2, enzymes of the glycolytic pathway (glucokinase, Gck; phosphofructokinase-1, Pfk1; aldolase-1, Aldo1; GAPDH, Gapd; phosphoglycerokinase, Pgk1; phosphoglyceromutase-1, Pgam1; enolase, Eno1; pyruvate kinase, Pk3; pyruvate), and the pyruvate dehydrogenase α subunit (Pdha1) and β subunit (Pdhb). The expression of each gene in rip13→Irs2 islets is reported relative to the normalized level in WT islets; the P value for this comparison is indicated. The accession number for each enzyme is indicated above the P value. (c) Glut2 immunostaining of pancreas sections from 8-week-old WT, rip13→Irs2, and Irs2–/–:rip13→Irs2 mice (original magnification, ×400).