Abstract
An appropriate β cell mass is pivotal for the maintenance of glucose homeostasis1. Both insulin and IGF-1 are important in regulation of β cell growth and function (reviewed in ref. 2). To define the roles of these hormones directly, we created a mouse model lacking functional receptors for both insulin and IGF-1 only in β cells (βDKO), as the hormones have overlapping mechanisms of action and activate common downstream proteins. Notably, βDKO mice were born with a normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants3,4. Normoglycemic 2-week-old βDKO mice manifest reduced β cell mass, reduced expression of phosphorylated Akt and the transcription factor MafA, increased apoptosis in islets and severely compromised β cell function. Analyses of compound knockouts showed a dominant role for insulin signaling in regulating β cell mass. Together, these data provide compelling genetic evidence that insulin and IGF-I–dependent pathways are not critical for development of β cells but that a loss of action of these hormones in β cells leads to diabetes. We propose that therapeutic improvement of insulin and IGF-I signaling in β cells might protect against type 2 diabetes.
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Acknowledgements
The authors thank K. Frayjo for secretarial assistance, K.C. Hayes for housing and care of mouse colonies (Brandeis University), E. Krutoholow for assistance with mouse genotyping and S. Lannon for clamp experiments. We thank M. Magnuson (Vanderbilt University) for RIP-Cre mice on original mixed background; D. Melton (Harvard University) for PDX-Cre mice; and U. Jhala (University of California, San Diego) and T. Maratos-Flier, J. Elmquist and E. Kokkotou (Beth Israel Deaconess Medical Center) for discussions. This study was supported by US National Institutes of Health grants R01 DK067536, R01 DK066207 (to R.N.K.), R01 DK046409 (to L.S.), R01 DK046960 (R.T.K.) and P01 DK042502 (R.S.) and by the Joslin Diabetes & Endocrinology Research Center Specialized Assay and Advanced Microscopy Cores. I.A. is supported by Juvenile Diabetes Research Foundation Fellowship Grant 3-2003-579.
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Ueki, K., Okada, T., Hu, J. et al. Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes. Nat Genet 38, 583–588 (2006). https://doi.org/10.1038/ng1787
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DOI: https://doi.org/10.1038/ng1787
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