Abstract
Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. We intercrossed mice heterozygous for two null alleles (Irs1+/– and Irs2+/–) and investigated growth and glucose metabolism in mice with viable genotypes. Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in β-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf-1 receptor in β-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. Our results reveal that Igf-1 receptors promote β-cell development and survival through the Irs-2 signalling pathway. Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic β-cells to maintain glucose homeostasis.
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Acknowledgements
We thank A. Efstratiadis for Igf1r+/– mice; B. Cheatham for anti-IRβ antibodies; and J. Marron for assistance in preparation of this manuscript. This work was supported by DK43808. D.J.W. is an MRC (UK) Clinician Scientist and D.J.B. was supported by a grant from the JDFI during a portion of these studies.
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Withers, D., Burks, D., Towery, H. et al. Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling. Nat Genet 23, 32–40 (1999). https://doi.org/10.1038/12631
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DOI: https://doi.org/10.1038/12631
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