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Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling

Nature Genetics volume 23, pages 32–40 (1999)Cite this article

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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Figure 1: Growth characteristics of progeny of Irs1+/–Irs2+/– intercross.
Figure 2: Metabolic characteristics of progeny of Irs1+/–Irs2+/– intercross.
Figure 3: Insulin signalling in skeletal muscle and liver of progeny of an Irs1+/–Irs2+/– intercross.
Figure 4: Islet morphology and β-cell analysis in progeny of Irs1+/–Irs2+/– intercross.
Figure 5: Islet morphology and β-cell mass in Igf1r–/– mice.
Figure 6: Weight and metabolic characteristics of progeny of Igf1r+/–Irs2+/– intercross.
Figure 7: Islet morphology in progeny of Igf1r+/–Irs2+/– intercross.
Figure 8: A model depicting the central role of Irs-2 signalling pathways in the maintenance of normal 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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  1. Dominic J. Withers

    Present address: Department of Metabolic Medicine, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London, W12ONN, UK

  2. Dominic J. Withers and Deborah J. Burks: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, 02215, Massachusetts, USA

    Dominic J. Withers, Deborah J. Burks, Heather H. Towery, Shari L. Altamuro, Carrie L. Flint & Morris F. White

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Correspondence to Morris F. White.

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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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