Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Total insulin and IGF-I resistance in pancreatic β cells causes overt diabetes

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Evidence for specificity of recombination, normal peripheral insulin sensitivity and expression of hypothalamic neuropeptides.
Figure 2: Severe fasting hyperglycemia and glucose intolerance in βDKO and PDKO mice and altered Ca2+ oscillations, reduced oxygen consumption and blunted insulin secretion in βDKO islets.
Figure 3: Alterations in β cell mass, apoptosis, MafA expression and signaling proteins in pancreas and islets.
Figure 4: Altered electrical activity of primary islets and β cells from βInsr−/− mice.

References

  1. Accili, D. Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic. Diabetes 53, 1633–1642 (2004).

    Article  CAS  Google Scholar 

  2. Kulkarni, R.N. New insights into the roles of insulin/IGF-I in the development and maintenance of beta-cell mass. Rev. Endocr. Metab. Disord. 6, 199–210 (2005).

    Article  CAS  Google Scholar 

  3. Kulkarni, R.N. et al. Tissue-specific knockout of the insulin receptor in pancreatic β cells creates an insulin secretory defect similar to that in Type 2 diabetes. Cell 96, 329–339 (1999).

    Article  CAS  Google Scholar 

  4. Kulkarni, R.N. et al. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat. Genet. 31, 111–115 (2002).

    Article  CAS  Google Scholar 

  5. Otani, K. et al. Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice. Am. J. Physiol. Endocrinol. Metab. 286, E41–E49 (2004).

    Article  CAS  Google Scholar 

  6. Xuan, S. et al. Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J. Clin. Invest. 110, 1011–1019 (2002).

    Article  CAS  Google Scholar 

  7. Nakae, J., Kido, Y. & Accili, D. Distinct and overlapping functions of insulin and IGF-1 receptors. Endocr. Rev 22, 818–835 (2001).

    Article  CAS  Google Scholar 

  8. Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728–1731 (2001).

    Article  CAS  Google Scholar 

  9. Alessi, D.R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261–269 (1997).

    Article  CAS  Google Scholar 

  10. Withers, D.J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).

    Article  CAS  Google Scholar 

  11. Miura, A. et al. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. J. Biol. Chem. 281, 5246–5257 (2005).

    Article  Google Scholar 

  12. Lee, J.Y. et al. RIP-Cre revisited: evidence for impairments of pancreatic beta-cell function. J. Biol. Chem. 281, 2649–2653 (2005).

    Article  Google Scholar 

  13. Kennedy, R.T., Kauri, L.M., Dahlgren, G.M. & Jung, S.K. Metabolic Oscillations in beta-Cells. Diabetes 51 (Suppl.), S152–S161 (2002).

    Article  CAS  Google Scholar 

  14. Kido, Y. et al. Effects of mutations in the insulin-like growth factor signaling system on embryonic pancreas development and beta-cell compensation to insulin resistance. J. Biol. Chem. 277, 36740–36747 (2002).

    Article  CAS  Google Scholar 

  15. Mathis, D., Vence, L. & Benoist, C. Beta-cell death during progression to diabetes. Nature 414, 792–798 (2001).

    Article  CAS  Google Scholar 

  16. Danial, N.N. & Korsmeyer, S.J. Cell death. Critical control points. Cell 116, 205–219 (2004).

    Article  CAS  Google Scholar 

  17. Louvi, A., Accili, D. & Efstratiadis, A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev. Biol. 189, 33–48 (1997).

    Article  CAS  Google Scholar 

  18. Olbrot, M. et al. Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc. Natl. Acad. Sci. USA 99, 6737–6742 (2002).

    Article  CAS  Google Scholar 

  19. Zhang, C. et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol. Cell Biol. 25, 4969–4976 (2005).

    Article  CAS  Google Scholar 

  20. Kitamura, Y.I. et al. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab. 2, 153–163 (2005).

    Article  CAS  Google Scholar 

  21. Da Silva Xavier, G., Qian, Q., Cullen, P.J. & Rutter, G.A. Distinct roles for insulin and insulin-like growth factor-1 receptors in pancreatic beta-cell glucose sensing revealed by RNA silencing. Biochem. J. 377, 149–158 (2004).

    Article  Google Scholar 

  22. Goforth, P.B. et al. Calcium-activated K+ channels of mouse beta-cells are controlled by both store and cytoplasmic Ca2+: experimental and theoretical studies. J. Gen. Physiol. 120, 307–322 (2002).

    Article  CAS  Google Scholar 

  23. Zhang, M., Houamed, K., Kupershmidt, S., Roden, D. & Satin, L.S. Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion. J. Gen. Physiol. 126, 353–363 (2005).

    Article  CAS  Google Scholar 

  24. Hashimoto, N. et al. Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nat. Genet. advance online publication 23 April 2006 (doi:10.1038/ng1774).

  25. Wolfer, D.P., Crusio, W.E. & Lipp, H.P. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci. 25, 336–340 (2002).

    Article  CAS  Google Scholar 

  26. Fisher, S.J. & Kahn, C.R. Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J. Clin. Invest. 111, 463–468 (2003).

    Article  CAS  Google Scholar 

  27. Kulkarni, R.N. et al. Impact of genetic background on development of hyperinsulinemia and diabetes in insulin receptor/insulin receptor substrate-1 double heterozygous mice. Diabetes 52, 1528–1534 (2003).

    Article  CAS  Google Scholar 

  28. Kokkotou, E.G., Tritos, N.A., Mastaitis, J.W., Slieker, L. & Maratos-Flier, E. Melanin-concentrating hormone receptor is a target of leptin action in the mouse brain. Endocrinology 142, 680–686 (2001).

    Article  CAS  Google Scholar 

  29. Kulkarni, R.N. et al. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J. Clin. Invest. 104, R69–R75 (1999).

    Article  CAS  Google Scholar 

  30. Aspinwall, C.A. et al. Role of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular ca2+stores in insulin-stimulated insulin secretion in beta-cell. J. Biol. Chem. 275, 22331–22338 (2000).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rohit N Kulkarni.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1787

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing