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Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice

Nature volume 408, pages 994–997 (2000)Cite this article

Abstract

Insulin controls glucose homeostasis by regulating glucose use in peripheral tissues, and its own production and secretion in pancreatic β cells1,2,3. These responses are largely mediated downstream of the insulin receptor substrates, IRS-1 and IRS-2 (refs 4,5,6,7,8), through distinct signalling pathways. Although a number of effectors of these pathways have been identified, their roles in mediating glucose homeostasis are poorly defined9. Here we show that mice deficient for S6 kinase 1, an effector of the phosphatidylinositide-3-OH kinase signalling pathway9, are hypoinsulinaemic and glucose intolerant. Whereas insulin resistance is not observed in isolated muscle, such mice exhibit a sharp reduction in glucose-induced insulin secretion and in pancreatic insulin content. This is not due to a lesion in glucose sensing or insulin production, but to a reduction in pancreatic endocrine mass, which is accounted for by a selective decrease in β-cell size. The observed phenotype closely parallels those of preclinical type 2 diabetes mellitus, in which malnutrition-induced hypoinsulinaemia predisposes individuals to glucose intolerance10,11,12.

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Figure 1: Analysis of glucose tolerance, plasma insulin levels and insulin action.
Figure 2: Insulin secretion.
Figure 3: Insulin production.
Figure 4: Islet morphology and β-cell mass.

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References

  1. Kahn, B. B. Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92, 593–596 (1998).

    Article  CAS  Google Scholar 

  2. Leibiger, I. B., Leibiger, B., Moede, T. & Berggren, P. O. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol. Cell 1, 933–938 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Tamemoto, H. et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Araki, E. et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190 (1994).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  7. Withers, D. J. et al. Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nature Genet. 23 , 32–40 (1999).

    Article  CAS  Google Scholar 

  8. 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 

  9. Shepherd, P. R., Withers, D. J. & Siddle, K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem. J. 333, 471–490 (1998); erratum ibid. 335, 711.

    Article  CAS  Google Scholar 

  10. Swenne, I., Borg, L. A., Crace, C. J. & Schnell Landstrom, A. Persistent reduction of pancreatic β-cell mass after a limited period of protein-energy malnutrition in the young rat. Diabetologia 35, 939–945 (1992).

    Article  CAS  Google Scholar 

  11. DeFronzo, R. A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 5, 177–269 (1997).

    Google Scholar 

  12. Phillips, D. I. Insulin resistance as a programmed response to fetal undernutrition. Diabetologia 39, 1119–1122 (1996).

    Article  CAS  Google Scholar 

  13. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  Google Scholar 

  14. Castellino, P., Luzi, L., Simonson, D. C., Haymond, M. & DeFronzo, R. A. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis. J. Clin. Invest. 80, 1784–1793 ( 1987).

    Article  CAS  Google Scholar 

  15. Jefferies, H. B. J. et al. Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k. EMBO J. 12, 3693–3704 (1997).

    Article  Google Scholar 

  16. Hugl, S. R., White, M. F. & Rhodes, C. J. Insulin-like growth factor I (IGF-I)-stimulated pancreatic beta-cell growth is glucose-dependent. Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 cells. J. Biol. Chem. 273, 17771– 17779 (1998).

    Article  CAS  Google Scholar 

  17. Shima, H. et al. Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase. EMBO J. 17, 6649–6659 ( 1998).

    Article  CAS  Google Scholar 

  18. Stenbit, A. E. et al. Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. J. Clin. Invest. 98, 629–634 (1996).

    Article  CAS  Google Scholar 

  19. Slack, J. M. Developmental biology of the pancreas. Development 121, 1569–1580 (1995).

    CAS  PubMed  Google Scholar 

  20. Dumonteil, E. et al. Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes. Endocrinology 139, 4540– 4546 (1998).

    Article  CAS  Google Scholar 

  21. Montagne, J. et al. Drosophila S6 kinase: A regulator of cell size. Science 285, 2126–2129 ( 1999).

    Article  CAS  Google Scholar 

  22. Giordano, E. et al. B-cell size influences glucose-stimulated insulin secretion. Am. J. Physiol. 265, C358– C364 (1993).

    Article  CAS  Google Scholar 

  23. Swenne, I., Crace, C. J. & Jansson, L. Intermittent protein-calorie malnutrition in the young rat causes long- term impairment of the insulin secretory response to glucose in vitro. J. Endocrinol. 118, 295– 302 (1988).

    Article  CAS  Google Scholar 

  24. Fabian, M. C., Lakey, J. R., Rajotte, R. V. & Kneteman, N. M. The efficacy and toxicity of rapamycin in murine islet transplantation. In vitro and in vivo studies. Transplantation 56, 1137–1142 (1993).

    Article  CAS  Google Scholar 

  25. Grace, C. J., Swenne, I., Kohn, P. G., Strain, A. J. & Milner, R. D. Protein-energy malnutrition induces changes in insulin sensitivity. Diabetes Metab. 16, 484– 491 (1990).

    CAS  Google Scholar 

  26. Swenne, I. Pancreatic beta-cell growth and diabetes mellitus. Diabetologia 35, 193–201 ( 1992).

    Article  CAS  Google Scholar 

  27. Guillam, M. T. et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nature Genet. 17, 327–330 (1997); errata ibid. 17, 503 (1997), and 18, 88 (1998).

    Article  CAS  Google Scholar 

  28. Hopcroft, D. W., Mason, D. R. & Scott, R. S. Standardization of insulin secretion from pancreatic islets: validation of a DNA assay. Horm. Metab. Res. 17, 559–561 (1985).

    Article  CAS  Google Scholar 

  29. Kuliawat, R., Klumperman, J., Ludwig, T. & Arvan, P. Differential sorting of lysosomal enzymes out of the regulated secretory pathway in pancreatic beta-cells. J. Cell Biol. 137, 595–608 (1997).

    Article  CAS  Google Scholar 

  30. Weibel, E. R. Morphometry of the human lung: the state of the art after two decades. Bull. Physiopathol. Respir. 15, 999– 1013 (1979).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank T. Gremeaux and P. Kopf for expert technical assistance, and M. Rothnie, R. Scriwaneck and T. van Rijn for their help in the rapid and high-quality production of photographic materials. We also thank C. Bendotti for help with statistical analysis. We are grateful to D. Withers, P. Caroni, S. Volarevic, G. Posthuma, J. Slot, H. Geuze, L. Hansen, S. Oldham and W. Krek for reading the manuscript and helpful discussions, and to the members of the Thomas laboratory for support. M.P. is a recipient of a stipend from the EEC and these studies were supported in part by grants from INSERM and Foundation pour la Recherché Medicale to Y.L-B., from the Swiss National Science Foundation to B.T. and from the EEC, HFSPO and Novartis Foundation to G.T.

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Authors and Affiliations

  1. Friedrich Miescher Institute, Basel, CH-4058, Switzerland

    Mario Pende, Sara C. Kozma & George Thomas

  2. Institute of Pharmacology and Toxicology , Lausanne, CH-1005, Switzerland

    Muriel Jaquet, Rémy Burcelin & Bernard Thorens

  3. Department of Cell Biology, University Medical Center and Research Institute of Biomembranes, Utrecht, 3584CX, The Netherlands

    Viola Oorschot & Judith Klumperman

  4. INSERM E 99-11, Biologie et physiologie de la Nutrition et Signalisation, Faculty of Medicine, Nice, 06107, France

    Yannick Le Marchand-Brustel

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Correspondence to George Thomas.

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Pende, M., Kozma, S., Jaquet, M. et al. Hypoinsulinaemia, glucose intolerance and diminished β-cell size in S6K1-deficient mice. Nature 408, 994–997 (2000). https://doi.org/10.1038/35050135

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