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Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice

Abstract

Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.

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Figure 1: Genetic analysis of HMGA1-deficient subjects.
Figure 2: Functional significance of HMGA1 in INSR gene expression and function.
Figure 3: Analysis of insulin signaling proteins, glucose homeostasis and insulin secretion, and insulin-tolerance test (ITT) in mice with different genotypes.
Figure 4: Glut4 and IGFBP1 protein expression, PET and glucose turnover studies in wild-type and mutant mice.
Figure 5: Pancreatic islet morphology and insulin content, analysis of Pdx1 and inhibition of in vitro insulin secretion.

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References

  1. Kahn, C.R. Insulin action, diabetogenes, and the cause of type II diabetes (Banting Lecture). Diabetes 43, 1066–1084 (1994).

    Article  CAS  Google Scholar 

  2. Polonsky, K.S., Sturis, J. & Bell G.I. Non-insulin-dependent diabetes mellitus – a genetically programmed failure of the beta cell to compensate for insulin resistance. N. Engl. J. Med. 334, 777–783 (1996).

    Article  CAS  Google Scholar 

  3. Taylor, S.I. Insulin resistance or insulin deficiency: which is the primary cause of NIDDM? Diabetes 43, 735–740 (1994).

    Article  CAS  Google Scholar 

  4. Goldfine, I.D. The insulin receptor: molecular biology and transmembrane signalling. Endocr. Rev. 8, 235–255 (1987).

    Article  CAS  Google Scholar 

  5. Taylor, S.I. et al. Mutations in the insulin receptor gene. Endocr. Rev. 13, 566–595 (1992).

    Article  CAS  Google Scholar 

  6. Bustin, M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol. Cell. Biol. 19, 5237–5246 (1999).

    Article  CAS  Google Scholar 

  7. Reeves, R., Beckerbauer, L. HMGI/Y proteins: flexible regulators of transcription and chromatin structure. Biochim. Biophys. Acta. 1519, 13–29 (2001).

    Article  CAS  Google Scholar 

  8. Thanos, D., & Maniatis, T. The high mobility group protein HMG I(Y) is required for NF-kB-dependent virus induction of the human IFN-β gene. Cell 71, 777–789 (1992).

    Article  CAS  Google Scholar 

  9. Brunetti, A., Manfioletti, G., Chiefari, E., Goldfine, I.D. & Foti, D. Transcriptional regulation of human insulin receptor gene by the high-mobility-group protein HMGI-Y. FASEB J. 15, 492–500 (2001).

    Article  CAS  Google Scholar 

  10. Foti, D., Iuliano, R., Chiefari, E. & Brunetti, A. A nucleoprotein complex containing Sp1, C/EBPβ, and HMGI-Y controls human insulin receptor gene transcription. Mol. Cell. Biol. 23, 2720–2732 (2003).

    Article  CAS  Google Scholar 

  11. Brunetti, A., Brunetti, L., Foti, D., Accili, D. & Goldfine, I.D. Human diabetes associated with defects in regulatory proteins for the insulin receptor gene. J.Clin. Invest. 97, 258–262 (1996).

    Article  CAS  Google Scholar 

  12. Holth, L.T., Thorlacius, A.E. & Reeves, R. Effect of epidermal growth factor and estrogen on the regulation of the HMGI/Y gene in human mammary epithelial cell lines. DNA Cell Biol. 16, 1299–1309 (1997).

    Article  CAS  Google Scholar 

  13. Borrmann, L., Wilkening, S. & Bullerdiek, J. The expression of HMGA genes is regulated by their 3'UTR. Oncogene 20, 4537–4541 (2001).

    Article  CAS  Google Scholar 

  14. Kahn, C.R. et al. The syndromes of insulin resistance and acanthosis nigricans. N. Engl. J. Med. 294, 739–745 (1976).

    Article  CAS  Google Scholar 

  15. Fidanza, V. et al. Double knockout of the ALL-1 gene blocks hematopoietic differentiation in vitro. Cancer. Res. 56, 1179–1183 (1996).

    CAS  PubMed  Google Scholar 

  16. White, M.F. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol. Cell. Biochem. 182, 3–11 (1998).

    Article  CAS  Google Scholar 

  17. Saltiel, A.R. & Pessin, J.E. Insulin signaling pathways in time and space. Trends Cell Biol. 12, 65–71 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Bruning, J.C. et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572 (1997).

    Article  CAS  Google Scholar 

  20. 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 

  21. Kitamura, T., Kahn, C.R. & Accili, D. Insulin receptor knockout mice. Annu. Rev. Physiol. 65, 313–332 (2003).

    Article  CAS  Google Scholar 

  22. Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell. 6, 77–86 (2000).

    Article  CAS  Google Scholar 

  23. Rane, S.G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat. Genet. 22, 44–52 (1999).

    Article  CAS  Google Scholar 

  24. Belke, D.D., Larsen, T.S., Gibbs, E.M., & Severson, D.L. Glucose metabolism in perfused mouse hearts overexpressing human GLUT-4 glucose transporter. Am. J. Physiol. Endocrinol. Metab. 280, E420–E427 (2001).

    Article  CAS  Google Scholar 

  25. Bilan, P.J., Ramlal, T., & Klip, A. IGF-1 mediated recruitment of glucose transporters from intracellular membranes to plasma membranes in L6 muscle cells. Adv. Exp. Med. Biol. 293, 273–288 (1991).

    Article  CAS  Google Scholar 

  26. Weiland, M. et al. The signaling potential of the receptors for insulin and insulin-like growth factor I (IGF-I) in 3T3-L1 adipocytes: comparison of glucose transport activity, induction of oncogene c-fos, glucose transporter mRNA, and DNA-synthesis. J. Cell. Physiol. 149, 428–435 (1991).

    Article  CAS  Google Scholar 

  27. Sandhu, M.S. et al. Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet. 359, 1740–1745 (2002).

    Article  CAS  Google Scholar 

  28. Allander, S.V. et al. Hepatic nuclear factor 3 and high mobility group I/Y proteins bind the insulin response element of the insulin-like growth factor-binding protein-1 promoter. Endocrinology. 138, 4291–4300 (1997).

    Article  CAS  Google Scholar 

  29. Di Cola, G., Cool, M.H., & Accili, D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J. Clin. Invest. 99, 2538–2544 (1997).

    Article  CAS  Google Scholar 

  30. Ohneda, K., Mirmira, R.G., Wang, J., Johnson, J.D. & German, M.S. The homeodomain of PDX-1 mediates multiple protein-protein interactions in the formation of a transcriptional activation complex on the insulin promoter. Mol. Cell. Biol. 20, 900–911 (2000).

    Article  CAS  Google Scholar 

  31. Taylor, S.I. Deconstructing type 2 diabetes. Cell 97, 9–12 (1999).

    Article  CAS  Google Scholar 

  32. Kim, S.K., & Hebrok, M. Intercellular signals regulating pancreas development and function. Genes & Dev. 15, 111–127 (2001).

    Article  CAS  Google Scholar 

  33. Eizirik, D.L. et al. Major species differences between humans and rodents in the susceptibility to pancreatic β-cell injury. Proc. Natl. Acad. Sci. USA. 91, 9253–9256 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to L. Levintow for critical reading of the manuscript, and N. Perrotti for helpful discussion. We thank T. Maniatis, D. Thanos and J. Bullerdiek for providing plasmids; V. Orlando and P. Malatesta for advice on ChIP and FISH, respectively; G. Donato for pancreatic histology studies; C. Capula for referring patients with insulin resistance. Also, we thank the Laboratorio di Diagnosi PrePostnatale Malattie Metaboliche (Istituto G. Gaslini) for the service of the “Cell line and DNA bank from patients affected by genetic disease”. We are indebted to A. Luciano and the staff of the Animal Facility for animal care. This work was supported by Telethon-Italy, grants E613 and GGP04245, and MIUR, protocols 2002062899-002 and 2004062059-002 Italy to A.B.We dedicate this article to the memory of Pope John Paul II, who said, “Science can purify religion from error and superstition. Religion can purify science from idolatry and false absolutes.”

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Correspondence to Antonio Brunetti.

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Foti, D., Chiefari, E., Fedele, M. et al. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med 11, 765–773 (2005). https://doi.org/10.1038/nm1254

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