Skip to main content
PMC home page
Transactions of the American Clinical and Climatological Association logoLink to Transactions of the American Clinical and Climatological Association
. 2003;114:125–148.

The Gordon Wilson Lecture. Lessons about the control of glucose homeostasis and the pathogenesis of diabetes from knockout mice.

C Ronald Kahn 1
PMCID: PMC2194492  PMID: 12813916

Abstract

The painstaking process of generating constitutive and conditional knockout mice has paid off handsomely. The roles of the insulin receptor and its intracellular substrates in insulin action has been established and begun to shed light onto some of the proteins less obvious functions. We have learned how genetic predisposition plays itself out in the oligogenic and heterogeneous pathogenesis of type 2 diabetes and how the balance of proteins can affect the efficiency of signaling both positively and negatively. The IRS knockout mice have taught us how these proteins provide unique and complementary signals in insulin action. From the tissue specific knockouts we have learned that [figure: see text] different tissues contribute uniquely to the pathogenesis of type 2 diabetes, but not always in the predicted way; that insulin resistance at different levels in the same tissue may produce different phenotypes; that tissues possess mechanisms of communication such that resistance in one tissue affects insulin signaling or metabolism in others; and that insulin has important effects in tissues not previously considered insulin responsive, including the brain and beta-cells. The result of this work has led us to develop new hypotheses about the nature of the insulin action network.

Full text

PDF
125

Images in this article

126Fig. 1
on p.126
127Fig. 2
on p.127
128Fig. 3
on p.128
131Fig. 4
on p.131
133Fig. 6
on p.133
136Fig. 7
on p.136

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abel E. D., Peroni O., Kim J. K., Kim Y. B., Boss O., Hadro E., Minnemann T., Shulman G. I., Kahn B. B. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature. 2001 Feb 8;409(6821):729–733. doi: 10.1038/35055575. [DOI] [PubMed] [Google Scholar]
  2. Accili D., Drago J., Lee E. J., Johnson M. D., Cool M. H., Salvatore P., Asico L. D., José P. A., Taylor S. I., Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet. 1996 Jan;12(1):106–109. doi: 10.1038/ng0196-106. [DOI] [PubMed] [Google Scholar]
  3. Accili D. Molecular defects of the insulin receptor gene. Diabetes Metab Rev. 1995 Apr;11(1):47–62. doi: 10.1002/dmr.5610110105. [DOI] [PubMed] [Google Scholar]
  4. Araki E., Lipes M. A., Patti M. E., Brüning J. C., Haag B., 3rd, Johnson R. S., Kahn C. R. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10;372(6502):186–190. doi: 10.1038/372186a0. [DOI] [PubMed] [Google Scholar]
  5. Baron A. D. Hemodynamic actions of insulin. Am J Physiol. 1994 Aug;267(2 Pt 1):E187–E202. doi: 10.1152/ajpendo.1994.267.2.E187. [DOI] [PubMed] [Google Scholar]
  6. Blüher Matthias, Michael M. Dodson, Peroni Odile D., Ueki Kohjiro, Carter Nathan, Kahn Barbara B., Kahn C. Ronald. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002 Jul;3(1):25–38. doi: 10.1016/s1534-5807(02)00199-5. [DOI] [PubMed] [Google Scholar]
  7. Brüning J. C., Gautam D., Burks D. J., Gillette J., Schubert M., Orban P. C., Klein R., Krone W., Müller-Wieland D., Kahn C. R. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000 Sep 22;289(5487):2122–2125. doi: 10.1126/science.289.5487.2122. [DOI] [PubMed] [Google Scholar]
  8. Brüning J. C., Michael M. D., Winnay J. N., Hayashi T., Hörsch D., Accili D., Goodyear L. J., Kahn C. R. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998 Nov;2(5):559–569. doi: 10.1016/s1097-2765(00)80155-0. [DOI] [PubMed] [Google Scholar]
  9. Brüning J. C., Winnay J., Bonner-Weir S., Taylor S. I., Accili D., Kahn C. R. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell. 1997 Feb 21;88(4):561–572. doi: 10.1016/s0092-8674(00)81896-6. [DOI] [PubMed] [Google Scholar]
  10. Capecchi M. R. Generating mice with targeted mutations. Nat Med. 2001 Oct;7(10):1086–1090. doi: 10.1038/nm1001-1086. [DOI] [PubMed] [Google Scholar]
  11. Cheatham B., Vlahos C. J., Cheatham L., Wang L., Blenis J., Kahn C. R. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol. 1994 Jul;14(7):4902–4911. doi: 10.1128/mcb.14.7.4902. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cherrington A. D. Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo. Diabetes. 1999 May;48(5):1198–1214. doi: 10.2337/diabetes.48.5.1198. [DOI] [PubMed] [Google Scholar]
  13. Cline G. W., Petersen K. F., Krssak M., Shen J., Hundal R. S., Trajanoski Z., Inzucchi S., Dresner A., Rothman D. L., Shulman G. I. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med. 1999 Jul 22;341(4):240–246. doi: 10.1056/NEJM199907223410404. [DOI] [PubMed] [Google Scholar]
  14. Coschigano K. T., Clemmons D., Bellush L. L., Kopchick J. J. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology. 2000 Jul;141(7):2608–2613. doi: 10.1210/endo.141.7.7586. [DOI] [PubMed] [Google Scholar]
  15. DeFronzo R. A. Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia. 1992 Apr;35(4):389–397. doi: 10.1007/BF00401208. [DOI] [PubMed] [Google Scholar]
  16. Di Cola G., Cool M. H., Accili D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J Clin Invest. 1997 May 15;99(10):2538–2544. doi: 10.1172/JCI119438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Duvillié B., Cordonnier N., Deltour L., Dandoy-Dron F., Itier J. M., Monthioux E., Jami J., Joshi R. L., Bucchini D. Phenotypic alterations in insulin-deficient mutant mice. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5137–5140. doi: 10.1073/pnas.94.10.5137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Etgen G. J., Jr, Fryburg D. A., Gibbs E. M. Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. Diabetes. 1997 Nov;46(11):1915–1919. doi: 10.2337/diab.46.11.1915. [DOI] [PubMed] [Google Scholar]
  19. Fantin V. R., Wang Q., Lienhard G. E., Keller S. R. Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab. 2000 Jan;278(1):E127–E133. doi: 10.1152/ajpendo.2000.278.1.E127. [DOI] [PubMed] [Google Scholar]
  20. Ferrannini E., Galvan A. Q., Gastaldelli A., Camastra S., Sironi A. M., Toschi E., Baldi S., Frascerra S., Monzani F., Antonelli A. Insulin: new roles for an ancient hormone. Eur J Clin Invest. 1999 Oct;29(10):842–852. doi: 10.1046/j.1365-2362.1999.00536.x. [DOI] [PubMed] [Google Scholar]
  21. Golay A., DeFronzo R. A., Ferrannini E., Simonson D. C., Thorin D., Acheson K., Thiébaud D., Curchod B., Jéquier E., Felber J. P. Oxidative and non-oxidative glucose metabolism in non-obese type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1988 Aug;31(8):585–591. doi: 10.1007/BF00264764. [DOI] [PubMed] [Google Scholar]
  22. Gu H., Marth J. D., Orban P. C., Mossmann H., Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science. 1994 Jul 1;265(5168):103–106. doi: 10.1126/science.8016642. [DOI] [PubMed] [Google Scholar]
  23. Guerra C., Navarro P., Valverde A. M., Arribas M., Brüning J., Kozak L. P., Kahn C. R., Benito M. Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance. J Clin Invest. 2001 Oct;108(8):1205–1213. doi: 10.1172/JCI13103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Havrankova J., Roth J., Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978 Apr 27;272(5656):827–829. doi: 10.1038/272827a0. [DOI] [PubMed] [Google Scholar]
  25. Hirayama I., Tamemoto H., Yokota H., Kubo S. K., Wang J., Kuwano H., Nagamachi Y., Takeuchi T., Izumi T. Insulin receptor-related receptor is expressed in pancreatic beta-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. Diabetes. 1999 Jun;48(6):1237–1244. doi: 10.2337/diabetes.48.6.1237. [DOI] [PubMed] [Google Scholar]
  26. Holgado-Madruga M., Emlet D. R., Moscatello D. K., Godwin A. K., Wong A. J. A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature. 1996 Feb 8;379(6565):560–564. doi: 10.1038/379560a0. [DOI] [PubMed] [Google Scholar]
  27. Kahn C. R. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994 Aug;43(8):1066–1084. doi: 10.2337/diab.43.8.1066. [DOI] [PubMed] [Google Scholar]
  28. Kido Y., Burks D. J., Withers D., Bruning J. C., Kahn C. R., White M. F., Accili D. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000 Jan;105(2):199–205. doi: 10.1172/JCI7917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kim J. K., Zisman A., Fillmore J. J., Peroni O. D., Kotani K., Perret P., Zong H., Dong J., Kahn C. R., Kahn B. B. Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. J Clin Invest. 2001 Jul;108(1):153–160. doi: 10.1172/JCI10294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kitamura T., Kido Y., Nef S., Merenmies J., Parada L. F., Accili D. Preserved pancreatic beta-cell development and function in mice lacking the insulin receptor-related receptor. Mol Cell Biol. 2001 Aug;21(16):5624–5630. doi: 10.1128/MCB.21.16.5624-5630.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kraegen E. W., Lazarus L., Campbell L. V. Failure of insulin infusion during euglycemia to influence endogenous basal insulin secretion. Metabolism. 1983 Jun;32(6):622–627. doi: 10.1016/0026-0495(83)90034-3. [DOI] [PubMed] [Google Scholar]
  32. Kuboki K., Jiang Z. Y., Takahara N., Ha S. W., Igarashi M., Yamauchi T., Feener E. P., Herbert T. P., Rhodes C. J., King G. L. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo : a specific vascular action of insulin. Circulation. 2000 Feb 15;101(6):676–681. doi: 10.1161/01.cir.101.6.676. [DOI] [PubMed] [Google Scholar]
  33. Kulkarni R. N., Brüning J. C., Winnay J. N., Postic C., Magnuson M. A., Kahn C. R. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999 Feb 5;96(3):329–339. doi: 10.1016/s0092-8674(00)80546-2. [DOI] [PubMed] [Google Scholar]
  34. Kulkarni R. N., Winnay J. N., Daniels M., Brüning J. C., Flier S. N., Hanahan D., Kahn C. R. Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest. 1999 Dec;104(12):R69–R75. doi: 10.1172/JCI8339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Larsen P. L., Albert P. S., Riddle D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics. 1995 Apr;139(4):1567–1583. doi: 10.1093/genetics/139.4.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lavan B. E., Fantin V. R., Chang E. T., Lane W. S., Keller S. R., Lienhard G. E. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem. 1997 Aug 22;272(34):21403–21407. doi: 10.1074/jbc.272.34.21403. [DOI] [PubMed] [Google Scholar]
  37. Lee C. H., Li W., Nishimura R., Zhou M., Batzer A. G., Myers M. G., Jr, White M. F., Schlessinger J., Skolnik E. Y. Nck associates with the SH2 domain-docking protein IRS-1 in insulin-stimulated cells. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11713–11717. doi: 10.1073/pnas.90.24.11713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Leibiger B., Leibiger I. B., Moede T., Kemper S., Kulkarni R. N., Kahn C. R., de Vargas L. M., Berggren P. O. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell. 2001 Mar;7(3):559–570. doi: 10.1016/s1097-2765(01)00203-9. [DOI] [PubMed] [Google Scholar]
  39. Liu S. C., Wang Q., Lienhard G. E., Keller S. R. Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J Biol Chem. 1999 Jun 18;274(25):18093–18099. doi: 10.1074/jbc.274.25.18093. [DOI] [PubMed] [Google Scholar]
  40. Louvi A., Accili D., Efstratiadis A. Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. Dev Biol. 1997 Sep 1;189(1):33–48. doi: 10.1006/dbio.1997.8666. [DOI] [PubMed] [Google Scholar]
  41. Lowell B. B., S-Susulic V., Hamann A., Lawitts J. A., Himms-Hagen J., Boyer B. B., Kozak L. P., Flier J. S. Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature. 1993 Dec 23;366(6457):740–742. doi: 10.1038/366740a0. [DOI] [PubMed] [Google Scholar]
  42. Matschinsky F. M. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes. 1996 Feb;45(2):223–241. doi: 10.2337/diab.45.2.223. [DOI] [PubMed] [Google Scholar]
  43. Mauvais-Jarvis Franck, Ueki Kohjiro, Fruman David A., Hirshman Michael F., Sakamoto Kei, Goodyear Laurie J., Iannacone Matteo, Accili Domenico, Cantley Lewis C., Kahn C. Ronald. Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest. 2002 Jan;109(1):141–149. doi: 10.1172/JCI13305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Michael M. D., Kulkarni R. N., Postic C., Previs S. F., Shulman G. I., Magnuson M. A., Kahn C. R. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000 Jul;6(1):87–97. [PubMed] [Google Scholar]
  45. Mårin P., Högh-Kristiansen I., Jansson S., Krotkiewski M., Holm G., Björntorp P. Uptake of glucose carbon in muscle glycogen and adipose tissue triglycerides in vivo in humans. Am J Physiol. 1992 Sep;263(3 Pt 1):E473–E480. doi: 10.1152/ajpendo.1992.263.3.E473. [DOI] [PubMed] [Google Scholar]
  46. Obici Silvana, Feng Zhaohui, Karkanias George, Baskin Denis G., Rossetti Luciano. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002 Jun;5(6):566–572. doi: 10.1038/nn0602-861. [DOI] [PubMed] [Google Scholar]
  47. Polonsky K. S., Sturis J., Bell G. I. Seminars in Medicine of the Beth Israel Hospital, Boston. Non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996 Mar 21;334(12):777–783. doi: 10.1056/NEJM199603213341207. [DOI] [PubMed] [Google Scholar]
  48. Postic C., Shiota M., Niswender K. D., Jetton T. L., Chen Y., Moates J. M., Shelton K. D., Lindner J., Cherrington A. D., Magnuson M. A. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem. 1999 Jan 1;274(1):305–315. doi: 10.1074/jbc.274.1.305. [DOI] [PubMed] [Google Scholar]
  49. Reaven G. M. Non-insulin-dependent diabetes mellitus, abnormal lipoprotein metabolism, and atherosclerosis. Metabolism. 1987 Feb;36(2 Suppl 1):1–8. doi: 10.1016/0026-0495(87)90193-4. [DOI] [PubMed] [Google Scholar]
  50. Rogina B., Reenan R. A., Nilsen S. P., Helfand S. L. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science. 2000 Dec 15;290(5499):2137–2140. doi: 10.1126/science.290.5499.2137. [DOI] [PubMed] [Google Scholar]
  51. Rosen E. D., Walkey C. J., Puigserver P., Spiegelman B. M. Transcriptional regulation of adipogenesis. Genes Dev. 2000 Jun 1;14(11):1293–1307. [PubMed] [Google Scholar]
  52. Skolnik E. Y., Batzer A., Li N., Lee C. H., Lowenstein E., Mohammadi M., Margolis B., Schlessinger J. The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science. 1993 Jun 25;260(5116):1953–1955. doi: 10.1126/science.8316835. [DOI] [PubMed] [Google Scholar]
  53. Sun X. J., Wang L. M., Zhang Y., Yenush L., Myers M. G., Jr, Glasheen E., Lane W. S., Pierce J. H., White M. F. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173–177. doi: 10.1038/377173a0. [DOI] [PubMed] [Google Scholar]
  54. Tamemoto H., Kadowaki T., Tobe K., Yagi T., Sakura H., Hayakawa T., Terauchi Y., Ueki K., Kaburagi Y., Satoh S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994 Nov 10;372(6502):182–186. doi: 10.1038/372182a0. [DOI] [PubMed] [Google Scholar]
  55. Taylor S. I. Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes. 1992 Nov;41(11):1473–1490. doi: 10.2337/diab.41.11.1473. [DOI] [PubMed] [Google Scholar]
  56. Thorell A., Hirshman M. F., Nygren J., Jorfeldt L., Wojtaszewski J. F., Dufresne S. D., Horton E. S., Ljungqvist O., Goodyear L. J. Exercise and insulin cause GLUT-4 translocation in human skeletal muscle. Am J Physiol. 1999 Oct;277(4 Pt 1):E733–E741. doi: 10.1152/ajpendo.1999.277.4.E733. [DOI] [PubMed] [Google Scholar]
  57. Ueki Kohjiro, Fruman David A., Brachmann Saskia M., Tseng Yu-Hua, Cantley Lewis C., Kahn C. Ronald. Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol. 2002 Feb;22(3):965–977. doi: 10.1128/MCB.22.3.965-977.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Virkamäki A., Ueki K., Kahn C. R. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999 Apr;103(7):931–943. doi: 10.1172/JCI6609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. White M. F. The IRS-signalling system: a network of docking proteins that mediate insulin action. Mol Cell Biochem. 1998 May;182(1-2):3–11. [PubMed] [Google Scholar]
  60. Withers D. J., Gutierrez J. S., Towery H., Burks D. J., Ren J. M., Previs S., Zhang Y., Bernal D., Pons S., Shulman G. I. Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998 Feb 26;391(6670):900–904. doi: 10.1038/36116. [DOI] [PubMed] [Google Scholar]
  61. Young M. E., Radda G. K., Leighton B. Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem J. 1997 Feb 15;322(Pt 1):223–228. doi: 10.1042/bj3220223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zeng G., Nystrom F. H., Ravichandran L. V., Cong L. N., Kirby M., Mostowski H., Quon M. J. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000 Apr 4;101(13):1539–1545. doi: 10.1161/01.cir.101.13.1539. [DOI] [PubMed] [Google Scholar]
  63. Zisman A., Peroni O. D., Abel E. D., Michael M. D., Mauvais-Jarvis F., Lowell B. B., Wojtaszewski J. F., Hirshman M. F., Virkamaki A., Goodyear L. J. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med. 2000 Aug;6(8):924–928. doi: 10.1038/78693. [DOI] [PubMed] [Google Scholar]

Articles from Transactions of the American Clinical and Climatological Association are provided here courtesy of American Clinical and Climatological Association

RESOURCES