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Lessons for human diabetes from experimental mouse models

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Abstract

A precise knowledge of the defects underlying type 1 and type 2 diabetes is essential for designing appropriate therapeutic strategies. Because experiments in humans are limited, naturally occurring, and especially genetically engineered rodent models, have revolutionized research in diabetes. We review some of the models created recently and discuss their impact on human diabetes.

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References and Recommended Reading

  1. Mathis D, Vence L, Benoist C: Beta-cell death during progression to diabetes. Nature 2002, 414:792–798.

    Article  Google Scholar 

  2. Diabetes Public Health Resource. Atlanta, GA: US Department of Health and Human Resources, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health promotion; 2002.

  3. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al.: Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000, 136:664–672.

    Article  CAS  PubMed  Google Scholar 

  4. Saltiel AR, Kahn CR: Insulin signaling and the regulation of glucose and lipid metabolism. Nature 2001, 414:799–806.

    Article  CAS  PubMed  Google Scholar 

  5. Elbein SC: Genetics of type 2 diabetes: an overview for the millennium. Diabetes Technol Ther 2000, 2:391–400.

    Article  CAS  PubMed  Google Scholar 

  6. Hribal ML, Oriente F, Accili D: Mouse models of insulin resistance. Am J Endocrinol Metab 2002, 282:E977-E981.

    CAS  Google Scholar 

  7. Adorini L, Gregori S, Harrison LC: Understanding autoimmune diabetes: insights from mouse models. Trends Mol Med 2002, 8:31–38.

    Article  CAS  PubMed  Google Scholar 

  8. French MB, Allison J, Cram DS, et al.: Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 1997, 46:34–39.

    Article  CAS  PubMed  Google Scholar 

  9. Pugliese A, Zeller M, Fernandez A Jr, et al.: The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997, 15:293–297.

    Article  CAS  PubMed  Google Scholar 

  10. Chentoufi AA, Polychronakos C: Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 2002, 51:1383–1390. To examine the role of thymic expression of insulin on the development of type 1 diabetes, graded thymic deficiency in insulin was created without altering pancreatic insulin in mice. Mice with low, but not normal, thymic insulin levels showed peripheral reactivity to insulin, indicating a role for thymic insulin in insulin-specific T-cell tolerance.

    Article  CAS  PubMed  Google Scholar 

  11. Duvillie B, Cordonnier N, Deltour L, et al.: Phenotypic alterations in insulin-deficient mutant mice. Proc Natl Acad Sci U S A 1997, 94:5137–5140.

    Article  CAS  PubMed  Google Scholar 

  12. Moriyama H, Paronen J, Liu E, et al.: Testing the hypothesis that the insulin 1 gene is essential for diabetogenesis and knockout of insulin 2 gene accelerates diabetes in NOD mice [abstract]. Diabetes Metab Res Rev 2002, 18(suppl 4):S26.

    Google Scholar 

  13. Ramsey C, Bukrinsky A, Peltonen L: Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. Hum Mol Genet 2002, 11:397–409.

    Article  CAS  PubMed  Google Scholar 

  14. Anderson MS, Venanzi ES, Klein L, et al.: Projection of an immunological self shadow within the thymus by the aire protein. Science 2002, 298:1395–1401. These studies provide evidence that mice deficient for a transcription factor, AIRE, develop a defined profile of autoimmune disease depending on the presence of the AIRE protein in the thymus. The mouse model has been likened to APECED, also known as APS-1. This mouse model will be useful to study the target organ specificity of autoimmune destruction.

    Article  CAS  PubMed  Google Scholar 

  15. Pugliese A, Diez J: Lymphoid organs contain diverse cells expressing self-molecules. Nat Immunol 2002, 3:335–336.

    Article  CAS  PubMed  Google Scholar 

  16. Pugliese A, Brown D, Garza D, et al.: Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J Clin Invest 2001, 107:555–564. Evidence for the presence of specialized cells synthesizing (pro)insulin, GAD, and IA-2 in the medullary thymus in humans and also in peripheral lymphoid organs (spleen and lymph nodes). The data demonstrate the existence of a novel subset of antigen-presenting cells expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.

    CAS  PubMed  Google Scholar 

  17. Raju R, Munn SR, David CS: T cell recognition of human preproinsulin peptides depends on the polymorphism at HLA DQ locus: a study using HLA DQ8 and DQ6 transgenic mice. Hum Immunol 1997, 58:21–29.

    Article  CAS  PubMed  Google Scholar 

  18. Wen L, Wong FS, Burkly L, et al.: Induction of insulitis by glutamic acid decarboxylase peptide-specific and HLA-DQ8- restricted CD4(+) T cells from human DQ transgenic mice. J Clin Invest 1998, 102:947–957.

    CAS  PubMed  Google Scholar 

  19. Wen L, Wong FS, Tang J, et al.: In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes. J Exp Med 2000, 191:97–104.

    Article  CAS  PubMed  Google Scholar 

  20. Wen L, Chen NY, Tang J, et al.: The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model. J Clin Invest 2001, 107:871–880.

    CAS  PubMed  Google Scholar 

  21. Corper AL, Stratmann T, Apostolopoulos V, et al.: A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 2000, 288:505–511.

    Article  CAS  PubMed  Google Scholar 

  22. Wen L, Wong FS, Sherwin R, Mora C: Human DQ8 can substitute for murine I-Ag7 in the selection of diabetogenic T cells restricted to I-Ag7. J Immunol 2002, 168:3635–3640.

    CAS  PubMed  Google Scholar 

  23. Abraham RS, Wen L, Marietta EV, David CS: Type 1 diabetespredisposing MHC alleles influence the selection of glutamic acid decarboxylase (GAD) 65-specific T cells in a transgenic model. J Immunol 2001, 166:1370–1379.

    CAS  PubMed  Google Scholar 

  24. Kudva YC, Rajagopalan G, Raju R, et al.: Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. Hum Immunol 2002, 63:987–999. HLA transgenic mice on the NOD background, I-Ag7, were examined for spontaneous and experimental (induced) autoimmune diabetes, in the absence of the endogenous class II molecule. In NOD mice lacking endogenous class II molecules and with a predisposition to diabetes, the transgenic expression of HLA-DR3 and -DQ8 does not appear to be adequate to induce spontaneous diabetes.

    Article  CAS  PubMed  Google Scholar 

  25. Kudva YC, Deng YJ, Govindarajan R, et al.: HLA-DQ8 transgenic and NOD mice recognize different epitopes within the cytoplasmic region of the tyrosine phosphatase-like molecule, IA-2. Hum Immunol 2001, 62:1099–1105.

    Article  CAS  PubMed  Google Scholar 

  26. Liu E, Moriyama H, Abiru N, et al.: Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin selfpeptides B:9-23 and B:13-23. J Clin Invest 2002, 110:1021–1027.

    Article  CAS  PubMed  Google Scholar 

  27. Balasa B, Boehm BO, Fortnagel A, et al.: Vaccination with glutamic acid decarboxylase plasmid DNA protects mice from spontaneous autoimmune diabetes and B7/CD28 costimulation circumvents that protection. Clin Immunol 2001, 99:241–252.

    Article  CAS  PubMed  Google Scholar 

  28. Karges W, Pechhold K, Al Dahouk S, et al.: Induction of autoimmune diabetes through insulin (but not GAD65) DNA vaccination in nonobese diabetic and in RIP-B7.1 mice. Diabetes 2002, 51:3237–3244.

    Article  CAS  PubMed  Google Scholar 

  29. Bot A, Smith D, Bot S, et al.: Plasmid vaccination with insulin B chain prevents autoimmune diabetes in nonobese diabetic mice. J Immunol 2001, 167:2950–2955.

    CAS  PubMed  Google Scholar 

  30. Effects of insulin in relatives of patients with type 1 diabetes mellitus [no authors listed]. N Engl J Med 2002, 346:1685–1691.

  31. Nitta Y, Tashiro F, Tokui M, et al.: Systemic delivery of interleukin 10 by intramuscular injection of expression plasmid DNA prevents autoimmune diabetes in nonobese diabetic mice. Hum Gene Ther 1998, 9:1701–1707.

    CAS  PubMed  Google Scholar 

  32. Cameron MJ, Strathdee CA, Holmes KD, et al.: Biolistic-mediated interleukin 4 gene transfer prevents the onset of type 1 diabetes. Hum Gene Ther 2000, 11:1647–1656.

    Article  CAS  PubMed  Google Scholar 

  33. Moritani M, Yoshimoto K, Tashiro F, et al.: Transgenic expression of IL-10 in pancreatic islet A cells accelerates autoimmune insulitis and diabetes in non-obese diabetic mice. Int Immunol 1994, 6:1927–1936.

    Article  CAS  PubMed  Google Scholar 

  34. Goudy K, Song S, Wasserfall C, et al.: Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice. Proc Natl Acad Sci U S A 2001, 98:13913–13918.

    Article  CAS  PubMed  Google Scholar 

  35. Saeki K, Zhu M, Kubosaki A, et al.: Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion. Diabetes 2002, 51:1842–1850.

    Article  CAS  PubMed  Google Scholar 

  36. Matarese G, Sanna V, Lechler RI, et al.: Leptin accelerates autoimmune diabetes in female NOD mice. Diabetes 2002, 51:1356–1361.

    Article  CAS  PubMed  Google Scholar 

  37. Beales PE, Pozzilli P: Thiazolidinediones for the prevention of diabetes in the non-obese diabetic (NOD) mouse: implications for human type 1 diabetes. Diabetes Metab Res Rev 2002, 18:114–117.

    Article  CAS  PubMed  Google Scholar 

  38. Warram JH, Martin BC, Krolewski AS, et al.: Slow glucose removal rate and hyperinsulinemia are predictors of the risk of type 2 diabetes in offspring of diabetic parents. Ann Intern Med 1990, 113:909–915.

    CAS  PubMed  Google Scholar 

  39. Almind K, Doria A, Kahn CR: Putting the genes for type 2 diabetes on the map. Nat Med 2001, 7:277–279.

    Article  CAS  PubMed  Google Scholar 

  40. Sethi JK, Hotamisligil GS: The role of TNF alpha in adipocyte metabolism. Semin Cell Dev Biol 1999, 10:19–29.

    Article  CAS  PubMed  Google Scholar 

  41. Aguirre V, Uchida T, Yenush L, et al.: The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 2000, 275:9047–9054.

    Article  CAS  PubMed  Google Scholar 

  42. Hirosumi J, Tuncman G, Chang L, et al.: A central role for JNK in obesity and insulin resistance. Nature 2002, 420:333–336. Mice with a KO of JNK show a reduced propensity for adiposity and enhanced insulin sensitivity in mouse models of obesity. JNK is also abnormally elevated in obesity. Mutations in the JNK scaffold protein, JIP1, in humans is associated with type 2 diabetes. JNK may be a potential target for the development of drugs to counter obesity and type 2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  43. Waeber G, Delplanque J, Bonny C, et al.: The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes. Nat Genet 2000, 24:291–295.

    Article  CAS  PubMed  Google Scholar 

  44. Araki E, Lipes MA, Patti ME, et al.: Alternative pathway of insulin signaling in mice with targeted disruption of the IRS-1 gene. Nature 1994, 372:186–190.

    Article  CAS  PubMed  Google Scholar 

  45. Kulkarni RN, Winnay JN, Daniels M, et al.: Altered function of insulin receptor substrate-1-deficient mouse islets and cultured beta-cell lines. J Clin Invest 1999, 104:R69-R75.

    Article  CAS  PubMed  Google Scholar 

  46. Almind K, Bjorbaek C, Vestergaard H, et al.: Amino acid polymorphisms of insulin receptor substrate-1 in non-insulindependent diabetes mellitus. Lancet 1993, 342:828–832.

    Article  CAS  PubMed  Google Scholar 

  47. Liu SC, Wang Q, Lienhard GE, Keller SR: Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. J Biol Chem 1999, 274:18093–18099.

    Article  CAS  PubMed  Google Scholar 

  48. Laustsen PG, Michael MD, Crute BE, et al.: Lipoatrophic diabetes in Irs1(-/-)/Irs3(-/-) double knockout mice. Genes Dev 2002, 16:3213–3222. Mice with double KO of IRS-1 and IRS-3 show hyperinsulinemia, hyperglycemia, and islet hyperplasia and represent a novel model of lipoatrophic diabetes. Adenoviral leptin therapy is able to reverse the hyperinsulinemia and hypergycemia in the double KOs. The lack of a human equivalent of IRS-3 in humans suggests the crucial importance of IRS-1 for adipogenesis.

    Article  CAS  PubMed  Google Scholar 

  49. Gavrilova O, Marcus-Samuels B, Leon LR, et al.: Leptin and diabetes in lipoatrophic mice. Nature 2000, 403:850–851.

    CAS  PubMed  Google Scholar 

  50. Bjornholm M, He AR, Attersand A, et al.: Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans. Diabetologia 2002, 45:1697–1702.

    Article  CAS  PubMed  Google Scholar 

  51. Yamauchi T, Kamon J, Waki H, et al.: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001, 7:941–946. Reduced expression of the adipocute-derived hormone, adiponectin, correlates with insulin resistance in mouse models of altered insulin sensitivity. Adiponectin reduces insulin resistance by lowering triglyceride content in muscle and liver in obese mice. Treatment with adiponectin may be a novel approach to counter insulin resistance and type 2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  52. Yamauchi T, Kamon J, Waki H, et al.: Globular adiponectin protected ob/ob mice from diabetes and apoE deficient mice from atherosclerosis. J Biol Chem 2003, 278:2461–2468.

    Article  CAS  PubMed  Google Scholar 

  53. Kubota N, Terauchi Y, Yamauchi T, et al.: Disruption of adiponectin causes insulin resistance and neointimal formation. J Biol Chem 2002, 277:25863–25866.

    Article  CAS  PubMed  Google Scholar 

  54. Yamauchi T, Kamon J, Minokoshi Y, et al.: Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002, 8:1288–1295. Adiponectin is secreted by adipocytes and is a hormone that regulates glucose and lipid metabolism. This paper describes the mechanism of action of adiponectin via activation of AMPK in directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.

    Article  CAS  PubMed  Google Scholar 

  55. Ma K, Cabrero A, Saha PK, et al.: Increased beta-oxidation but no insulin resistance or glucose intolerance in mice lacking adiponectin. J Biol Chem 2002, 277:34658–34661.

    Article  CAS  PubMed  Google Scholar 

  56. Zisman A, Peroni OD, Abel D, et al.: Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 2000, 6:924–928.

    Article  CAS  PubMed  Google Scholar 

  57. Kim JK, Zisman A, Fillmore JJ, et al.: Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4. J Clin Invest 2001, 108:153–160.

    Article  CAS  PubMed  Google Scholar 

  58. McPherron AC, Lee SJ: Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 2002, 109:595–601. Myostatin negatively regulates muscle growth. Mice lacking myostatin have reduced fat accumulation even with a normal food intake. Loss of myostatin, in two mouse models of obesity, led to partial suppression of adiposity, suggesting that agents that block myostatin may be useful in the prevention of type 2 diabetes.

    Article  CAS  PubMed  Google Scholar 

  59. Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al.: Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proc Natl Acad Sci U S A 1998, 95:14938–14943.

    Article  CAS  PubMed  Google Scholar 

  60. Shih DQ, Stoffel M: Dissecting the transcriptional network of pancreatic islets during development and differentiation. Proc Natl Acad Sci U S A 2001, 98:14189–14191.

    Article  CAS  PubMed  Google Scholar 

  61. Shih DQ, Heimesaat M, Kuwajima S, et al.: Profound defects in pancreatic beta-cell function in mice with combined heterozygous mutations in Pdx-1, Hnf-1a, and Hnf-3b. Proc Natl Acad Sci U S A 2002, 99:3818–3823. Defects in pancreatic endocrine function are a feature of type 2 diabetes. This study describes that partial defects in multiple transcription factors in the â-cells leads to diabetes. The data provide evidence for a polygenic mouse model for examining the functional interactions between transcription factors for optimal â-cell function.

    Article  CAS  PubMed  Google Scholar 

  62. Thomas MK, Devon ON, Lee JH, et al.: Development of diabetes mellitus in aging transgenic mice following suppression of pancreatic homeoprotein IDX-1. J Clin Invest 2001, 108:319–329.

    Article  CAS  PubMed  Google Scholar 

  63. Bernassola F, Federici M, Corazzari M, et al.: Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient. FASEB J 2002, 11:1371–1378.

    Article  Google Scholar 

  64. Kulkarni RN: Receptors for insulin and insulin-like growth factor- 1 and insulin receptor substrate-1 mediate pathways that regulate islet function. Biochem Soc Trans 2002, 30:317–322.

    Article  CAS  PubMed  Google Scholar 

  65. Hill DJ, Duvillie B: Pancreatic development and adult diabetes. Pediatr Res 2000, 48:269–274.

    Article  CAS  PubMed  Google Scholar 

  66. Kulkarni RN, Holzenberger M, Shih DQ, et al.: Beta-cellspecific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 2002, 31:111–115. In these studies, mice with â-cell-specific disruption of the IGF-1 receptor develop a normal complement of â-cells, suggesting that the IGF-1 receptor is not crucial for the early growth of the â-cells. These KOs manifest defects in glucose-stimulated insulin secretion secondary to reduced expression of glucokinase and the glucose transporter glut2. These findings have implications for both type 1 and type 2 diabetes.

    CAS  PubMed  Google Scholar 

  67. Xuan S, Kitamura T, Nakae J, et al.: Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. J Clin Invest 2002, 110:1011–1019.

    Article  CAS  PubMed  Google Scholar 

  68. Vaessen N, Heutink P, Janssen JA, et al.: A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes 2001, 50:637–642.

    Article  CAS  PubMed  Google Scholar 

  69. Boss O, Hagen T, Lowell BB: Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 2000, 49:143–156.

    Article  CAS  PubMed  Google Scholar 

  70. Zhang CY, Baffy G, Perret P, et al.: Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 2002, 105:745–755. The role of UCP2 in the regulation of â-cell function was evaluated by creating a UCP2 KO mouse. The KOs exhibited higher ATP levels and an increased glucose-stimulated insulin secretion. Ob/ob mice lacking UCP2 had a restored first-phase insulin secretion. The data suggest UCP2 is a link between obesity and type 2 diabetes.

    Article  Google Scholar 

  71. Esterbauer H, Schneitler C, Oberkofler H, et al.: A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet 2001, 28:178–183.

    Article  CAS  PubMed  Google Scholar 

  72. Watanabe H, Katakami C, Miyata S, Negi A: Corneal disorders in KKAy mouse: a type 2 diabetes model. Jpn J Ophthalmol 2002, 46:130–139.

    Article  CAS  PubMed  Google Scholar 

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  1. Joslin Diabetes Center, One Joslin Place, Room 602, 02215, Boston, MA, USA

    Rohit N. Kulkarni MD, PhD

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  1. Rohit N. Kulkarni MD, PhD
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  2. Ariel Zisman MD
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Kulkarni, R.N., Zisman, A. Lessons for human diabetes from experimental mouse models. Curr Diab Rep 3, 168–175 (2003). https://doi.org/10.1007/s11892-003-0041-x

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