Genetic and Pharmacologic Models for Type 1 Diabetes
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Abstract
Type 1 diabetes (T1D) is characterized by a partial or total insufficiency of insulin. The premiere animal model of autoimmune T cell?mediated T1D is the NOD mouse. A dominant negative mutation in the mouse insulin 2 gene ( Ins2 Akita ) produces a severe insulin deficiency syndrome without autoimmune involvement, as do a variety of transgenes overexpressed in beta cells. Pharmacologically induced T1D (without autoimmunity) elicited by alloxan or streptozotocin at high doses can generate hyperglycemia in almost any strain of mouse by direct toxicity. Multiple low doses of streptozotocin combine direct beta cell toxicity with local inflammation to elicit T1D in a male?sex?specific fashion. A summary of protocols relevant to the management of these different mouse models will be covered in this overview. Curr. Protoc. Mouse Biol. 3:9?19 © 2013 by John Wiley & Sons, Inc.
Keywords: mice; NOD; diabetes; alloxan; streptozotocin; beta cells
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PDF or HTML at Wiley Online LibraryTable of Contents
- Introduction
- The NOD Mouse
- The Akita Mouse: A Model of Insulin‐Responsive Diabetes without Insulitis
- Experimentally Induced Diabetes: Toxins
- Experimentally Induced Diabetes: Knockouts and Transgenes
- Experimentally Induced Diabetes: Viral Infection Models
- Notes and Conclusions
- Acknowledgments
- Literature Cited
- Figures
- Tables
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Figure 1. Histologic appearance of pancreatic islets in 5‐ to 6‐week‐old C57BL/6 wild‐type control (+/+) and heterozygous Ins2 Akita mice of both sexes. Insulin‐containing beta cells are stained with aldehyde fuchsin (blue color). Note the beta cell degranulation (loss of staining) in mutant mice of both sexes. At the time of necropsy, both mutant mice were hyperglycemic. At later ages, islets from severely hyperglycemic males are almost completely degranulated and markedly reduced in number; mutant females show a similar reduction in islet number, but more residual insulin‐positive beta cells per islet. View Image
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Literature Cited
| Literature Cited | |
| Babaya, N. , Nakayama, M. , Moriyama, H. , Gianani, R. , Still, T. , Miao, D. , Yu, L. , Hutton, J.C. , and Eisenbarth, G.S. 2006. A new model of insulin‐deficient diabetes: Male NOD mice with a single copy of Ins1 and no Ins2. Diabetologia 49: 1222‐ 1228. | |
| Barber, A.J. , Antonetti, D.A. , Kern, T.S. , Reiter, C.E. , Soans, R.S. , Krady, J.K. , Levison, S.W. , Gardner, T.W. , and Bronson, S.K. 2005. The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest. Ophthalmol. Vis. Sci. 46: 2210‐ 2218. | |
| Bonnevie‐Nielsen, V. , Steffes, M.W. , and Lernmark, Å . 1981. A major loss in islet mass and B‐cell function precedes hyperglycemia in mice given multiple low doses of streptozotocin. Diabetes 30: 424‐ 429. | |
| Brosius, F.C. 3rd , Alpers, C.E. , Bottinger, E.P. , Breyer, M.D. , Coffman, T.M. , Gurley, S.B. , Harris, R.C. , Kakoki, M. , Kretzler, M. , Leiter, E.H. , Levi, M. , McIndoe, R.A. , Sharma, K. , Smithies, O. , Susztak, K. , Takahashi, N. , and Takahashi, T. 2009. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 20: 2503‐ 2512. | |
| Bugger, H. , Chen, D. , Riehle, C. , Soto, J. , Theobald, H.A. , Hu, X.X. , Ganesan, B. , Weimer, B.C. , and Abel, E.D. 2009. Tissue‐specific remodeling of the mitochondrial proteome in type 1 diabetic akita mice. Diabetes 58: 1986‐ 1997. | |
| Chang, A.S. , Dale, A.N. , and Moley, K.H. 2005. Maternal diabetes adversely affects preovulatory oocyte maturation, development, and granulosa cell apoptosis. Endocrinology 146: 2445‐ 2453. | |
| Chatenoud, L. and Bach, J.F. 2005. Regulatory T cells in the control of autoimmune diabetes: The case of the NOD mouse. Int. Rev. Immunol. 24: 247‐ 267. | |
| Choeiri, C. , Hewitt, K. , Durkin, J. , Simard, C.J. , Renaud, J.M. , and Messier, C. 2005. Longitudinal evaluation of memory performance and peripheral neuropathy in the Ins2C96Y Akita mice. Behav. Brain Res. 157: 31‐ 38. | |
| Christianson, S.W. , Shultz, L.D. , and Leiter, E.H. 1993. Adoptive transfer of diabetes into immunodeficient NOD‐ scid/scidmice: relative contributions of CD4 +and CD8 +T lymphocytes from diabetic versus prediabetic NOD.NON‐Thy‐1 adonors. Diabetes 42: 44‐ 55. | |
| Craighead, J.E. 1975. Animal model of human disease. Mice infected with the M variant of Encephalomyocarditis virus. Am. J. Pathol. 76: 537‐ 540. | |
| DiLorenzo, T.P. 2011. Multiple antigens versus single major antigen in type 1 diabetes: Arguing for multiple antigens. Diabetes Metab. Res. Rev. 27: 778‐ 783. | |
| DiLorenzo, T.P. , Lieberman, S.M. , Takaki, T. , Honda, S. , Chapman, H.D. , Santamaria, P. , Serreze, D.V. , and Nathenson, S.G. 2002. During the early prediabetic period in NOD mice, the pathogenic CD8(+) T‐cell population comprises multiple antigenic specificities. Clin. Immunol. 105: 332‐ 341. | |
| Driver, J.P. , Scheuplein, F. , Chen, Y.G. , Grier, A.E. , Wilson, S.B. , and Serreze, D.V. 2010. Invariant natural killer T‐cell control of type 1 diabetes: A dendritic cell genetic decision of a silver bullet or Russian roulette. Diabetes 59: 423‐ 432. | |
| Driver, J.P. , Serreze, D.V. , and Chen, Y.G. 2011. Mouse models for the study of autoimmune type 1 diabetes: A NOD to similarities and differences to human disease. Semin. Immunopathol. 33: 67‐ 87. | |
| Epstein, P.N. , Ribar, T.J. , Decker, G.L. , Yaney, G. , and Means, A.R. 1992. Elevated beta‐cell calmodulin produces a unique insulin secretory defect in transgenic mice. Endocrinology 130: 1387‐ 1393. | |
| Gaskins, H.R. , Prochazka, M. , Hamaguchi, K. , Serreze, D.V. , and Leiter, E.H. 1992. Beta cell expression of endogenous xenotropic retrovirus distinguishes diabetes‐susceptible NOD/Lt from resistant NON/Lt mice. J. Clin. Invest. 90: 2220‐ 2227. | |
| Gerling, I.C. , Freidman, H. , Greiner, D.L. , Shultz, L.D. , and Leiter, E.H. 1994. Multiple low dose streptozotocin‐induced diabetes in NOD‐ scid/scidmice in the absence of functional lymphocytes. Diabetes 43: 433‐ 440. | |
| Gurley, S.B. , Mach, C.L. , Stegbauer, J. , Yang, J. , Snow, K.P. , Hu, A. , Meyer, T.W. , and Coffman, T.M. 2010. Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am. J. Physiol. Renal. Physiol. 298: F788‐ F795. | |
| Hamilton‐Williams, E.E. , Serreze, D.V. , Charlton, B. , Johnson, E.A. , Marron, M.P. , Mullbacher, A. , and Slattery, R.M. 2001. Transgenic rescue implicates β2‐microglobulin as a diabetes susceptibility gene in NOD mice. Proc. Natl. Acad. Sci. U.S.A. 98: 11533‐ 11538. | |
| Harlan, D.M. , Barnett, M.A. , Abe, R. , Pechhold, K. , Patterson, N.B. , Gray, G.S. , and June, C.H. 1995. Very‐low‐dose streptozotocin induces diabetes in insulin promoter‐mB7‐1 transgenic mice. Diabetes 44: 816‐ 823. | |
| Haskins, K. and Cooke, A. 2011. CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes. Curr. Opin. Immunol. 23: 739‐ 745. | |
| Herbach, N. , Rathkolb, B. , Kemter, E. , Pichl, L. , Klaften, M. , de Angelis, M.H. , Halban, P.A. , Wolf, E. , Aigner, B. , and Wanke, R. 2007. Dominant‐negative effects of a novel mutated Ins2 allele causes early‐onset diabetes and severe beta‐cell loss in Munich Ins2C95S mutant mice. Diabetes 56: 1268‐ 1276. | |
| Hong, E.G. , Jung, D.Y. , Ko, H.J. , Zhang, Z. , Ma, Z. , Jun, J.Y. , Kim, J.H. , Sumner, A.D. , Vary, T.C. , Gardner, T.W. , Bronson, S.K. , and Kim, J.K. 2007. Nonobese, insulin‐deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling. Am. J. Physiol. Endocrinol. Metab. 293: E1687‐ E1696. | |
| Ino, T. , Kawamoto, Y. , Sato, K. , Nishikawa, K. , Yamada, A. , Ishibashi, K. , and Sekiguchi, F. 1991. Selection of mouse strains showing high and low incidences of alloxan‐induced diabetes. Exp. Anim. 40: 61‐ 67. | |
| Ize‐Ludlow, D. , Lightfoot, Y.L. , Parker, M. , Xue, S. , Wasserfall, C. , Haller, M.J. , Schatz, D. , Becker, D.J. , Atkinson, M.A. , and Mathews, C.E. 2011. Progressive erosion of β‐cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes. Diabetes 60: 2086‐ 2091. | |
| Jordan, G.W. and Cohen, S.W. 1987. Encephalomyocarditis virus‐induced diabetes mellitus in mice: Model of viral pathogenesis. Rev. Infect. Dis. 9: 917‐ 924. | |
| Kolb, H. and Kroncke, K.‐D. 1993. IDDM. Lessons from the low‐dose streptozotocin model in mice. Diabetes Rev. 1: 116‐ 126. | |
| Laguens, R.P. , Candela, S. , Hernandez, R.E. , and Gagliardino, J.J. 1980. Streptozotocin‐induced liver damage in mice. Horm. Metab. Res. 12: 197‐ 201. | |
| Lamothe, B. , Baudry, A. , Desbois, P. , Lamotte, L. , Bucchini, D. , De Meyts, P. , and Joshi, R.L. 1998. Genetic engineering in mice: Impact on insulin signalling and action. Biochem. J. 335: 193‐ 204. | |
| Lee, J.Y. , Ristow, M. , Lin, X. , White, M.F. , Magnuson, M.A. , and Hennighausen, L. 2006. RIP‐Cre revisited, evidence for impairments of pancreatic beta‐cell function. J. Biol. Chem. 281: 2649‐ 2653. | |
| Leiter, E.H. 1987. Analysis of differential survival of syngeneic islets transplanted into hyperglycemic C57BL/KsJ versus C57BL/6J mice. Transplantation 44: 401‐ 406. | |
| Leiter, E.H. 1990. The role of environmental factors in modulating insulin dependent diabetes. In Current Topics in Immunology and Microbiology. The Role of Microorganisms in Non‐infectious Disease. ( R. de Vries , I. Cohen , and J. van Rood , eds.) pp. 39‐ 55. Springer Verlag, Berlin. | |
| Leiter, E.H. 1997. The NOD mouse: A model for insulin dependent diabetes mellitus. Curr. Protoc. Immunol. 3: 15.19.11‐ 15.19.23. | |
| Leiter, E.H. and Atkinson, M.A. 1998. NOD mice and related strains: Research applications in diabetes, AIDS, cancer, and other diseases. In Medical Intelligence Unit, pp. 208. R.G. Landes Company, Austin. | |
| Leiter, E.H. , Gerling, I.C. , and Flynn, J.C. 1999. Spontaneous insulin dependent diabetes mellitus (IDDM) in Nonobese Diabetic (NOD) mice: Comparisons with experimentally‐induced IDDM. In Experimental Models of Diabetes( J.H. McNeill , ed.) pp. 257‐ 295. CRC Press, Boca Raton, Fla. | |
| Leiter, E.H. , Reifsnyder, P.C. , Driver, J. , Kamdar, S. , Choisy‐Rossi, C. , Serreze, D.V. , Hara, M. , and Chervonsky, A. 2007. Unexpected functional consequences of xenogeneic transgene expression in beta cells of NOD mice. Diabetes Obes. Metab. 2: 14‐ 22. | |
| Lennon, G.P. , Bettini, M. , Burton, A.R. , Vincent, E. , Arnold, P.Y. , Santamaria, P. , and Vignali, D.A. 2009. T cell islet accumulation in type 1 diabetes is a tightly regulated, cell‐autonomous event. Immunity 31: 643‐ 653. | |
| Lenzen, S. 2008. The mechanisms of alloxan‐ and streptozotocin‐induced diabetes. Diabetologia 51: 216‐ 226. | |
| Lenzen, S. , Drinkgern, J. , and Tiedge, M. 1996. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic. Biol. Med. 20: 463‐ 466. | |
| Like, A.A. and Rossini, A.A. 1976. Streptozotocin‐induced pancreatic insulitis: New model of diabetes mellitus. Science 193: 415‐ 417. | |
| Lo, D. , Burkly, L.C. , Widera, G. , Cowing, C. , Flavell, R.A. , Palmiter, R.D. , and Brinster, R.L. 1988. Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. Cell 53: 159‐ 168. | |
| Makino, S. , Kunimoto, K. , Muraoka, Y. , Mizushima, Y. , Katagiri, K. , and Tochino, Y. 1980. Breeding of a non‐obese, diabetic strain of mice. Exp. Anim. 29: 1‐ 8. | |
| Martinez, C. , Grande, F. , and Bittner, J.J. 1954. Alloxan diabetes in different strains of mice. Proc. Soc. Exp. Biol. Med. 87: 236‐ 238. | |
| Masiello, P. , Wollheim, C.B. , Gori, Z. , Blondel, B. , and Bergamini, E. 1984. Streptozotocin‐induced functioning islet cell tumor in the rat: High frequency of induction and biological properties of the tumor cells. Toxicol. Pathol. 12: 274‐ 280. | |
| Mathews, C.E. , Langley, S.H. , and Leiter, E.H. 2002. New mouse model to study islet transplantation in insulin‐dependent diabetes mellitus. Transplantation 73: 1333‐ 1336. | |
| Mathews, C.E. , Graser, R.T. , Bagley, R.J. , Caldwell, J.W. , Li, R. , Churchill, G.A. , Serreze, D.V. , and Leiter, E.H. 2003. Genetic analysis of resistance to type 1 diabetes in ALR/Lt mice, a NOD‐related strain with defenses against autoimmune‐mediated diabetogenic stress. Immunogenetics 55: 491‐ 496. | |
| Mathews, C.E. , Suarez‐Pinzon, W.L. , Baust, J.J. , Strynadka, K. , Leiter, E.H. , and Rabinovitch, A. 2005. Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine‐induced destruction. J. Immunol. 175: 1248‐ 1256. | |
| Nichols, W.K. , Vann, L.L. , and Spellman, J.B. 1981. Streptozotocin effects on T lymphocytes and bone marrow cells. Clin. Exp. Immunol. 46: 627‐ 632. | |
| Oldstone, M.B.A. 1988. Prevention of type 1 diabetes in nonobese diabetic mice by virus infection. Science 23: 500‐ 502. | |
| Oldstone, M.B.A. , Southern, P. , Rodriguez, M. , and Lampert, P. 1984. Virus persists in β cells of islets of langerhans and is associated with chemical manifestations of diabetes. Science 224: 1440‐ 1443. | |
| Oldstone, M.B.A. , Nerenber, M. , Southern, P. , Price, J. , and Lewicki, H. 1991. Virus‐infection triggers insulin‐dependent diabetes‐mellitus in a transgenic model—role of anti‐self (virus) immune‐response. Cell 65: 319‐ 331. | |
| Pearson, T. , Shultz, L.D. , Lief, J. , Burzenski, L. , Gott, B. , Chase, T. , Foreman, O. , Rossini, A.A. , Bottino, R. , Trucco, M. , and Greiner, D.L. 2008. A new immunodeficient hyperglycaemic mouse model based on the Ins2Akita mutation for analyses of human islet and beta stem and progenitor cell function. Diabetologia 51: 1449‐ 1456. | |
| Pujol‐Borrell, R. and Bottazzo, G.F. 1988. Puzzling diabetic transgenic mice. Immunol. Today 9: 303‐ 306. | |
| Schott, M. , Scherbaum, W.A. , and Feldkamp, J. 2000. Drug therapy of endocrine neoplasms. Part II: Malignant gastrinomas, insulinomas, glucagonomas, carcinoids and other tumors. Med. Klin. (Munich) 95: 81‐ 84. | |
| Serreze, D.V. , Prochazka, M. , Reifsnyder, P.C. , Bridgett, M.M. , and Leiter, E.H. 1994. Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin dependent diabetes resistance gene. J. Exp. Med. 180: 1553‐ 1558. | |
| Serreze, D.V. , Chapman, H.C. , Gerling, I.C. , Leiter, E.H. , and Shultz, L.D. 1997. Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I‐dependent. J. Immunol. 158: 3978‐ 3986. | |
| Serreze, D.V. , Fleming, S.A. , Chapman, H.D. , Richard, S.D. , Leiter, E.H. , and Tisch, R.M. 1998. B‐lymphocytes are critical antigen presenting cells for the initiation of T cell mediated autoimmune insulin dependent diabetes in NOD mice. J. Immunol. 161: 3912‐ 3918. | |
| Serreze, D.V. , Wasserfall, C. , Ottendorfer, E.W. , Stalvey, M. , Pierce, M.A. , Gauntt, C. , O'Donnell, B. , Flanagan, J.B. , Campbell‐Thompson, M. , Ellis, T.M. , and Atkinson, M.A. 2005. Diabetes acceleration or prevention by a coxsackievirus B4 infection: Critical requirements for both interleukin‐4 and gamma interferon. J. Virol. 79: 1045‐ 1052. | |
| Serreze, D.V. , Chapman, H.D. , Niens, M. , Dunn, R. , Kehry, M.R. , Driver, J.P. , Haller, M. , Wasserfall, C. , and Atkinson, M.A. 2011. Loss of intra‐islet CD20 expression may complicate efficacy of B‐cell‐directed type 1 diabetes therapies. Diabetes 60: 2914‐ 2921. | |
| Shameli, A. , Yamanouchi, J. , Thiessen, S. , and Santamaria, P. 2007. Endoplasmic reticulum stress caused by overexpression of islet‐specific glucose‐6‐phosphatase catalytic subunit‐related protein in pancreatic Beta‐cells. Rev. Diabet. Stud. 4: 25‐ 32. | |
| Shultz, L.D. , Lang, P.A. , Christianson, S.W. , Gott, B. , Lyons, B. , Umeda, S. , Leiter, E. , Hesselton, R. , Wagar, E.J. , Leif, J.H. , Kollet, O. , Lapidot, T. , and Greiner, D.L. 2000. NOD/LtSz‐Rag1(null) mice: An immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. J. Immunol. 164: 2496‐ 2507. | |
| Socha, L. , Silva, D. , Lesage, S. , Goodnow, C. , and Petrovsky, N. 2003. The role of endoplasmic reticulum stress in nonimmune diabetes: NOD.k iHEL, a novel model of beta cell death. Ann. N.Y. Acad. Sci. 1005: 178‐ 183. | |
| Susztak, K. , Raff, A.C. , Schiffer, M. , and Bottinger, E.P. 2006. Glucose‐induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55: 225‐ 233. | |
| Szkudelski, T. 2001. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol. Res. 50: 537‐ 546. | |
| Takamura, T. , Kato, I. , Kimura, N. , Nakazawa, T. , Yonekura, H. , Takasawa, S. , and Okamoto, H. 1998. Transgenic mice overexpressing type 2 nitric‐oxide synthase in pancreatic beta cells develop insulin‐dependent diabetes without insulitis. J. Biol. Chem. 273: 2493‐ 2496. | |
| Terauchi, Y. , Sakura, H. , Yasuda, K. , Iwamoto, K. , Takahashi, N. , Ito, K. , Kasai, H. , Suzuki, H. , Ueda, O. , Kamada, N. , et al. 1995. Pancreatic beta‐cell‐specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J. Biol. Chem. 270: 30253‐ 30256. | |
| Wang, J. , Takeuchi, T. , Tanaka, S. , Kubo, S.K. , Kayo, T. , Lu, D. , Takata, K. , Koizumi, A. , and Izumi, T. 1999. A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta‐cell dysfunction in the Mody mouse. J. Clin. Invest. 103: 27‐ 37. | |
| Wang, W. , Guo, Y. , Xu, M. , Huang, H.H. , Novikova, L. , Larade, K. , Jiang, Z.G. , Thayer, T.C. , Frontera, J.R. , Aires, D. , Ding, H. , Turk, J. , Mathews, C.E. , Bunn, H.F. , Stehno‐Bittel, L. , and Zhu, H. 2011. Development of diabetes in lean Ncb5or‐null mice is associated with manifestations of endoplasmic reticulum and oxidative stress in beta cells. Biochim. Biophys. Acta 1812: 1532‐ 1541. | |
| Wilson, G.L. and Leiter, E.H. 1990. Streptozotocin interactions with pancreatic β cells and the induction of insulin dependent diabetes. In Current Topics in Microbiology and Immunobiology( T. Dyrberg , ed.) pp. 27‐ 54. Springer Verlag, Berlin. | |
| Yaguchi, M. , Nagashima, K. , Izumi, T. , and Okamoto, K. 2003. Neuropathological study of C57BL/6Akita mouse, type 2 diabetic model: Enhanced expression of alphaB‐crystallin in oligodendrocytes. Neuropathology 23: 44‐ 50. | |
| Yamagami, T. , Miwa, A. , Takasawa, S. , Yamamoto, H. , and Okamoto, H. 1985. Induction of rat pancreatic B‐cell tumors by the combined administration of streptozotocin or alloxan and poly(adenosine diphosphate ribose) synthetase inhibitors. Cancer Res. 45: 1845‐ 1849. | |
| Yamanouchi, J. , Rainbow, D. , Serra, P. , Howlett, S. , Hunter, K. , Garner, V.E. , Gonzalez‐Munoz, A. , Clark, J. , Veijola, R. , Cubbon, R. , Chen, S.L. , Rosa, R. , Cumiskey, A.M. , Serreze, D.V. , Gregory, S. , Rogers, J. , Lyons, P.A. , Healy, B. , Smink, L.J. , Todd, J.A. , Peterson, L.B. , Wicker, L.S. , and Santamaria, P. 2007. Interleukin‐2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39: 329‐ 337. | |
| Yoon, J.‐W. 1991. Role of viruses in the pathogenesis of IDDM. Ann. Med. 23: 437‐ 445. | |
| Yoshioka, M. , Kayo, T. , Ikeda, T. , and Koizumi, A. 1997. A novel locus, MODY4, distal to D7MIT189 on Chromosome‐7 determines early‐onset NIDDM in nonobese C57BL/6 (AKITA) mutant mice. Diabetes 46: 887‐ 894. | |
| Zipris, D. , Lien, E. , Nair, A. , Xie, J.X. , Greiner, D.L. , Mordes, J.P. , and Rossini, A.A. 2007. TLR9‐signaling pathways are involved in Kilham rat virus‐induced autoimmune diabetes in the biobreeding diabetes‐resistant rat. J. Immunol. 178: 693‐ 701. |
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