My 33+ year career at The Jackson Laboratory has concentrated on the interaction between genetic and environmental factors that predispose inbred mouse strains to development of both forms of diabetes: autoimmune and non-autoimmune forms of type 1 insulin-dependent diabetes (T1D), and type 2 diabetes, associated with insulin resistance and obesity. I am in the process of closing my active research career but will continue to be involved with diabetes resources development and management at the Laboratory under the aegis of the Type 1 Diabetes Resource (T1DR). The T1DR imports or, as necessary, develops genetically modified stocks of non-obese diabetic (NOD) mice important for diabetes research.
Genetics and Pathogenesis of Diabetes and Inflammatory Bowel Disease in Mice
My 33+ year career at The Jackson Laboratory has concentrated on the interaction between genetic and environmental factors that predispose inbred mouse strains to development of both forms of diabetes: autoimmune and non-autoimmune forms of Type I insulin-dependent diabetes (T1D), and Type 2 diabetes, associated with insulin resistance and obesity. With collaborators, I have also contributed an analysis of the genetic basis for differential inbred strain susceptibility to development of inflammatory bowel disease. At this writing, I am in the process of closing my active research career but will continue to be involved with diabetes resources development and management at the Laboratory. The studies described below done under the aegis of The Type 1 Diabetes Resource at The Jackson Laboratory emphasize the importance of thoroughly characterizing genetically manipulated mouse models used in diabetes research.
Confounding effects on T1D pathogenesis mediated by transgene expression in NOD/ShiLtJ beta cells
The Type 1 Diabetes Resource (TIDR) imports, or, as necessary, develops genetically-modified stocks of NOD mice important for diabetes research. One such NOD transgenic stock strongly expressing enhanced green fluorescent protein under control of the mouse insulin 1 promoter (commonly designated MIP-GFP, formally designated NOD.Tg(Ins1-EGFP/GH1)12Hara) was imported from Dr. Manami Hara at the University of Chicago. We found that homozygous transgene expression produced a developmental lethal with only small numbers of homozygous mice surviving to wean. All survivors developed severe diabetes within weeks of weaning that was not associated with insulitis; rather, beta cell-depleted islets indicated a defect in beta cell survival. Hemizygous mice were born in normal numbers and were diabetes-free post weaning. Indeed, development of clinical diabetes was almost completely suppressed in a cohort of MIP-GFP hemizygous females followed to 30 weeks of age. Whereas standard NOD/ShiLtJ males are typically more diabetes-resistant than are females, MIP-GFP hemizygous males showed a higher frequency of diabetes than hemizygous females. Our evidence indicates that hemizygous MIP-GFP expression impaired beta cell glucose responsiveness in an age- and male sex-dependent fashion. Plasma insulin of non-diabetic hemizygous males were marginally lower at 8 weeks, but markedly (4-fold) lower by 30 weeks Insulitis, when present at 30 weeks, varied considerably among individuals. Some pancreata (2/22 males and 3/17 females) showed widespread, invasive insulitis typical of standard NOD/Lt mice, and these mice may potentially have developed insulitis-driven T1D had they been aged for a longer period. However, pancreata from other individuals (13/22 males, 9/17 females) were completely free of intra-islet insulitis, showing only perivascular-periductular infiltrates, while the islets themselves exhibited hyperplastic/hypertrophic size increases. A third category included a combination of insulitic and insulitis-free islets (7/22 males, 5/17 females). What was most notable in the two latter classes, regardless of the presence or absence of insulitis, was the appearance of extensive peri-insular and intra-islet fibroconnective material, a phenotype not seen in standard NOD/ShiLtJ mice at any stage of the insulitic process. A final peculiarity of the stock was the finding that enriched populations of two distinct islet-reactive CD8+ T cells (AI4 and NY8.3 specificities) adoptively transferred clinical diabetes into 600R-irradiated MIP-GFP recipients at a much lower frequency than observed in standard NOD controls. Hence, high beta cell expression of the enhanced GFP clearly deviated from NOD model characteristics.
Because only one NOD-MIP-GFP line was available for study, it could not be established whether the transgene-mediated effects were due to copy number-induced toxicity or integration site mutagenesis that affected immune recognition of beta cells by down-regulating their function. However, analysis of differential diabetes protection produced in another important set of NOD transgenic stocks indicated that copy number and level of expression was the critical factor. The ability to generate beta cell-specific "knockout" mice on the NOD background required an NOD stock constitutively expressing the Cre recombinase if a Cre-loxP system is employed. To generate such a stock, a RIP2-Cre construct was microinjected directly into NOD/ShiLtJ zygotes. Four NOD-RIP-Cre-expressing lines were established, only two of which could be bred to homozygosity (Line 5 and Line 9). A significant diabetes-suppressive effect was observed in transgene homozygous Line 5 mice of both sexes that was not observed in Line 9. Line 5 was distinguished from Line 9 homozygotes by a non-mosaic beta cell expression pattern in the former that was not observed in the latter. This major difference in Cre expression was confirmed by qPCR comparison of whole pancreatic mRNA. The diabetes-suppressive effect of homozygous Line 5 transgene expression was alleviated in the hemizygous mice, whose expression was half that of homozygotes. Thus, expression level rather than site of integration likely accounts for the diabetes suppression.
Development of a non-invasive glucose monitor for mice
With a one-year innovative grant from the Juvenile Diabetes Research Foundation, and in collaboration with Dr. Michael Grunze and Mr. Marcel Müller of the Institute for Molecular Biophysics, we have used infrared spectroscopy to indirectly measure blood glucose fluctuations in the tail of a mouse via heat emanating from the tail. We have developed a prototype instrument that establishes proof of principle. However, considerably more technical improvements will be required to overcome problems in reproducibility and to allow faster measurements.
Principal Investigator: Edward H. Leiter, Ph.D.
Research Administrative Assistant: Norma D. Buckley
Chen YG, Scheuplein F, Driver JP, Hewes AA, Reifsnyder PC, Leiter EH, Serreze DV. 2011. Testing the role of P2X(7) receptors in the development of type 1 diabetes in nonobese diabetic mice. J Immunol 186: 4278-4284. PMCID: PMC3094905
Chen J, Gusdon AM, Piganelli J, Leiter EH, Mathews CE. 2011. mt-Nd2(a) modifies resistance against autoimmune type 1 diabetes in NOD mice at the level of the pancreatic beta-cell. Diabetes 60: 355-359. PMCID: PMC3012193
Bleich A, Buchler G, Beckwith J, Petell LM, Affourtit JP, King BL, Shaffer DJ, Roopenian DC, Hedrich HJ, Sundberg JP, Leiter EH. 2010. Cdcs1 a major colitis susceptibility locus in mice: Subcongenic analysis reveals genetic complexity. Inflamm Bowel Dis 16:765-775. PMCID: PMC2857671
Jurisic G, Sundberg JP, Bleich A, Leiter EH, Broman KW, Buechler G, Alley L, Vestweber D, Detmar M. 2010. Quantitative lymphatic vessel trait analysis suggests Vcam1 as candidate modifier gene of inflammatory bowel disease. Genes Immun 11:219-231. PMCID: PMC2865135
Nicholson A, Reifsnyder PC, Malcolm RD, Lucas CA, MacGregor GR, Zhang We, Leiter EH. 2010. Diet-induced obesity in two C57BL/6 substrains with intact or mutant nicotinamide nucleotide transhydrogenase (Nnt) gene. Obesity. PMCID: PMC2888716
Leiter EH, Reifsnyder PC, Wallace R, Li R, King B, Churchill GC. 2009. NOD x 129.H2(g7) backcross delineates 129S1/SvlmJ-derived genomic regions modulating Type 1 diabetes (T1D) development in mice. Diabetes 58:1700-1703. PMCID: PMC2699846
Su Z, Ishimori N, Chen Y, Leiter EH, Churchill GA, Paigen B, Stylianou IM. 2009. Four additional mouse crosses improve the lipid QTL landscape and identify Lipg as a QTL gene. J Lipid Res 50:2083-2094. PMCID: PMC2739753
Leiter EH. 2009. Type 1 diabetes genes in rats: few or many? Diabetes 58:796-797. PMCID: PMC2661579
Chen J, Lu Y, Lee CH, Li R, Leiter EH, Mathews CE. 2008. Commonalities of genetic resistance to spontaneous autoimmune and free radical-mediated diabetes. Free Radic Biol Med. 45:1263-1270. PMCID: PMC2872108
Miller AL, Komak S, Webb MS, Leiter EH, Thompson EB. 2007. Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoids. Cancer Cell Int 7:18. PMCID: PMC2228275
Leiter EH, Reifsnyder P, Driver J, Kamdar S, Choisy-Rossi C, Serreze DV, Hara M, Chervonsky A. 2007. Unexpected functional consequences of xenogeneic transgene expression in beta-cells of NOD mice. Diabetes Obes Metab Suppl 2:14-22
Leiter EH, Reifsnyder PC, Xiao Q, Mistry J. 2007. Adipokine and insulin profiles distinguish diabetogenic and non-diabetogenic obesities in mice. Obesity 15(8):1961-1968.
Cho Y-R, Kim H-J, Park S-Y, Ko HJ, Hong E-G, Higashimori T, Zhang Z, Jung DY, Ola MS, LaNoue KF, Leiter EH, Kim JK. 2007. Hyperglycemia, maturity-onset obesity,and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes. Am J Physiol Endocrinol Metab 293:E327-E336.
Pan H-J, Agate DS, King BL, Roderick SL, Leiter EH, Cohen DE. 2006. A polymorphism in New Zealand inbred mouse strains that inactivates phosphatidylcholine transfer protein. FEBS Lett 580:5953-5958. PMCID: PMC1693963
Chen Y-G, Chen J, Osborne MA, Chapman HD, Besra GS, Porcelli SA, Leiter EH, Wilson SB, Serreze DV. 2006. CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice. J Immunol 177:2939-2947.
Hamano S, Asgharpour A, Stroup SE, Wynn TA, Leiter EH, Houpt E. 2006. Resistance of C57BL/6 mice to amoebiasis is mediated by nonhemopoietic cells but requires hemopoietic IL-10 production. J Immunol 177:1208-1213.
Pan HJ, Watkins S, Lin Y, Chen YE, Vance DE, Leiter EH. 2006. Adverse hepatic and cardiac responses to rosiglitazone in a new mouse model of type 2 diabetes: Relation to dysregulated phosphatidylcholine metabolism. Vasc Pharm 45:65-71.
Chen J, Chen Y-G, Reifsnyder PC, Schott WH, Lee C-H, Scheuplein F, Haag F, Koch-Nolte F, Serreze DV, Leiter EH. 2006. Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ART2-dependent fashion. J Immunol 176:4590-4599.
Lange C, Jeruschke K, Herberg L, Leiter EH, Junger E. 2006. The diabetes-prone NZO/HI strain. Proliferation capacity of beta cells in hyperinsulinemia and hyperglycemia. Arch Physiol Biochem 112:49-58.
Leiter, E. H., Reifsnyder, P. C., Pan, H. J., Xiao, Q., and Mistry, J. 2006. Differential endocrine responses to Rosiglitazone therapy in new mouse models of type 2 diabetes. Endocrinology 147:919-926.
Lee C-H, Chen Y-G, Chen J, Reifsnyder PC, Serreze DV, Clare-Salzler M, Rodriguez M, Wasserfall C, Atkinson MA, Leiter EH. 2006. Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression. II. Immunologic analysis. Diabetes 55:171-178.
Beckwith J, Cong Y, Sundberg JP, Elson CO, Leiter EH. 2005. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology 129:1473-1484.
Chen J, Reifsnyder PC, Scheuplein F, Schott WH, Mileikovsky M, Soodeen-Karamath S, Nagy A, Dosch MH, Ellis J, Koch-Nolte F, Leiter EH. 2005. "Agouti NOD": identification of a CBA-derived Idd locus on Chromosome 7 and its use for chimera production with NOD embryonic stem cells. Mamm Genome 16:775-783.
Lee, C. H., Reifsnyder, P. C., Naggert, J. K., Wasserfall, C., Atkinson, M. A.,Chen, J., and Leiter, E. H . 2005. Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: I. Pathophysiological analysis. Diabetes 54:2525-2532.
Reifsnyder, PC, Li, R, Silveira, P, Churchill, G, Serreze, DV, Leiter, EH. 2005. Conditioning the genome identifies additional diabetes resistance loci in Type 1 Diabetes resistant NOR/Lt mice. Genes Immun 6:528-538.
Mathews CE, Suarez-Pinzon WL, Baust JL, Strynadka K, Leiter EH, Rabinovitch A. 2005. Mechanisms underlying resistance of pancreatic islets from ALR/Lt mice to cytokine-mediated destruction. J Immunol 175:1248-1256.
Pan HJ, Reifsnyder P, Vance DE, Xiao Q, Leiter EH. 2005. Pharmacogenetic analysis of rosiglitazone-induced hepatosteatosis in new mouse models of type 2 diabetes. Diabetes 54(6):1854-1862.
Pomerleau DP, Bagley RJ, Serreze DV, Mathews CE, Leiter EH. 2005. Major histocompatibility complex-linked diabetes susceptibility in NOD/Lt mice: subcongenic analysis localizes a component of Idd16 at the H2-D end of the diabetogenic H2 g7 complex. Diabetes 54:1603-1606.
Kitiphongspattana K, Mathews CE, Leiter EH, Gaskins HR. 2005. Proteasome inhibition alters glucose-stimulated (pro)insulin secretion and turnover in pancreatic β-cells. J Biol Chem 280:15727-15734.
Krebs C, Adriouch S, Braasch F, Koestner W, Leiter EH, Seman M, Lund F, Oppenheimer N, Haag F, Koch-Nolte F. 2005. CD38 controls ART2-catalyzed ADP-ribosylation of T cell surface proteins. J. Immunol 174:3298-3305.
Kawamura H, Aswad F, Minagawa M, Malone K, Kaslow H, Koch-Nolte F, Schott WH, Leiter EH, Dennert G. 2005. P2X7 Receptor-dependent and -independent T cell death is induced by Nicotinamide Adenine Dinucleotide. J Immunol 174:1971-1979.
Mathews CE, Leiter EH, Spirina O, Bykhovskaya Y, Gusdon AM, Ringquist S, Fischel-Ghodsian N. 2005. mt-Nd2 Allele of the ALR/Lt mouse confers resistance against both chemically induced and autoimmune diabetes. Diabetologia 48:261-267.
Bleich A, Mahler M, Most C, Leiter EH, Liebler-Tenorio E, Elson CO, Hedrich HJ, Schlegelberger B, Sundberg JP. 2004. Refined histopathologic scoring system improves power to detect colitis QTL in mice. Mammalian Genome 15:865-871.
Xie J, Zhu H, Larade K, Ladoux A, Seguritan A, Chu M, Ito S, Bronson RT, Leiter EH, Zhang CY, Rosen ED. 2004. Absence of a reductase, NCB5OR, causes insulin-deficient diabetes. Proc Natl Acad Sci USA 101:10750-10755.
McInerney MF, Najjar SM, Brickley D, Lutzke M, Abou-Rjaily GA, Reifsnyder P, Haskell BD, Flurkey K, Zhang YJ, Pietropaolo SL, Pietropaolo M, Byers JP, Leiter EH. 2004. Anti-insulin receptor autoantibodies are not required for type 2 diabetes pathogenesis in NZL/Lt mice, a New Zealand obese (NZO)-derived mouse strain. Exp Diabesity Res 5(3):177-185.
Koza RA, Flurkey K, Graunke DM, Braun C, Pan HJ, Reifsnyder PC, Kozak LP, Leiter EH. 2004. Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/HlLt mice with polygenic obesity. Metabolism 53:799-808.
Schott WH, Haskell BD, Tse HM, Milton MJ, Piganelli JD, Choisy-Rossi CM, Reifsnyder PC, Chervonsky AV, Leiter EH. 2004. Caspase-1 is not required for type 1 diabetes in the NOD mouse. Diabetes 53:99-104.
BOOKS, BOOK CHAPTER, AND REVIEWS
Brosius FC 3rd, Alpers CE, Bottinger EP, Breyer MD, Coffman TM, Gurley SB, Harris RC, Kakoki M, Kretzler M, Leiter EH, Levi M, McIndoe RA, Sharma K, Smithies O, Susztak K, Takahashi N, Takahashi T, and for the Animal Models of Diabetic Complications Consortium. 2009. Mouse models of diabetic nephropathy. J Am Soc Nephrol 20:2503-2512. Review
Daneshgari F, Leiter EH, Liu G, Reeder J. 2009. Animal models of diabetic uropathy. J Urol 182(6 Suppl):S8-13. Review
Leiter EH. 2009. Selecting the "right" mouse model for metabolic syndrome and type 2 diabetes research. Methods Mol Biol 560:1-17. Book chapter
Reifsnyder P, Schott W, Pomerleau D, Lessard MD, Soper BW, Leiter EH. 2008. Bone marrow expressing a diabetes resistance MHC class II allele: Diabetes deviation by chronic immune stimulation. In: Novartis Foundation Symposia 292. Defining optimal immunotherapies for type 1 diabetes. John Wiley and Sons, Inc 32-46; DISCUSSION 46-49,122-129, 202-203. Book chapter
Chua S, Herberg L, Leiter EH. 2007. Obesity/diabetes in mice with mutations in leptin or leptin receptor genes. In: Animal Models of Diabetes: Frontiers in Research. Shafrir E, (ed). CRC-Taylor and Francis Press, Boca Raton FL.
Matarese G, Leiter EH, Cava AL. 2007. Leptin in autoimmunity: many questions, some answers. Tissue Antigens 70:87-95.
Leiter, E. H., and Lee, C.-H. 2005. Mouse models and the genetics of diabetes: Is there evidence for genetic overlap between type 1 and type 2 diabetes? Diabetes 54:S151-S158.
Leiter EH. 2005. Nonobese diabetic (NOD) mice and the genetics of diabetes susceptibility. Curr Diab Rep 2:141-148.
Leiter EH, Reifsnyder PC. 2004. Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes. Diabetes 53:S4-S11.
Leiter EH, von Herrath M. 2004. Animal models have little to teach us about type 1 diabetes: 2. In opposition to this proposal. Diabetologia 47:1657-1660.
Mathews CE, Bagley R, Leiter EH. 2004. ALS/Lt: A new type 2 diabetes mouse model associated with low free radical scavenging potential. Diabetes 53:S125-S129.
Leiter EH, Reifsnyder PC. 2004. Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes. Diabetes 53 Suppl 1: S4-11.
Mathews CE, Leiter EH. 2004. Rodent models of spontaneous diabetes. In: Joslin's Diabetes Mellitus, 14th edition, Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ (eds). Lippincott Williams & Wilkins, Philadelphia, pp.291-327.