Role of genetics in resistance to type 1 diabetes

Background A single nucleotide polymorphism in the mitochondrial gene encoding NADH dehydrogenase subunit 2 (mt-ND2) has been associated with reduced incidence of human type 1 diabetes (T1D). We identified the orthologue of this mitochondrial single nucleotide polymorphism in mouse and using NOD mouse models linked this genetic polymorphism to T1D resistance. The mechanism how this single nucleotide polymorphism affects the development of diabetes is studied using mouse models and beta cell lines. Methods The impact of this single nucleotide polymorphism on mitochondrial function and resistance to reactive oxygen species was assessed. For these studies we measured oxygen consumption by isolated mitochondria under different doses of nitric oxide. In addition, alloxan sensitivity of beta cell lines was tested using the MTT method to measure cell survival. Results mt-Nd2(a) is associated with protection against mouse T1D and alloxan-induced diabetes. Mice with mt-Nd2(a) exhibited resistance to transfer of diabetes by single clone of diabetogenic CD4(+) or CD8(+) T cells. Beta cell line with mt-Nd2(a) resist in vitro attack of diabetogenic CD8(+) cytotoxic T cells, as well as free radicals generated by alloxan; isolated mitochondria with mt-Nd2(a) showed lower reactive oxygen species production and were more resistant to nitric oxide. Conclusion mt-Nd2(a) protects against T1D in mouse models. The protection is at beta cell level and is associated with resistance against reactive oxygen species-mediated damage and death. Copyright (C) 2011 John Wiley & Sons, Ltd.