title: Role of genetics in resistance to type 1 diabetes.
abstract: 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-Nd2a is associated with protection against mouse T1D and alloxan-induced diabetes. Mice with mt-Nd2a exhibited resistance to transfer of diabetes by single clone of diabetogenic CD4+ or CD8+ T cells. Beta cell line with mt-Nd2a resist in vitro attack of diabetogenic CD8+ cytotoxic T cells, as well as free radicals generated by alloxan; isolated mitochondria with mt-Nd2a showed lower reactive oxygen species production and were more resistant to nitric oxide.
  
  
  CONCLUSIONS
  mt-Nd2a 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.
authors: Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
authors: Jing
authors: J
authors: Chen
authors: Aaron M
authors: AM
authors: Gusdon
authors: Clayton E
authors: CE
authors: Mathews
mesh_terms: D000496:Alloxan / Q000633:toxicity; D000818:Animals; D004268:DNA-Binding Proteins; D003921:Diabetes Mellitus, Experimental / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D029721:Drosophila Proteins; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; C460142:Su(Tpl) protein, Drosophila; D014157:Transcription Factors; D000496:Alloxan; D009245:NADH Dehydrogenase; C502385:mt-Nd2 protein, mouse