title: Elevated systemic glutamic acid level in the non-obese diabetic mouse is Idd linked and induces beta cell apoptosis.
abstract: Although type 1 diabetes (T1D) is a T-cell-mediated disease in the effector stage, the mechanism behind the initial beta cell assault is less understood. Metabolomic differences, including elevated levels of glutamic acid, have been observed in patients with T1D before disease onset, as well as in pre-diabetic non-obese diabetic (NOD) mice. Increased levels of glutamic acid damage both neurons and beta cells, implying that this could contribute to the initial events of T1D pathogenesis. We investigated the underlying genetic factors and consequences of the increased levels of glutamic acid in NOD mice. Serum glutamic acid levels from a (NOD×B6)F2cohort (n = 182) were measured. By genome-wide and Idd region targeted microsatellite mapping, genetic association was detected for six regions including Idd2, Idd4 and Idd22. In silico analysis of potential enzymes and transporters located in and around the mapped regions that are involved in glutamic acid metabolism consisted of alanine aminotransferase, glutamic-oxaloacetic transaminase, aldehyde dehydrogenase 18 family, alutamyl-prolyl-tRNA synthetase, glutamic acid transporters GLAST and EAAC1. Increased EAAC1 protein expression was observed in lysates from livers of NOD mice compared with B6 mice. Functional consequence of the elevated glutamic acid level in NOD mice was tested by culturing NOD. Rag2-/-Langerhans' islets with glutamic acid. Induction of apoptosis of the islets was detected upon glutamic acid challenge using TUNEL assay. Our results support the notion that a dysregulated metabolome could contribute to the initiation of T1D. We suggest that targeting of the increased glutamic acid in pre-diabetic patients could be used as a potential therapy.
authors.affiliation: Division of Immunology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Viqar Showkat
authors.initials: VS
authors.lastname: Banday
authors.affiliation: Division of Immunology, Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lejon
mesh_terms: D000410:Alanine Transaminase / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007515:Islets of Langerhans / Q000502:physiology*; D055442:Metabolome / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D018895:Microsatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D004268:DNA-Binding Proteins; D027341:Excitatory Amino Acid Transporter 1; D050580:Excitatory Amino Acid Transporter 3; C499308:Rag2 protein, mouse; C493399:Slc1a1 protein, mouse; C493393:Slc1a3 protein, mouse; D018698:Glutamic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: 
  Idd
  ; beta cell apoptosis; genetics; glutamic acid; non-obese diabetic mice