title: Lipidomic and metabolomic characterization of a genetically modified mouse model of the early stages of human type 1 diabetes pathogenesis.
abstract: The early mechanisms regulating progression towards beta cell failure in type 1 diabetes (T1D) are poorly understood, but it is generally acknowledged that genetic and environmental components are involved. The metabolomic phenotype is sensitive to minor variations in both, and accordingly reflects changes that may lead to the development of T1D. We used two different extraction methods in combination with both liquid- and gas chromatographic techniques coupled to mass spectrometry to profile the metabolites in a transgenic non-diabetes prone C57BL/6 mouse expressing CD154 under the control of the rat insulin promoter (RIP) crossed into the immuno-deficient recombination-activating gene (RAG) knockout (-/-) C57BL/6 mouse, resembling the early stages of human T1D. We hypothesized that alterations in the metabolomic phenotype would characterize the early pathogenesis of T1D, thus metabolomic profiling could provide new insight to the development of T1D. Comparison of the metabolome of the RIP CD154 × RAG-/-mice to RAG-/-mice and C57BL/6 mice revealed alterations of >100 different lipids and metabolites in serum. Low lysophosphatidylcholine levels, accumulation of ceramides as well as methionine deficits were detected in the pre-type 1 diabetic mice. Additionally higher lysophosphatidylinositol levels and low phosphatidylglycerol levels where novel findings in the pre-type 1 diabetic mice. These observations suggest that metabolomic disturbances precede the onset of T1D.
authors.affiliation: Pediatric Department, Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.
authors.forename: Anne Julie
authors.initials: AJ
authors.lastname: Overgaard
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Weir
authors.affiliation: Metabolomics Australia, Bio21 Institute, University of Melbourne, Parkville, Melbourne, Australia.
authors.forename: David Peter
authors.initials: DP
authors.lastname: De Souza
authors.affiliation: Metabolomics Australia, Bio21 Institute, University of Melbourne, Parkville, Melbourne, Australia.
authors.forename: Dedreia
authors.initials: D
authors.lastname: Tull
authors.affiliation: Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Haase
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Australia ; Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: Pediatric Department, Herlev Hospital, Herlev Ringvej 75, 2730 Herlev, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
keywords: Lipidomics; Metabolomics; Type 1 diabetes