title: Diabetes Associated Metabolomic Perturbations in NOD Mice.
abstract: Non-obese diabetic (NOD) mice are a widely-used model oftype1 diabetes (T1D). However, not all animals develop overt diabetes. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressinggreen fluorescent protein under the control of mouse insulin I promoter.While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue;overt T1D did not develop until animals lost ~70% of the total beta-cell mass.Gas chromatography time of flight mass spectrometry (GC-TOF) was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n=76) across a wide range of ages (neonates to >40-wk).Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals' metabolic profiles. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control; (2) increased allantoin, gluconic acid and nitric oxide-derived saccharic acid markers of oxidative stress; (3) reduced lysine, an insulin secretagogue; (4) increased branched-chain amino acids, isoleucine and valine; (5) reduced unsaturated fatty acids including arachidonic acid; and (6)perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression.
authors.affiliation: NIH West Coast Metabolomics Center, University of California Davis, Davis, California.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Grapov
authors.affiliation: NIH West Coast Metabolomics Center, University of California Davis, Davis, California.
authors.forename: Johannes
authors.initials: J
authors.lastname: Fahrmann
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hwang
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Ananta
authors.initials: A
authors.lastname: Poudel
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Junghyo
authors.initials: J
authors.lastname: Jo
authors.affiliation: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Vipul
authors.initials: V
authors.lastname: Periwal
authors.affiliation: NIH West Coast Metabolomics Center, University of California Davis, Davis, California.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors.forename: Manami
authors.initials: M
authors.lastname: Hara
keywords: Beta-cell loss; Metabolomics; Pancreatic beta-cells; Type 1 diabetes