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Diabetes associated metabolomic perturbations in NOD mice

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Abstract

Non-obese diabetic (NOD) mice are a widely-used model of type 1 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 expressing green 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 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-week). 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 acid-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.

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Acknowledgments

The study is supported as a pilot project by the West Coast Metabolomics Center,US Public Health Service Grant DK097154 (to OF); DK-020595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, AG-042151, and a gift from the Kovler Family Foundation (to MH); and the Intramural research program of the NIH, NIDDK (to VP). The authors thank Mrs. German Kilimnik, Billy Zhao and Mark Zielinski, and Drs. Xioajun Wang and Ryosuke Misawa at the University of Chicagofor the technical assistance.

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  1. Junghyo Jo

    Present address: Asia Pacific Center for Theoretical Physics, Pohang, Korea

Authors and Affiliations

  1. NIH West Coast Metabolomics Center, University of California Davis, Davis, CA, USA

    Dmitry Grapov, Johannes Fahrmann & Oliver Fiehn

  2. Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL, MC1027, USA

    Jessica Hwang, Ananta Poudel & Manami Hara

  3. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Junghyo Jo & Vipul Periwal

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  1. Dmitry Grapov
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Correspondence to Manami Hara.

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Dmitry Grapov and Johannes Fahrmann have contributed equally to this work.

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Grapov, D., Fahrmann, J., Hwang, J. et al. Diabetes associated metabolomic perturbations in NOD mice. Metabolomics 11, 425–437 (2015). https://doi.org/10.1007/s11306-014-0706-2

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