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Metabolomics

, Volume 11, Issue 2, pp 425–437 | Cite as

Diabetes associated metabolomic perturbations in NOD mice

  • Dmitry Grapov
  • Johannes Fahrmann
  • Jessica Hwang
  • Ananta Poudel
  • Junghyo Jo
  • Vipul Periwal
  • Oliver Fiehn
  • Manami HaraEmail author
Original Article

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.

Keywords

Type 1 diabetes Pancreatic beta-cells Beta-cell loss Metabolomics 

Notes

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.

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

Supplementary material

11306_2014_706_MOESM1_ESM.docx (102 kb)
Supplementary material 1 (DOCX 101 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Dmitry Grapov
    • 1
  • Johannes Fahrmann
    • 1
  • Jessica Hwang
    • 2
  • Ananta Poudel
    • 2
  • Junghyo Jo
    • 3
    • 4
  • Vipul Periwal
    • 3
  • Oliver Fiehn
    • 1
  • Manami Hara
    • 2
    Email author
  1. 1.NIH West Coast Metabolomics CenterUniversity of California DavisDavisUSA
  2. 2.Department of MedicineThe University of ChicagoChicagoUSA
  3. 3.Laboratory of Biological ModelingNational Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthBethesdaUSA
  4. 4.Asia Pacific Center for Theoretical PhysicsPohangKorea

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