Diabetes associated metabolomic perturbations in NOD mice

Dmitry Grapov, Johannes Fahrmann, Jessica Hwang, Ananta Poudel, Junghyo Jo, Vipul Periwal, Oliver Fiehn, Manami Hara

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)425-437
Number of pages13
JournalMetabolomics
Volume11
Issue number2
DOIs
StatePublished - Apr 1 2015

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

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    Grapov, D., Fahrmann, J., Hwang, J., Poudel, A., Jo, J., Periwal, V., Fiehn, O., & Hara, M. (2015). Diabetes associated metabolomic perturbations in NOD mice. Metabolomics, 11(2), 425-437. https://doi.org/10.1007/s11306-014-0706-2