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

19 Citations (Scopus)

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

Fingerprint

Inbred NOD Mouse
Metabolomics
Medical problems
Type 1 Diabetes Mellitus
Animals
Pancreas
Glucaric Acid
Allantoin
Nitric Acid
Branched Chain Amino Acids
Endoplasmic Reticulum Stress
Metabolome
Isoleucine
Valine
Green Fluorescent Proteins
Oxidative stress
Unsaturated Fatty Acids
Lymphocytes
Arachidonic Acid
Gas Chromatography

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

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

Diabetes associated metabolomic perturbations in NOD mice. / Grapov, Dmitry; Fahrmann, Johannes; Hwang, Jessica; Poudel, Ananta; Jo, Junghyo; Periwal, Vipul; Fiehn, Oliver; Hara, Manami.

In: Metabolomics, Vol. 11, No. 2, 01.04.2015, p. 425-437.

Research output: Contribution to journalArticle

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, vol. 11, no. 2, pp. 425-437. https://doi.org/10.1007/s11306-014-0706-2
Grapov D, Fahrmann J, Hwang J, Poudel A, Jo J, Periwal V et al. Diabetes associated metabolomic perturbations in NOD mice. Metabolomics. 2015 Apr 1;11(2):425-437. https://doi.org/10.1007/s11306-014-0706-2
Grapov, Dmitry ; Fahrmann, Johannes ; Hwang, Jessica ; Poudel, Ananta ; Jo, Junghyo ; Periwal, Vipul ; Fiehn, Oliver ; Hara, Manami. / Diabetes associated metabolomic perturbations in NOD mice. In: Metabolomics. 2015 ; Vol. 11, No. 2. pp. 425-437.
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