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Grapov D, Fahrmann J, Hwang J, et al. Diabetes Associated Metabolomic Perturbations in NOD Mice. Metabolomics. 2015;11(2):425-437doi: 10.1007/s11306-014-0706-2.
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 : Official journal of the Metabolomic Society, 11(2), 425-437. https://doi.org/10.1007/s11306-014-0706-2
Grapov, Dmitry, et al. "Diabetes Associated Metabolomic Perturbations in NOD Mice." Metabolomics : Official journal of the Metabolomic Society vol. 11,2 (2015): 425-437. doi: https://doi.org/10.1007/s11306-014-0706-2
Grapov D, Fahrmann J, Hwang J, Poudel A, Jo J, Periwal V, Fiehn O, Hara M. Diabetes Associated Metabolomic Perturbations in NOD Mice. Metabolomics. 2015 Apr;11(2):425-437. doi: 10.1007/s11306-014-0706-2. PMID: 25755629; PMCID: PMC4351755.
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Metabolomics. 2015 Apr;11(2):425-437. doi: 10.1007/s11306-014-0706-2.

Diabetes Associated Metabolomic Perturbations in NOD Mice.

Metabolomics : Official journal of the Metabolomic Society

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

Affiliations

  1. NIH West Coast Metabolomics Center, University of California Davis, Davis, California.
  2. Department of Medicine, The University of Chicago, Chicago, Illinois.
  3. Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.

PMID: 25755629 PMCID: PMC4351755 DOI: 10.1007/s11306-014-0706-2

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.

Keywords: Beta-cell loss; Metabolomics; Pancreatic beta-cells; Type 1 diabetes

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