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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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References

  • Adeva, M. M., Calvino, J., Souto, G., & Donapetry, C. (2012). Insulin resistance and the metabolism of branched-chain amino acids in humans. Amino Acids, 43, 171–181.

    Article  CAS  PubMed  Google Scholar 

  • Akirav, E., Kushner, J. A., & Herold, K. C. (2008). Beta-cell mass and type 1 diabetes: Going, going, gone? Diabetes, 57, 2883–2888.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bankar, S. B., Bule, M. V., Singhal, R. S., & Ananthanarayan, L. (2009). Glucose oxidase: An overview. Biotechnology Advances, 27, 489–501.

    Article  CAS  PubMed  Google Scholar 

  • Barupal, D. K., Haldiya, P. K., Wohlgemuth, G., Kind, T., Kothari, S. L., Pinkerton, K. E., et al. (2012). MetaMapp: Mapping and visualizing metabolomic data by integrating information from biochemical pathways and chemical and mass spectral similarity. BMC Bioinformatics, 13, 99.

    Article  PubMed Central  PubMed  Google Scholar 

  • Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B-Methodological, 57, 289–300.

    Google Scholar 

  • Bolton, E. E., Chen, J., Kim, S., Han, L., He, S., Shi, W., et al. (2011). PubChem3D: A new resource for scientists. Journal of Cheminformatics, 3, 32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Castelo, R., & Roverato, A. (2009). Reverse engineering molecular regulatory networks from microarray data with qp-graphs. Journal of Computational Biology, 16, 213–227.

    Article  CAS  PubMed  Google Scholar 

  • Chen, M., Yang, Z. D., Smith, K. M., Carter, J. D., & Nadler, J. L. (2005). Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity. Diabetologia, 48, 486–495.

    Article  CAS  PubMed  Google Scholar 

  • Davidson, M. B., & Schriger, D. L. (2010). Effect of age and race/ethnicity on HbA1c levels in people without known diabetes mellitus: implications for the diagnosis of diabetes. Diabetes Research and Clinical Practice, 87, 415–421.

    Article  PubMed  Google Scholar 

  • Dutta, T., Chai, H. S., Ward, L. E., Ghosh, A., Persson, X. M., Ford, G. C., et al. (2012). Concordance of changes in metabolic pathways based on plasma metabolomics and skeletal muscle transcriptomics in type 1 diabetes. Diabetes, 61, 1004–1016.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fiehn, O., Wohlgemuth, G., & Scholz, M. (2005). Setup and annotation of metabolomic experiments by integrating biological and mass spectrometric metadata. In B. Ludäscher & L. Raschid (Eds.), Lecture Notes in Computer Science (Vol. 3615, pp. 224–239)., Data integration in the life sciences Berlin Heidelberg: Springer.

    Google Scholar 

  • Fiehn, O., Wohlgemuth, G., Scholz, M., Kind, T., Lee do, Y., Lu, Y., et al. (2008). Quality control for plant metabolomics: Reporting MSI-compliant studies. Plant Journal, 53, 691–704.

    Article  CAS  PubMed  Google Scholar 

  • Gianani, R., Campbell-Thompson, M., Sarkar, S. A., Wasserfall, C., Pugliese, A., Solis, J. M., et al. (2010). Dimorphic histopathology of long-standing childhood-onset diabetes. Diabetologia, 53, 690–698.

    Article  CAS  PubMed  Google Scholar 

  • Grapov, D., Adams, S. H., Pedersen, T. L., Garvey, W. T., & Newman, J. W. (2012). Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids. PLoS One, 7, e48852.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Heitmeier, M. R., Kelly, C. B., Ensor, N. J., Gibson, K. A., Mullis, K. G., Corbett, J. A., et al. (2004). Role of cyclooxygenase-2 in cytokine-induced beta-cell dysfunction and damage by isolated rat and human islets. Journal of Biological Chemistry, 279, 53145–53151.

    Article  CAS  PubMed  Google Scholar 

  • Holohan, C., Szegezdi, E., Ritter, T., O’Brien, T., & Samali, A. (2008). Cytokine-induced beta-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL. Journal of Cellular and Molecular Medicine, 12, 591–606.

    Article  CAS  PubMed  Google Scholar 

  • Jo, J., Kilimnik, G., Kim, A., Guo, C., Periwal, V., & Hara, M. (2011). Formation of pancreatic islets involves coordinated expansion of small islets and fission of large interconnected islet-like structures. Biophysical Journal, 101, 565–574.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Juraschek, S. P., Steffes, M. W., Miller, E. R, 3rd, & Selvin, E. (2012). Alternative markers of hyperglycemia and risk of diabetes. Diabetes Care, 35, 2265–2270.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kacheva, S., Lenzen, S., & Gurgul-Convey, E. (2011). Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide. Cytokine, 55, 195–201.

    Article  CAS  PubMed  Google Scholar 

  • Kalogeropoulou, D., LaFave, L., Schweim, K., Gannon, M. C., & Nuttall, F. Q. (2009). Lysine ingestion markedly attenuates the glucose response to ingested glucose without a change in insulin response. American Journal of Clinical Nutrition, 90, 314–320.

    Article  CAS  PubMed  Google Scholar 

  • Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., & Tanabe, M. (2012). KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Research, 40(Database issue), D109–D114.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kawasaki, H., Hori, T., Nakajima, M., & Takeshita, K. (1988). Plasma levels of pipecolic acid in patients with chronic liver disease. Hepatology, 8, 286–289.

    Article  CAS  PubMed  Google Scholar 

  • Kilimnik, G., Jo, J., Periwal, V., Zielinski, M. C., & Hara, M. (2012). Quantification of islet size and architecture. Islets, 4, 167–172.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kilimnik, G., Kim, A., Jo, J., Miller, K., & Hara, M. (2009). Quantification of pancreatic islet distribution in situ in mice. American Journal of Physiology - Endocrinology and Metabolism, 297, E1331–E1338.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim, A., Miller, K., Jo, J., Kilimnik, G., Wojcik, P., & Hara, M. (2009). Islet architecture: A comparative study. Islets, 1, 129–136.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kolb, H., & Kolb-Bachofen, V. (1992). Type 1 (insulin-dependent) diabetes mellitus and nitric oxide. Diabetologia, 35, 796–797.

    CAS  PubMed  Google Scholar 

  • Lanza, I. R., Zhang, S., Ward, L. E., Karakelides, H., Raftery, D., & Nair, K. S. (2010). Quantitative metabolomics by H-NMR and LC-MS/MS confirms altered metabolic pathways in diabetes. PLoS One, 5, e10538.

    Article  PubMed Central  PubMed  Google Scholar 

  • Lebastchi, J., & Herold, K. C. (2012). Immunologic and metabolic biomarkers of beta-cell destruction in the diagnosis of type 1 diabetes. Cold Spring Harbor Perspectives in Medicine, 2, a007708.

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu, Z., Jeppesen, P. B., Gregersen, S., Chen, X., & Hermansen, K. (2008). Dose- and glucose-dependent effects of amino acids on insulin secretion from isolated mouse islets and clonal INS-1E beta-cells. Review of Diabetic Studies, 5, 232–244.

    Article  PubMed Central  PubMed  Google Scholar 

  • Lu, J., Zhou, J., Bao, Y., Chen, T., Zhang, Y., Zhao, A., et al. (2012). Serum metabolic signatures of fulminant type 1 diabetes. Journal of Proteome Research, 11, 4705–4711.

    Article  CAS  PubMed  Google Scholar 

  • Madsen, R., Banday, V. S., Moritz, T., Trygg, J., & Lejon, K. (2012). Altered metabolic signature in pre-diabetic NOD mice. PLoS One, 7, e35445.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maritim, A. C., Sanders, R. A., & Watkins, J. B, 3rd. (2003). Diabetes, oxidative stress, and antioxidants: A review. Journal of Biochemical and Molecular Toxicology, 17, 24–38.

    Article  CAS  PubMed  Google Scholar 

  • McKillop, A. M., & Flatt, P. R. (2011). Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine. Diabetes Care, 34, 2624–2630.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Meier, J. J., Bhushan, A., Butler, A. E., Rizza, R. A., & Butler, P. C. (2005). Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: Indirect evidence for islet regeneration? Diabetologia, 48, 2221–2228.

    Article  CAS  PubMed  Google Scholar 

  • Miller, K., Kim, A., Kilimnik, G., Jo, J., Moka, U., Periwal, V., et al. (2009). Islet formation during the neonatal development in mice. PLoS One, 4, e7739.

    Article  PubMed Central  PubMed  Google Scholar 

  • Mori, M. (2007). Regulation of nitric oxide synthesis and apoptosis by arginase and arginine recycling. Journal of Nutrition, 137, 1616S–1620S.

    CAS  PubMed  Google Scholar 

  • Nakagawa, Y., & Ishii, E. (1996). Changes in arachidonic acid metabolism and the aggregation of polymorphonuclear leukocytes in rats with streptozotocin-induced diabetes. Biochimica et Biophysica Acta, 1315, 145–151.

    Article  PubMed  Google Scholar 

  • Newgard, C. B. (2012). Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metabolism, 15, 606–614.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nokoff, N., & Rewers, M. (2013). Pathogenesis of type 1 diabetes: Lessons from natural history studies of high-risk individuals. Annals of the New York Academy of Sciences, 1281, 1–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oresic, M., Seppanen-Laakso, T., Sun, D., Tang, J., Therman, S., Viehman, R., et al. (2012). Phospholipids and insulin resistance in psychosis: A lipidomics study of twin pairs discordant for schizophrenia. Genome Medicine, 4, 1.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oresic, M., Simell, S., Sysi-Aho, M., Nanto-Salonen, K., Seppanen-Laakso, T., Parikka, V., et al. (2008). Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. Journal of Experimental Medicine, 205, 2975–2984.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Oyadomari, S., Takeda, K., Takiguchi, M., Gotoh, T., Matsumoto, M., Wada, I., et al. (2001). Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proceedings of the National Academy of Sciences USA, 98, 10845–10850.

    Article  CAS  Google Scholar 

  • Palermo, G., Piraino, P., & Zucht, H. D. (2009). Performance of PLS regression coefficients in selecting variables for each response of a multivariate PLS for omics-type data. Advances and Applications in Bioinformatics and Chemistry, 2, 57–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parazzoli, S., Harmon, J. S., Vallerie, S. N., Zhang, T., Zhou, H., & Robertson, R. P. (2012). Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1beta-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets. Journal of Biological Chemistry, 287, 32246–32253.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pflueger, M., Seppanen-Laakso, T., Suortti, T., Hyotylainen, T., Achenbach, P., Bonifacio, E., et al. (2011). Age- and islet autoimmunity-associated differences in amino acid and lipid metabolites in children at risk for type 1 diabetes. Diabetes, 60, 2740–2747.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • R Development Core Team. R: A language and environment for statistical computing. (2011). R Foundation for Statistical Computing, ISBN 3-900051-900007-900050.

  • Robinson, T. W., & Freedman, B. I. (2013). Assessing glycemic control in diabetic patients with severe nephropathy. Journal of Renal Nutrition, 23, 199–202.

    Article  CAS  PubMed  Google Scholar 

  • Sampson, S. R., Bucris, E., Horovitz-Fried, M., Parnas, A., Kahana, S., Abitbol, G., et al. (2010). Insulin increases H2O2-induced pancreatic beta cell death. Apoptosis, 15, 1165–1176.

    Article  CAS  PubMed  Google Scholar 

  • Scholz, M., & Fiehn, O. (2007). SetupX: A public study design database for metabolomic projects. Pacific Symposium on Biocomputing, 12, 169–180.

    Google Scholar 

  • Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., et al. (2003). Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Research, 13, 2498–2504.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smith, T. N., Hash, K., Davey, C. L., Mills, H., Williams, H., & Kiely, D. E. (2012). Modifications in the nitric acid oxidation of d-glucose. Carbohydrate Research, 350, 6–13.

    Article  CAS  PubMed  Google Scholar 

  • Southern, C., Schulster, D., & Green, I. C. (1990). Inhibition of insulin secretion by interleukin-1 beta and tumour necrosis factor-alpha via an l-arginine-dependent nitric oxide generating mechanism. FEBS Letters, 276, 42–44.

    Article  CAS  PubMed  Google Scholar 

  • Standards of medical care in diabetes 2013. (2013). Diabetes Care, 36, S11.

    Article  Google Scholar 

  • Stojanovic, V., & Ihle, S. (2011). Role of beta-hydroxybutyric acid in diabetic ketoacidosis: A review. Canadian Veterinary Journal, 52, 426–430.

    CAS  Google Scholar 

  • Strimmer, K. (2008). fdrtool: A versatile R package for estimating local and tail area-based false discovery rates. Bioinformatics, 24, 1461–1462.

    Article  CAS  PubMed  Google Scholar 

  • Svensson, O., Kourti, T., & MacGregor, J. F. (2002). An investigation of orthogonal signal correction algorithms and their characteristics. Journal of Chemometrics, 16, 176–188.

    Article  CAS  Google Scholar 

  • Sysi-Aho, M., Ermolov, A., Gopalacharyulu, P. V., Tripathi, A., Seppanen-Laakso, T., Maukonen, J., et al. (2011). Metabolic regulation in progression to autoimmune diabetes. PLoS Computational Biology, 7, e1002257.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tran, P. O., Gleason, C. E., & Robertson, R. P. (2002). Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function. Diabetes, 51, 1772–1778.

    Article  CAS  PubMed  Google Scholar 

  • Wang, T. J., Larson, M. G., Vasan, R. S., Cheng, S., Rhee, E. P., McCabe, E., et al. (2011). Metabolite profiles and the risk of developing diabetes. Nature Medicine, 17, 448–453.

    Article  PubMed Central  PubMed  Google Scholar 

  • Wiklund, S., Johansson, E., Sjostrom, L., Mellerowicz, E. J., Edlund, U., Shockcor, J. P., et al. (2008). Visualization of GC/TOF-MS-based metabolomics data for identification of biochemically interesting compounds using OPLS class models. Analytical Chemistry, 80, 115–122.

    Article  CAS  PubMed  Google Scholar 

  • Ziemer, D. C., Kolm, P., Weintraub, W. S., Vaccarino, V., Rhee, M. K., Twombly, J. G., et al. (2010). Glucose-independent, black-white differences in hemoglobin A1c levels: A cross-sectional analysis of 2 studies. Annals of Internal Medicine, 152, 770–777.

    Article  PubMed  Google Scholar 

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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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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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