Metabolic regulation in progression to autoimmune diabetes

Marko Sysi-Aho, A. Erlomov, Peddinti Gopalacharyulu, A. Tripathi, Tuulikki Seppänen-Laakso, Johanna Maukonen, Ismo Mattila, S.T. Ruohonen, L. Vähätalo, Laxman Yetukuri, T. Härkönen, Erno Lindfors, J. Nikkilä, J. Ilonen, O. Simell, Maria Saarela, M. Knip, Samuel Kaski, E. Savontaus, Matej Orešič (Corresponding Author)

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Abstract

Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.
Original languageEnglish
Article numbere1002257
Number of pages16
JournalPLoS Computational Biology
Volume7
Issue number10
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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    Sysi-Aho, M., Erlomov, A., Gopalacharyulu, P., Tripathi, A., Seppänen-Laakso, T., Maukonen, J., Mattila, I., Ruohonen, S. T., Vähätalo, L., Yetukuri, L., Härkönen, T., Lindfors, E., Nikkilä, J., Ilonen, J., Simell, O., Saarela, M., Knip, M., Kaski, S., Savontaus, E., & Orešič, M. (2011). Metabolic regulation in progression to autoimmune diabetes. PLoS Computational Biology, 7(10), [e1002257]. https://doi.org/10.1371/journal.pcbi.1002257