Metabolic Regulation in Progression to Autoimmune Diabetes

Marko Sysi-Aho, Andrey Ermolov, Peddinti V Gopalacharyulu, Abhishek Tripathi, Tuulikki Seppänen-Laakso, Johanna Maukonen, Ismo Mattila, Suvi T Ruohonen, Laura Vähätalo, Laxman Yetukuri, Taina Härkönen, Erno Lindfors, Janne Nikkilä, Jorma Ilonen, Olli Simell, Maria Saarela, Mikael Knip, Samuel Kaski, Eriika Savontaus and Matej Orešič

PLOS Computational Biology, 2011, vol. 7, issue 10, 1-16

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. Author Summary: We have recently found that distinct metabolic disturbances precede β-cell autoimmunity in children who later progress to type 1 diabetes (T1D). Here we performed a murine study using non-obese diabetic (NOD) mice that recapitulated the protocol used in human, followed up by independent studies where NOD mice were studied in relation to risk of diabetes progression. We found that young 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, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum subgroup. The metabolic phenotypes observed in our study could be relevant as end points for studies investigating T1D pathogenesis and/or responses to interventions. By proceeding from a clinical study via metabolomics and modeling to an experimental model using a similar study design, then evolving further to tissue-specific studies, we hereby also present a conceptually novel approach to reversed translation that may be useful in future therapeutic studies in the context of prevention and treatment of T1D as well as of other diseases characterized by long prodromal periods.

Date: 2011
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1002257

DOI: 10.1371/journal.pcbi.1002257

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