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, Matej Orešič

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.