@article{10.1371/journal.pcbi.1002257, doi = {10.1371/journal.pcbi.1002257}, author = {Sysi-Aho, Marko AND Ermolov, Andrey AND Gopalacharyulu, Peddinti V. AND Tripathi, Abhishek AND Seppänen-Laakso, Tuulikki AND Maukonen, Johanna AND Mattila, Ismo AND Ruohonen, Suvi T. AND Vähätalo, Laura AND Yetukuri, Laxman AND Härkönen, Taina AND Lindfors, Erno AND Nikkilä, Janne AND Ilonen, Jorma AND Simell, Olli AND Saarela, Maria AND Knip, Mikael AND Kaski, Samuel AND Savontaus, Eriika AND Orešič, Matej}, journal = {PLOS Computational Biology}, publisher = {Public Library of Science}, title = {Metabolic Regulation in Progression to Autoimmune Diabetes}, year = {2011}, month = {10}, volume = {7}, url = {https://doi.org/10.1371/journal.pcbi.1002257}, pages = {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.}, number = {10}, }