title: Metabolic regulation in progression to autoimmune diabetes.
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.
authors: VTT Technical Research Centre of Finland, Espoo, Finland.
authors: Marko
authors: M
authors: Sysi-Aho
authors: Andrey
authors: A
authors: Ermolov
authors: Peddinti V
authors: PV
authors: Gopalacharyulu
authors: Abhishek
authors: A
authors: Tripathi
authors: Tuulikki
authors: T
authors: Seppänen-Laakso
authors: Johanna
authors: J
authors: Maukonen
authors: Ismo
authors: I
authors: Mattila
authors: Suvi T
authors: ST
authors: Ruohonen
authors: Laura
authors: L
authors: Vähätalo
authors: Laxman
authors: L
authors: Yetukuri
authors: Taina
authors: T
authors: Härkönen
authors: Erno
authors: E
authors: Lindfors
authors: Janne
authors: J
authors: Nikkilä
authors: Jorma
authors: J
authors: Ilonen
authors: Olli
authors: O
authors: Simell
authors: Maria
authors: M
authors: Saarela
authors: Mikael
authors: M
authors: Knip
authors: Samuel
authors: S
authors: Kaski
authors: Eriika
authors: E
authors: Savontaus
authors: Matej
authors: M
authors: Orešič
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D016000:Cluster Analysis; D019295:Computational Biology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D012307:Risk Factors
chemical_list: D052242:Adiponectin; D007328:Insulin; D020738:Leptin; D008244:Lysophosphatidylcholines