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PMID: 22046124 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Metabolic regulation in progression to autoimmune diabetes.

PLoS computational biology ·Vol. 7 ·No. 10 ·2011-10-00 ·Pages e1002257

Sysi-Aho M, Ermolov A, Gopalacharyulu PV, Tripathi A, Seppänen-Laakso T, Maukonen J, Mattila I, Ruohonen ST, Vähätalo L, Yetukuri L, Härkönen T, Lindfors E, Nikkilä J, Ilonen J, Simell O, Saarela M, Knip M, Kaski S, Savontaus E, Orešič M

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.

MeSH Terms
Adiponectin/metabolism Animals Cluster Analysis Computational Biology Diabetes Mellitus, Type 1/metabolism,physiopathology Disease Progression Female Humans Insulin/metabolism Insulin Resistance Insulin-Secreting Cells/metabolism Leptin/metabolism Liver/metabolism Lysophosphatidylcholines/metabolism Male Metabolic Networks and Pathways Metabolome/physiology Mice Mice, Inbred NOD Models, Biological Risk Factors
Chemicals
Adiponectin Insulin Leptin Lysophosphatidylcholines
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Sysi-Aho Marko
VTT Technical Research Centre of Finland, Espoo, Finland.
Ermolov Andrey
Gopalacharyulu Peddinti V
Tripathi Abhishek
Seppänen-Laakso Tuulikki
Maukonen Johanna
Mattila Ismo
Ruohonen Suvi T
Vähätalo Laura
Yetukuri Laxman
Härkönen Taina
Lindfors Erno
Nikkilä Janne
Ilonen Jorma
Simell Olli
Saarela Maria
Knip Mikael
Kaski Samuel
Savontaus Eriika
Orešič Matej
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Article Info
Journal
PLoS computational biology
Abbr.
PLoS Comput Biol
ISSN
1553-7358
DOI
10.1371/journal.pcbi.1002257
Published
2011-10-00
Epub
2011-00-27
Pages
e1002257
Language
English
Region
United States
NLM ID
101238922
PMCID
PMC3203065
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pcbi.1002257 PMC Full Text View journal details
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