Metabolic regulation in progression to autoimmune diabetes

Marko Sysi-Aho, A. Erlomov, Peddinti Gopalacharyulu, A. Tripathi, Tuulikki Seppänen-Laakso, Johanna Maukonen, Ismo Mattila, S.T. Ruohonen, L. Vähätalo, Laxman Yetukuri, T. Härkönen, Erno Lindfors, J. Nikkilä, J. Ilonen, O. Simell, Maria Saarela, M. Knip, Samuel Kaski, E. Savontaus, Matej Orešič (Corresponding Author)

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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.
Original languageEnglish
Article numbere1002257
Number of pages16
JournalPLoS Computational Biology
Volume7
Issue number10
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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insulin-dependent diabetes mellitus
diabetes
Diabetes
Medical problems
Type 1 Diabetes Mellitus
Progression
insulin secretion
Insulin
Secretion
Clostridium leptum
secretion
Mouse
Disturbance
adiponectin
autoimmunity
Autoimmunity
Metabolomics
Clostridium
Adiponectin
mice

Cite this

Sysi-Aho, M., Erlomov, A., Gopalacharyulu, P., Tripathi, A., Seppänen-Laakso, T., Maukonen, J., ... Orešič, M. (2011). Metabolic regulation in progression to autoimmune diabetes. PLoS Computational Biology, 7(10), [e1002257]. https://doi.org/10.1371/journal.pcbi.1002257
Sysi-Aho, Marko ; Erlomov, A. ; Gopalacharyulu, Peddinti ; Tripathi, A. ; Seppänen-Laakso, Tuulikki ; Maukonen, Johanna ; Mattila, Ismo ; Ruohonen, S.T. ; Vähätalo, L. ; Yetukuri, Laxman ; Härkönen, T. ; Lindfors, Erno ; Nikkilä, J. ; Ilonen, J. ; Simell, O. ; Saarela, Maria ; Knip, M. ; Kaski, Samuel ; Savontaus, E. ; Orešič, Matej. / Metabolic regulation in progression to autoimmune diabetes. In: PLoS Computational Biology. 2011 ; Vol. 7, No. 10.
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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.",
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Sysi-Aho, M, Erlomov, A, Gopalacharyulu, P, 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 2011, 'Metabolic regulation in progression to autoimmune diabetes', PLoS Computational Biology, vol. 7, no. 10, e1002257. https://doi.org/10.1371/journal.pcbi.1002257

Metabolic regulation in progression to autoimmune diabetes. / Sysi-Aho, Marko; Erlomov, A.; Gopalacharyulu, Peddinti; Tripathi, A.; Seppänen-Laakso, Tuulikki; Maukonen, Johanna; Mattila, Ismo; Ruohonen, S.T.; Vähätalo, L.; Yetukuri, Laxman; Härkönen, T.; Lindfors, Erno; Nikkilä, J.; Ilonen, J.; Simell, O.; Saarela, Maria; Knip, M.; Kaski, Samuel; Savontaus, E.; Orešič, Matej (Corresponding Author).

In: PLoS Computational Biology, Vol. 7, No. 10, e1002257, 2011.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Metabolic regulation in progression to autoimmune diabetes

AU - Sysi-Aho, Marko

AU - Erlomov, A.

AU - Gopalacharyulu, Peddinti

AU - Tripathi, A.

AU - Seppänen-Laakso, Tuulikki

AU - Maukonen, Johanna

AU - Mattila, Ismo

AU - Ruohonen, S.T.

AU - Vähätalo, L.

AU - Yetukuri, Laxman

AU - Härkönen, T.

AU - Lindfors, Erno

AU - Nikkilä, J.

AU - Ilonen, J.

AU - Simell, O.

AU - Saarela, Maria

AU - Knip, M.

AU - Kaski, Samuel

AU - Savontaus, E.

AU - Orešič, Matej

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pcbi.1002257

DO - 10.1371/journal.pcbi.1002257

M3 - Article

VL - 7

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 10

M1 - e1002257

ER -