TY - JOUR
T1 - Metabolic regulation in progression to autoimmune diabetes
AU - Sysi-Aho, Marko
AU - Ermolov, Andrey
AU - Gopalacharyulu, Peddinti V.
AU - Tripathi, Abhishek
AU - Seppänen-Laakso, Tuulikki
AU - Maukonen, Johanna
AU - Mattila, Ismo
AU - Ruohonen, Suvi T.
AU - Vähätalo, Laura
AU - Yetukuri, Laxman
AU - Härkönen, Taina
AU - Lindfors, Erno
AU - Nikkilä, Janne
AU - Ilonen, Jorma
AU - Simell, Olli
AU - Saarela, Maria
AU - Knip, Mikael
AU - Kaski, Samuel
AU - Savontaus, Eriika
AU - Oresic, Matej
N1 - VK: airc hiit
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.
UR - http://dx.doi.org/10.1371/journal.pcbi.1002257
U2 - 10.1371/journal.pcbi.1002257
DO - 10.1371/journal.pcbi.1002257
M3 - Article
VL - 7
SP - 1
EP - 16
JO - PLoS computational biology
JF - PLoS computational biology
SN - 1553-734X
IS - 10
M1 - e1002257
ER -