Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

Matej Oresic (Corresponding Author), S. Simell, Marko Sysi-Aho, K. Nantö-Salonen, Tuulikki Seppänen-Laakso, V. Parikka, Mikko Katajamaa, A. Hekkala, Ismo Mattila, P. Keskinen, Laxman Yetukuri, Arja Reinikainen, Jyrki Lähde, Tapani Suortti, Jari Hakalax, Tuula Simell, Heikki Hyöty, Riitta Veijola, Jorma Ilonen, Riitta LahesmaaMikael Knip, Olli Simell

Research output: Contribution to journalArticleScientificpeer-review

Abstract

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
Original languageEnglish
Pages (from-to)2975-2984
JournalJournal of Experimental Medicine
Volume205
Issue number13
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed
Event44th Annual Meeting of the European Association for the Study of Diabetes, EASD - Rome, Italy
Duration: 8 Sep 200811 Sep 2008

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Autoimmunity
Type 1 Diabetes Mellitus
Autoantibodies
Lipids
Amino Acids
Metabolome
Phospholipid Ethers
Serum
Glutamate Decarboxylase
Succinic Acid
Phosphatidylcholines
Glutamic Acid
Triglycerides
Antioxidants
Parturition
Insulin
Seroconversion

Cite this

Oresic, Matej ; Simell, S. ; Sysi-Aho, Marko ; Nantö-Salonen, K. ; Seppänen-Laakso, Tuulikki ; Parikka, V. ; Katajamaa, Mikko ; Hekkala, A. ; Mattila, Ismo ; Keskinen, P. ; Yetukuri, Laxman ; Reinikainen, Arja ; Lähde, Jyrki ; Suortti, Tapani ; Hakalax, Jari ; Simell, Tuula ; Hyöty, Heikki ; Veijola, Riitta ; Ilonen, Jorma ; Lahesmaa, Riitta ; Knip, Mikael ; Simell, Olli. / Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. In: Journal of Experimental Medicine. 2008 ; Vol. 205, No. 13. pp. 2975-2984.
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abstract = "The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.",
author = "Matej Oresic and S. Simell and Marko Sysi-Aho and K. Nant{\"o}-Salonen and Tuulikki Sepp{\"a}nen-Laakso and V. Parikka and Mikko Katajamaa and A. Hekkala and Ismo Mattila and P. Keskinen and Laxman Yetukuri and Arja Reinikainen and Jyrki L{\"a}hde and Tapani Suortti and Jari Hakalax and Tuula Simell and Heikki Hy{\"o}ty and Riitta Veijola and Jorma Ilonen and Riitta Lahesmaa and Mikael Knip and Olli Simell",
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Oresic, M, Simell, S, Sysi-Aho, M, Nantö-Salonen, K, Seppänen-Laakso, T, Parikka, V, Katajamaa, M, Hekkala, A, Mattila, I, Keskinen, P, Yetukuri, L, Reinikainen, A, Lähde, J, Suortti, T, Hakalax, J, Simell, T, Hyöty, H, Veijola, R, Ilonen, J, Lahesmaa, R, Knip, M & Simell, O 2008, 'Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes', Journal of Experimental Medicine, vol. 205, no. 13, pp. 2975-2984. https://doi.org/10.1084/jem.20081800

Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. / Oresic, Matej (Corresponding Author); Simell, S.; Sysi-Aho, Marko; Nantö-Salonen, K.; Seppänen-Laakso, Tuulikki; Parikka, V.; Katajamaa, Mikko; Hekkala, A.; Mattila, Ismo; Keskinen, P.; Yetukuri, Laxman; Reinikainen, Arja; Lähde, Jyrki; Suortti, Tapani; Hakalax, Jari; Simell, Tuula; Hyöty, Heikki; Veijola, Riitta; Ilonen, Jorma; Lahesmaa, Riitta; Knip, Mikael; Simell, Olli.

In: Journal of Experimental Medicine, Vol. 205, No. 13, 2008, p. 2975-2984.

Research output: Contribution to journalArticleScientificpeer-review

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T1 - Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

AU - Oresic, Matej

AU - Simell, S.

AU - Sysi-Aho, Marko

AU - Nantö-Salonen, K.

AU - Seppänen-Laakso, Tuulikki

AU - Parikka, V.

AU - Katajamaa, Mikko

AU - Hekkala, A.

AU - Mattila, Ismo

AU - Keskinen, P.

AU - Yetukuri, Laxman

AU - Reinikainen, Arja

AU - Lähde, Jyrki

AU - Suortti, Tapani

AU - Hakalax, Jari

AU - Simell, Tuula

AU - Hyöty, Heikki

AU - Veijola, Riitta

AU - Ilonen, Jorma

AU - Lahesmaa, Riitta

AU - Knip, Mikael

AU - Simell, Olli

PY - 2008

Y1 - 2008

N2 - The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

AB - The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

U2 - 10.1084/jem.20081800

DO - 10.1084/jem.20081800

M3 - Article

VL - 205

SP - 2975

EP - 2984

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

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