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Diabetes. 2020 Feb 6. pii: db190756. doi: 10.2337/db19-0756. [Epub ahead of print]

Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study.

Collaborators (246)

Rewers M, Barbour A, Bautista K, Baxter J, Felipe-Morales D, Driscoll K, Frohnert BI, Stahl M, Gesualdo P, Hoffman M, Karban R, Liu E, Norris J, Peacock S, Shorrosh H, Steck A, Stern M, Villegas E, Waugh K, Toppari J, Simell OG, Adamsson A, Ahonen S, Åkerlund M, Hakola L, Hekkala A, Holappa H, Hyöty H, Ikonen A, Ilonen J, Jäminki S, Jokipuu S, Karlsson L, Kero J, Kähönen M, Knip M, Koivikko ML, Koskinen M, Koreasalo M, Kurppa K, Kytölä J, Latva-Aho T, Lindfors K, Lönnrot M, Mäntymäki E, Mattila M, Miettinen M, Multasuo K, Mykkänen T, Niininen T, Niinistö S, Nyblom M, Oikarinen S, Ollikainen P, Othmani Z, Pohjola S, Rajala P, Rautanen J, Riikonen A, Riski E, Pekkola M, Romo M, Ruohonen S, Simell S, Sjöberg M, Stenius A, Tossavainen P, Vähä-Mäkilä M, Vainionpää S, Varjonen E, Veijola R, Viinikangas I, Virtanen SM, She JX, Schatz D, Hopkins D, Steed L, Bryant J, Silvis K, Haller M, Gardiner M, McIndoe R, Sharma A, Anderson SW, Jacobsen L, Marks J, Towe PD, Ziegler AG, Bonifacio E, Gavrisan A, Gezginci C, Heublein A, Hoffmann V, Hummel S, Keimer A, Knopff A, Koch C, Koletzko S, Ramminger C, Roth R, Scholz M, Stock J, Warncke K, Wendel L, Winkler C, Lernmark Å, Agardh D, Aronsson CA, Ask M, Bennet R, Cilio C, Engqvist H, Ericson-Hallström E, Fors A, Fransson L, Gard T, Hansen M, Jisser H, Johansen F, Jonsdottir B, Jovic S, Larsson HE, Lindström M, Lundgren M, Maziarz M, Månsson-Martinez M, Markan M, Melin J, Mestan Z, Nilsson C, Ottosson K, Rahmati K, Ramelius A, Salami F, Sjöberg A, Sjöberg B, Svensson M, Törn C, Wallin A, Wimar Å, Åberg S, Hagopian WA, Killian M, Crouch CC, Skidmore J, Chavoshi M, Hervey R, Lyons R, Meyer A, Mulenga D, Radtke J, Romancik M, Schmitt D, Zink S, Becker D, Franciscus M, Dalmagro-Elias Smith M, Daftary A, Klein MB, Yates C, Krischer JP, Austin-Gonzalez S, Avendano M, Baethke S, Brown R, Burkhardt B, Butterworth M, Clasen J, Cuthbertson D, Dankyi S, Eberhard C, Fiske S, Garmeson J, Gowda V, Heyman K, Hsiao B, Karges C, Laras FP, Lee HS, Li Q, Liu S, Liu X, Lynch K, Maguire C, Malloy J, McCarthy C, Merrell A, Parikh H, Quigley R, Remedios C, Shaffer C, Smith L, Smith S, Sulman N, Tamura R, Tewey D, Toth M, Uusitalo U, Vehik K, Vijayakandipan P, Wood K, Yang J, Abbondondolo M, Ballard L, Hadley D, McLeod W, Meulemans S, Akolkar B, Bourcier K, Briese T, Johnson SB, Triplett E, Miao LYD, Bingley P, Williams A, Chandler K, Ball O, Kelland I, Grace S, Hagopian W, Chavoshi M, Radtke J, Zink S, Erlich H, Mack SJ, Fear AL, Fiehn O, Wikoff B, Defelice B, Grapov D, Kind T, Palazoglu M, Valdiviez L, Wancewicz B, Wohlgemuth G, Wong J, Rich SS, Chen WM, Onengut-Gumuscu S, Farber E, Pickin RR, Davis J, Davis J, Gallo D, Bonnie J, Campolieto P.

Author information

1
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL qian.li@epi.usf.edu.
2
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL.
3
Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden.
4
Pacific Northwest Diabetes Research Institute, Seattle, WA.
5
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO.
6
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA.
7
Department of Pediatrics, Turku University Hospital, Turku, Finland.
8
Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland.
9
Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany.
10
Forschergruppe Diabetes, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany.
11
Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Munich, Germany.
12
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
13
Genome Center, University of California, Davis, Davis, CA.
14
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL jeffrey.krischer@epi.usf.edu.

Abstract

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

PMID:
32029481
DOI:
10.2337/db19-0756

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