Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study
Authors: Li Qian , Parikh Hemang , Butterworth Martha D. , Lernmark Åke , Hagopian William , Rewers Marian , She Jin-Xiong , Toppari Jorma , Ziegler Anette-G. , Akolkar Beena , Fiehn Oliver , Fan Sili , Krischer Jeffrey P. ,   TEDDY Study Group, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Villegas Erica , Waugh Kathleen , Toppari Jorma , Simell Olli G. , Adamsson Annika , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jäminki Sinikka , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kytölä Jarita , Latva-aho Tiina , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Multasuo Katja , Mykkänen Teija , Niininen Tiina , Niinistö Sari , Nyblom Mia , Oikarinen Sami , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Rajala Petra , Rautanen Jenna , Riikonen Anne , Riski Eija , Pekkola Miia , Romo Minna , Ruohonen Satu , Simell Satu , Sjöberg Maija , Stenius Aino , Tossavainen Päivi , Vähä-Mäkilä Mari , Vainionpää Sini , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Virtanen Suvi M. , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson Stephen W. , Jacobsen Laura , Marks John , Towe P.D. , Ziegler Anette G. , Bonifacio Ezio , Gavrisan Anita , Gezginci Cigdem , Heublein Anja , Hoffmann Verena , Hummel Sandra , Keimer Andrea , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Aronsson Carin Andrén , Ask Maria , Bennet Rasmus , Cilio Corrado , Engqvist Helene , Ericson-Hallström Emelie , Fors Annika , Fransson Lina , Gard Thomas , Hansen Monika , Jisser Hanna , Johansen Fredrik , Jonsdottir Berglind , Jovic Silvija , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Månsson-Martinez Maria , Markan Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottosson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Sjöberg Birgitta , Svensson Malin , Törn Carina , Wallin Anne , Wimar Åsa , Åberg Sofie , Hagopian William A. , Killian Michael , Crouch Claire Cowen , Skidmore Jennifer , Chavoshi Masumeh , Hervey Rachel , Lyons Rachel , Meyer Arlene , Mulenga Denise , Radtke Jared , Romancik Matei , Schmitt Davey , Zink Sarah , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Brown Rasheedah , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Dankyi Stephen , Eberhard Christopher , Fiske Steven , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Karges Christina , Laras Francisco Perez , Lee Hye-Seung , Li Qian , Liu Shu , Liu Xiang , Lynch Kristian , Maguire Colleen , Malloy Jamie , McCarthy Cristina , Merrell Aubrie , Parikh Hemang , Quigley Ryan , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wood Keith , Yang Jimin , Abbondondolo Michael , Ballard Lori , Hadley David , McLeod Wendy , Meulemans Steven , Akolkar Beena , Bourcier Kasia , Briese Thomas , Johnson Suzanne Bennett , Triplett Eric , Miao Liping Yu Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Ball Olivia , Kelland Ilana , Grace Sian , Hagopian William , Chavoshi Masumeh , Radtke Jared , Zink Sarah , Erlich Henry , Mack Steven J. , Fear Anna Lisa , Fiehn Oliver , Wikoff Bill , Defelice Brian , Grapov Dmitry , Kind Tobias , Palazoglu Mine , Valdiviez Luis , Wancewicz Benjamin , Wohlgemuth Gert , Wong Joyce , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Pickin Rebecca Roche , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul 
Published: February 2020

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.