Longitudinal Metabolome-Wide Signals Prior to the Appearance of a First Islet Autoantibody in Children Participating in the TEDDY Study
Qian Li, Hemang Parikh, Martha Butterworth, Åke Lernmark, William Hagopian, Marian Rewers, Jin‐Xiong She, Jorma Toppari, Anette‐G. Ziegler, Beena Akolkar, Oliver Fiehn, Sili Fan, Jeffrey P. Krischer, TEDDY Study Group, Marian Rewers, Aaron Barbour, Kimberly Bautista, Judith Baxter, Daniel Felipe-Morales, Kimberly A. Driscoll, Brigitte I. Frohnert, Marisa Stahl, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Edwin Liu, Jill M. Norris, Stesha Peacock, Hanan Shorrosh, Andrea K. Steck, Megan Stern, Erica Villegas, Kathleen Waugh, Jorma Toppari, Olli Simell, Annika Adamsson, Suvi Ahonen, Iris Erlund, Leena Hakola, Anne Hekkala, Henna Holappa, Heikki Hyöty, Anni Ikonen, Jorma Ilonen, Sinikka Jäminki, Sanna Jokipuu, Leena Eklund Karlsson, Jukka Kero, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Jarita Kytölä, Tiina Latva-aho, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija E. Miettinen, Katja Multasuo, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Mia Nyblom, Sami Oikarinen, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Petra Rajala, Jenna Rautanen, Anne Riikonen, Eija Riski, Miia Pekkola, Minna Romo, Satu Ruohonen, Satu Simell, Maija Sjöberg, Aino Stenius, Päivi Tossavainen, Mari Vähä-Mäkilä, Sini Vainionpää, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Suvi Μ. Virtanen, Jin‐Xiong She, Desmond Schatz, Diane Hopkins, Leigh Steed, Jennifer Bryant, Katherine Silvis, Michael J. Haller, Melissa Gardiner, Richard McIndoe, Ashok Sharma, Stephen W. Anderson, Laura M. Jacobsen, John Marks
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.