Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program

• DOI: 10.2337/db19-0236
• Publication Date: 2019-10-03T22:45:12Z
• Authors: Zsu-Zsu Chen; Jinxi Liu; Jordan Morningstar; Brandy M. Heckman...; Christine G. Lee; Samuel Dagogo-Jack; Jane F. Ferguson; Richard F. Hamman; William C. Knowler; Kieren J. Mather; Leigh Perreault; Jose C. Florez; Thomas J. Wang; Clary Clish; Marinella Temprosa; Robert E. Gerszten; ; George A. Bray; Kishore Gadde; Annie Chatellier; Jennifer Arceneaux; Amber Dragg; Crystal Duncan; Frank L. Greenway; Daniel Hsia; Erma Levy; Monica Lockett; Donna H. Ryan; David Ehrmann; Margaret J. Matulik; Kirsten Czech; Catherine DeSandre; Barry J. Goldstein; Kevin Furlong; Kellie A. Smith; Wendi Wildman; Constance Pepe; Ronald B. Goldberg; Jeanette Calles; Juliet Ojito; Sumaya Castillo-F...; Hermes J. Florez; Anna Giannella; Olga Lara; Beth Veciana; Steven M. Haffner; Helen P. Hazuda; Maria G. Montez; Kathy Hattaway; Carlos Lorenzo; Arlene Martinez; Tatiana Walker; Richard F. Hamman; Dana Dabelea; Lisa Testaverde; Denise Anderson; Alexis Bouffard; Tonya Jenkins; Dione Lenz; Leigh Perreault; David W. Price; Sheila C. Steinke; Edward S. Horton; Catherine S. Poirier; Kati Swift; Enrique Caballero; Barbara Fargnoli; Ashley Guidi; Mathew Guido; Sharon D. Jackson; Lori Lambert; Kathleen E. Lawton; Sarah Ledbury; Jessica Sansoucy; Jeanne Spellman; Steven E. Kahn; Brenda K. Montgomery; Wilfred Fujimoto; Robert H. Knopp; Edward W. Lipkin; Ivy Morgan-Taggart; Anne Murillo; Lonnese Taylor; April Thomas; Elaine C. Tsai; Dace Trence; Abbas E. Kitabchi; Samuel Dagogo-Jack; Mary E. Murphy; Laura Taylor; Jennifer Dolgoff; Debra Clark; Uzoma Ibebuogu; Helen Lambeth; Harriet Ricks; Lily M.K. Rutledge; Judith E. Soberman; Mark E. Molitch; Boyd E. Metzger; Mariana K. Johnson; Mimi M. Giles; Diane Larsen; Samsam C. Pen; David M. Nathan; Mary Larkin; Charles McKitrick; Heather Turgeon; Ellen Anderson; Laurie Bissett; Kristy Bondi; Enrico Cagliero; Kali D’Anna; Linda Delahanty; Jose C. Florez; Valerie Goldman; Peter Lou; Alexandra Poulos; Elyse Raymond; Christine Stevens; Beverly Tseng; Elizabeth Barrett...; Mary Lou Carrion-...; Lauren N. Claravall; Jonalle M. Dowden; Javiva Horne; Diana Leos; Sundar Mudaliar; Jean Smith; Simona Szerdi Jan...; Karen Vejvoda; F. Xavier Pi-Sunyer; Jane E. Lee; Sandra T. Foo; Susan Hagamen; David G. Marrero; Kieren J. Mather; Susie M. Kelly; Paula Putenney; Marcia A. Jackson; Gina McAtee; Ronald T. Ackermann; Carolyn M. Cantrell; Edwin S. Fineberg; Angela Hadden; Mario S. Kirkman; Erin O’Kelly Phil...; Paris J. Roach; Robert E. Ratner; Vanita Aroda; Sue Shapiro; Catherine Bavido-...; Peggy Gibbs; Gabriel Uwaifo; Renee Wiggins; Mohammed F. Saad; Karol Watson; Medhat Botrous; Sujata Jinagouda; Maria Budget; Claudia Conzues; Perpetua Magpuri; Kathy Ngo; Kathy Xapthalamous; Neil H. White; Angela L. Brown; Samia Das; Prajakta Khare-Ra...; Tamara Stich; Ana Santiago; Cormarie Wernimont; Christopher D. Sa...; Sherita Hill Golden; Tracy Whittington; Frederick L. Bran...; Jeanne M. Clark; Alicia Greene; Dawn Jiggetts; Henry Mosley; John Reusing; Richard R. Rubin; Shawne Stephens; Evonne Utsey; David S. Schade; Karwyn S. Adams; Claire Hemphill; Penny Hyde; Janene L. Canady; Kathleen Colleran; Ysela Gonzales; Doris A. Hernande...; Carolyn King; Jill Crandall; Janet O. Brown; Gilda Trandafirescu; Elsie Adorno; Helena Duffy; Angela Goldstein; Jennifer Lukin; Helen Martinez; Dorothy Pompi; Harry Shamoon; Jonathan Scheindlin; Elizabeth A. Walker; Judith Wylie-Rosett; Trevor Orchard; Andrea Kriska; Susan Jeffries; M. Kaye Kramer; Marie Smith; Catherine Benchoff; Stephanie Guimond; Jessica Pettigrew; Debra Rubinstein; Linda Semler; Elizabeth Venditti; Valarie Weinzierl; Richard F. Arakaki; Narleen K. Baker-...; Mae K. Isonaga; Nina E. Bermudez; Marjorie K. Mau; John S. Melish; Robin E. Yamamoto; William C. Knowler; Norman Cooeyate; Alvera Enote; Mary A. Hoskin; Camille Natewa; Carol A. Percy; Kelly J. Acton; Vickie L. Andre; Roz Barber; Shandiin Begay; Brian C. Bucca; Sherron Cook; Jeff Curtis; Charlotte Dodge; Matthew S. Doughty; Jason Kurland; Justin Glass; Martia Glass; Robert L. Hanson; Louise E. Ingraham; Kathleen M. Kobus; Jonathan Krakoff; Catherine Manus; Cherie McCabe; Sara Michaels; Tina Morgan; Julie A. Nelson; Christopher Pirom...; Robert J. Roy; Sandra Sangster; Miranda Smart; Darryl P. Tonemah; Rachel Williams; Charlton Wilson; Sarah Fowler; Marinella Temprosa; Michael Larsen; Tina Brenneman; Hanna Sherif; Sharon L. Edelstein; Solome Abebe; Julie Bamdad; Melanie Barkalow; Joel Bethepu; Tsedenia Bezabeh; Nicole Butler; Jackie Callaghan; Caitlin E. Carter; Costas Christophi; Gregory M. Dwyer; Mary Foulkes; Yuping Gao; Robert Gooding; Adrienne Gottlieb; Nisha Grover; Heather Hoffman; Ashley Hogan Tjaden; Kathleen Jablonski; Richard Katz; Preethy Kolinjivadi; John M. Lachin; Yong Ma; Qing Pan; Susan Reamer; Alla Sapozhnikova; Elizabeth M. Vend...; Andrea M. Kriska; Linda Semler; Valerie Weinzierl; Santica Marcovina; Greg Strylewicz; John Albers; Judith Fradkin; Sanford Garfield; Christine Lee; Edward Gregg; Ping Zhang; Jose C. Florez; David Altshuler; Liana K. Billings; Ling Chen; Maegan Harden; Robert L. Hanson; William C. Knowler; Toni I. Pollin; Alan R. Shuldiner; Kathleen Jablonski; Paul W. Franks; Marie-France Hivert
• Keywords: Adult; Male; 0303 health sciences; Incidence; Middle Aged; 3. Good health; Cytosine; 03 medical and health sciences; Risk factors; Diabetes Mellitus, Type 2; Risk Factors; Diabetes Mellitus; Metabolome; Humans; Female; Life Style; Type 2; Biomarkers; Aged

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.