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

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.