Time to Peak Glucose and Peak C-Peptide During the Progression to Type 1 Diabetes in the Diabetes Prevention Trial and TrialNet Cohorts
Authors: Voss Michael G. , Cuthbertson David D. , Cleves Mario M. , Xu Ping , Evans-Molina Carmella , Palmer Jerry P. , Redondo Maria J. , Steck Andrea K. , Lundgren Markus , Larsson Helena , Moore Wayne V. , Atkinson Mark A. , Sosenko Jay M. , Ismail Heba M. ,   DPT-1 and TrialNet Study Groups, Greenbaum Carla J. , Anderson Mark , Atkinson Mark A. , Bosi Emanuele , Brusko Todd M. , Buckner Jane , Clements Mark , Colman Peter G. , Daniels Mark , DiMeglio Linda , Evans-Molina Carmella , Gaglia Jason , Gitelman Stephen E. , Goland Robin , Gottlieb Peter , Haller Michael , Herold Kevan , Hessner Martin J. , Knip Mikael , Krischer Jeffrey P. , Lernmark Ake , Libman Ingrid , Linsley Peter S. , Liu Yuk-Fun , Long Alice , Moore Wayne , Moran Antoinette , Muir Andrew , Palmer Jerry , Russell William , Spain Lisa , Steck Andrea , Wentworth John , Wherrett Diane , Wilson Darrell M. , Winter William , White Perrin , Ziegler Anette , Baidal David A. , Battaglia Manuela , Becker Dorothy , Bingley Penelope , Peakman Mark , Philipson Louis , Raskin Philip , Redondo Maria , Rodriguez Henry , Schatz Desmond A. , Sosenko Jay M. , Greenbaum Carla J. , Krischer Jeffrey P. , Spain Lisa , Greenbaum Carla J. , Rafkin Lisa , Sosenko Jay M. , Krischer Jeffrey P. , Bundy Brian , Abbondondolo Michael , Adams Timothy , Alford Logan , Bjellquist Jenna , Boonstra Matthew , Brehon Brandie , Cuthbertson David , Eberhard Christopher , Fiske Steve , Ford Julie , Garmeson Jennifer , Hainline Cameron , Hays Brian , Heyman Kathleen , Hsiao Belinda , Karges Christina , Loechelt Brett , Liu Shu , Maddox Kristin , Maguire Colleen M. , Malloy Jamie , Matos Alexandria , McNeill Cameron , Moore Margaret , Muller Sarah , Nguyen Thuy , O’Donnell Ryan , Parker Melissa , Pereyra MJ , Sadler Kelly , Tamura Roy , Walker-Veras Elon , Wood Keith , Young Kenneth , Asif Ilma , Burroughs Cristina , Cleves Mario , DeSalvatore Meagan , Geyer Susan , Henderson Courtney , Henry Martha , Koziol Beata-Gabriela , Lane Lindsay , Lloyd Jennifer , Martin Julie , Nunez Jodie , Roberts Amy , Sullivan Christine , Warnock Megan V. , Wood Rebecca , Xu Ping , Yanek Vanessa , Spain Lisa , Blumberg Emily , Aas Sean , Beck Gerald , Gubitosi-Klug Rose , Wallace Dennis , Laffel Lori , Vigersky Robert , Baden Lindsey , Gottlieb Peter , Green Michael , Weinberg Adriana , Gottlieb Peter A. , Anderson Mark , Atkinson Mark A. , Brusko Todd M. , Buckner Jane H. , Evans-Molina Carmella , Herold Kevan C. , Hessner Martin J. , Linsley Peter S. , Long Alice , Muller Sarah , Skibinski David A. G. , White Perrin , Battaglia Manuela , Peakman Mark , Marcovina Santica , Palmer Jerry P. , Tischfield Jay , Weinberg Adriana , Winter William , Yu Liping , Shultz Annie , Batts Emily , Pagryzinski Arielle , Staal Michele Patience , Fitzpatrick Kristin , Romasco Melita , Webb Christopher , Ramey Mary , Tobin Meghan , Steck Andrea K. , Bradfield Brenda , Chesshir Lexie , Gottlieb Peter A. , Michels Aaron W. , Quist Morgan , Robinson Becky , Seligova Sona , Simmons Kimber , Triolo Taylor , Greenbaum Carla J. , Buckner Jane H. , Hao Wei , Kook David , Lord Sandra , McCulloch-Olson Marli , Ramey Mary , Sachter Elaine , Snavely Jenna , Tordillos Corinna , Dana VanBuecken , Nancy Wickstrom , Moore Wayne , Beidelschies Marissa , Brenson-Hughes Darlene , Boyd Jennifer , Clements Mark , Dolan Jennifer , Elrod Aliza , Haith Emily , Halpin Kelsee , Howell Kelsye , James Jennifer , Jones Laura , Luetjen Terri , McClain Cassandra , McDonough Ryan , Mitchell Susan , Muhaisen Fadi Al , Orlich Steve , Paprocki Emily , Seuferling Barbara , Sexton Jill , Goland Robin , Alvarez Analia , Bogun Magdalena , Gandica Rachelle , Lonier Jacqueline , Pollak Sarah , Williams Kristen , Muir Andrew , Antich Amber , Cossen Kristina , Felner Eric , Jenkins Margaret , Powell-Lee Brittney , Sanchez Wanda , Wherrett Diane K. , Demoe Lindsay , Dias Danyella , Eisel Lesley , Kovalakovska Roze , Ricci Mary Jo , Stochinsky Rebecca , DiMeglio Linda A. , Evans-Molina Carmella , Grubbs Eric , Ismail Heba M. , Legge Megan , Neyman Anna , Sanchez Juan , Sims Emily K. , Spall Maria , Woerner Stephanie , Bosi Emanuele , Bianconi Eleonora , Bolla rea , Bonfanti Ricardo , Caretto Amelia , Frontino Giulio , Grogan Pauline , Laurenzi rea , Molinari Chiara , Pastore Matteo , Petrelli Alessandra , Lernmark Åke , Ahlkvist Linda , Borg Henrik , Jónsdóttir Berglind , Katsarou Anastasia , Larsson Helena , Lundgren Markus , Ulvenhag Ulrika , Wilson Darrell M. , Aye Tandy , Bachrach Laura , Esrey Trudy , Nally Laura , Prahalad Priya , Anderson Chris , Liu Yuk-Fun , Srinivasan Ramesh , Field Benjamin , Hughes Tracey , King Vicky , Loud Sam , Thorne Beth , Gitelman Stephen E. , Abdulhussein Fatema , Aceves Natalie , Anderson Mark S. , Auerback Glenna , Buchanan Jeanne , Chesser Hannah , Cobb-Walch Abby , Dapkus Laura , Ko Karen , Lee Janet , Long Roger , Niu Isabella , Sanda Srinath , Schulmeister Caroline , Torok Christine , Wesch Rebecca , Haller Jenise , Wong Michael J. , Abraham Annie , Adams Janey , Albanese-O'Neill Anastasia , Atkinson Mark A. , Bruggeman Brittany , Brusko Todd M. , Claire-Salzler Michael J. , Dayton Kristin , Hiers Paul , Hosford Jennifer , Jacobsen Laura M. , Marks John , Rohrs Henry , Schatz Desmond A. , Silverstein Janet , Towe Paula , Winter William E. , Knip Mikael , Hirvasniemi Minna , Koski Katriina , Luopajärvi Kristiina , Siljander Heli , Veijola Riitta , Moran Antoinette M. , Beasley Shannon , Bellin Melena D. , Leschyshyn Janice , McVean Jennifer , Nathan Brandon M. , Nelson Brittney , Pappenfus Beth , Ruedy Jessica , Street Anne , Becker Dorothy J. , Libman Ingrid M. , DeLallo Kelli , Groscost David , Klein Mary Beth , Riley Karen , Shelleby Carly , Toledo Frederico , White Perrin , Boyles Lauren , Dominguez Yasmin , Raskin Philip , Russell William E. , Brendle Faith , Brown Anne , Hammel Brenna , Leshko Jenny , Moore Daniel J. , Rainer Kimberly , Smith Tyler , Thomas James W. , Williams George , Wright Sarah , Colman Peter , Bjorasen Marika , Fourlanos Spiros , Harrison Leonard C. , Healy Felicity , Redl Leanne , Wentworth John M. , Herold Kevan C. , Feldman Laurie , Tamborlane William V. , Weinzimer Stuart A. 
Published: August 2021

OBJECTIVE
To assess the progression of type 1 diabetes using time to peak glucose or C-peptide during oral glucose tolerance tests (OGTTs) in autoantibody-positive relatives of people with type 1 diabetes.

RESEARCH DESIGN AND METHODS
We examined 2-h OGTTs of participants in the Diabetes Prevention Trial Type 1 (DPT-1) and TrialNet Pathway to Prevention (PTP) studies. We included 706 DPT-1 participants (mean ± SD age, 13.84 ± 9.53 years; BMI Z-score, 0.33 ± 1.07; 56.1% male) and 3,720 PTP participants (age, 16.01 ± 12.33 years; BMI Z-score, 0.66 ± 1.3; 49.7% male). Log-rank testing and Cox regression analyses with adjustments (age, sex, race, BMI Z-score, HOMA-insulin resistance, and peak glucose/C-peptide levels, respectively) were performed.

RESULTS
In each of DPT-1 and PTP, higher 5-year diabetes progression risk was seen in those with time to peak glucose &gt;30 min and time to peak C-peptide &gt;60 min (P &lt; 0.001 for all groups), before and after adjustments. In models examining strength of association with diabetes development, associations were greater for time to peak C-peptide versus peak C-peptide value (DPT-1: χ2 = 25.76 vs. χ2 = 8.62; PTP: χ2 = 149.19 vs. χ2 = 79.98; all P &lt; 0.001). Changes in the percentage of individuals with delayed glucose and/or C-peptide peaks were noted over time.

CONCLUSIONS
In two independent at-risk populations, we show that those with delayed OGTT peak times for glucose or C-peptide are at higher risk of diabetes development within 5 years, independent of peak levels. Moreover, time to peak C-peptide appears more predictive than the peak level, suggesting its potential use as a specific biomarker for diabetes progression.