The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in β-Cell Function in TODAY
Authors: Arslanian Silva , El ghormli Laure , Young Kim Joon , Bacha Fida , Chan Christine , Ismail Heba M. , Levitt Katz Lorraine E. , Levitsky Lynne , Tryggestad Jeanie B. , White Neil H. ,   TODAY Study Group, McKay S. , Haymond M. , Anderson B. , Bush C. , Gunn S. , Holden H. , Jones S.M. , Jeha G. , McGirk S. , Thamotharan S. , Cuttler L. , Abrams E. , Casey T. , Dahms W. , Ievers-Landis C. , Kaminski B. , Koontz M. , MacLeish S. , McGuigan P. , Narasimhan S. , Geffner M. , Barraza V. , Chang N. , Conrad B. , Dreimane D. , Estrada S. , Fisher L. , Fleury-Milfort E. , Hernandez S. , Hollen B. , Kaufman F. , Law E. , Mansilla V. , Miller D. , Muñoz C. , Ortiz R. , Ward A. , Wexler K. , Xu Y.K. , Yasuda P. , Levitt Katz L. , Berkowitz R. , Boyd S. , Johnson B. , Kaplan J. , Keating C. , Lassiter C. , Lipman T. , McGinley G. , McKnight H. , Schwartzman B. , Willi S. , Arslanian S. , Bacha F. , Foster S. , Galvin B. , Hannon T. , Kriska A. , Libman I. , Marcus M. , Porter K. , Songer T. , Venditti E. , Goland R. , Gallagher D. , Kringas P. , Leibel N. , Ng D. , Ovalles M. , Seidman D. , Laffel L. , Goebel-Fabbri A. , Hall M. , Higgins L. , Keady J. , Malloy M. , Milaszewski K. , Rasbach L. , Nathan D.M. , Angelescu A. , Bissett L. , Ciccarelli C. , Delahanty L. , Goldman V. , Hardy O. , Larkin M. , Levitsky L. , McEachern R. , Norman D. , Nwosu D. , Park-Bennett S. , Richards D. , Sherry N. , Steiner B. , Tollefsen S. , Carnes S. , Dempsher D. , Flomo D. , Whelan T. , Wolff B. , Weinstock R. , Bowerman D. , Bristol S. , Bulger J. , Hartsig J. , Izquierdo R. , Kearns J. , Saletsky R. , Trief P. , Zeitler P. , Abramson N. , Bradhurst A. , Celona-Jacobs N. , Higgins J. , Kelsey M. , Klingensmith G. , Nadeau K. , Witten T. , Copeland K. , Boss E. , Brown R. , Chadwick J. , Chalmers L. , Chernausek S. , Hebensperger A. , Macha C. , Newgent R. , Nordyke A. , Olson D. , Poulsen T. , Pratt L. , Preske J. , Schanuel J. , Sternlof S. , Lynch J. , Amodei N. , Barajas R. , Cody C. , Hale D. , Hernandez J. , Ibarra C. , Morales E. , Rivera S. , Rupert G. , Wauters A. , White N. , Arbeláez A. , Flomo D. , Jones J. , Jones T. , Sadler M. , Tanner M. , Timpson A. , Welch R. , Caprio S. , Grey M. , Guandalini C. , Lavietes S. , Rose P. , Syme A. , Tamborlane W. , Hirst K. , Edelstein S. , Feit P. , Grover N. , Long C. , Pyle L. , Linder B. , Marcovina S.M. , Harting J. , Shepherd J. , Fan B. , Marquez L. , Sherman M. , Wang J. , Nichols M. , Mayer-Davis E. , Liu Y. , Lima J. , Gidding S. , Puccella J. , Ricketts E. , Danis R. , Domalpally A. , Goulding A. , Neill S. , Vargo P. , Wilfley D. , Aldrich-Rasche D. , Franklin K. , Massmann C. , O’Brien D. , Patterson J. , Tibbs T. , Van Buren D. , Palmert M. , Ratner R. , Dremaine D. , Silverstein J. 
Published: November 2018

OBJECTIVE
Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose response curves have lower insulin sensitivity and impaired β-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in β-cell function.

RESEARCH DESIGN AND METHODS
OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, insulin sensitivity (1/fasting insulin), C-peptide index (△C30/△G30), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]) were compared among the three groups.

RESULTS
At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar insulin sensitivity but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus the biphasic group (39.1%) (P &lt; 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in insulin sensitivity.

CONCLUSIONS
In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced β-cell function and foretells increased glycemic failure rates with accelerated deterioration in β-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes.