The Pathological Evolution of Glucose Response Curves (GRCs) during the Progression to Type 1 Diabetes (T1D) in the TrialNet Pathway to Prevention Study

Abstract

Individuals with a biphasic (BP; two peaks) GRC during a 2-hour oral glucose tolerance test (OGTT) are at lower risk of T1D than those with monophasic (MP; one peak) and monotonic (MT; continuous increase) GRCs. We thus performed a longitudinal analysis to examine whether: 1) the different GRC risks are indicative of changes in GRC shapes during the progression to T1D, and 2) changes in GRCs are related to a deterioration in β-cell function. Changes in shapes of GRCs were compared between progressors [n=360; mean age 13.8±10.9 years; 47.3% male] and non-progressors [n=2404; mean age 18.1±13.1 years; 52.1% male] from first OGTTs to last OGTTs (before diagnosis for progressors). Median intervals from first to last OGTTs for progressors and non-progressors were 1.6 (0.9, 3.0) and 2.1 (1.0, 4.4) years, respectively. Logistic regression was used with adjustments for baseline age, sex, BMIZ and the interval between OGTTs. Progressor GRCs changed significantly more frequently than non-progressor GRCs from BP to MP [70.7% (29/41) vs. 46.3% (271/585); adjusted OR 3.00 (1.42-6.33); p=0.004)], and from MP to MT [12.4% (31/251) vs. 1.7% (19/1119); adjusted OR 8.85 (4.60-17.00); p<0.001)]. Overall, progressors had a higher frequency of MT than non-progressors at the last visit [12.8% (46/360) vs. 1.3% (31/2404); p<0.001)]. Of progressors with OGTTs at diagnosis, 39.7% (91/229) had MT GRCs. Among progressors, the early (30-0 min) C-peptide response (ng/ml) decreased in those who changed from BP to MP (3.27±1.78 vs. 2.44±1.63, p=0.003) and from MP to MT (2.31±1.31 vs. 0.96±0.71, p<0.001). In conclusion, GRC risk differences for T1D result from characteristic changes in GRCs during progression. A substantial proportion of progressors to T1D evolve to MT GRCs at diagnosis. Reductions in the early C-peptide response correspond to changes in GRCs from BP to MP and from MP to MT, which suggests that the changes in GRCs reflect a pathological decline in β-cell function. Disclosure H.M. Ismail: None. P. Xu: None. D.J. Becker: None. I. Libman: Consultant; Self; Novo Nordisk A/S. J.B. Marks: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Abvance. Consultant; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Dance Biopharm. Consultant; Self; Diavacs, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Ideal Life Inc., ImmunoMolecular Therapeutics, Intrexon, Merck & Co., Inc.. Advisory Panel; Self; Orgenesis Inc.. Consultant; Self; Sanofi, Servier, VTV Therapeutics, Valeritas, Inc., Viacyte, Inc.. Board Member; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Board Member; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. Board Member; Self; Moerae Matrix. Stock/Shareholder; Self; Moerae Matrix, Dance Biopharm, Ideal Life Inc., Intrexon, VasoPrep Surgical. J.P. Palmer: None. J. Sosenko: None.