Emerging evidence suggests intrinsic β cell dysfunction contributes to T1D development. However, it is unclear whether defects in β cell response are evident in individuals at genetic risk for T1D without detectable islet autoimmunity. To explore this, we performed mixed meal tolerance tests (MMTTs) and hyperglycemic clamps to measure stimulated β cell response in 2 groups: Islet Ab negative 1st-degree adult relatives of persons with T1D (FDR-) and normoglycemic, age, sex, and BMI-matched controls without T1D family history. Median and IQR values for 1st phase responses, including C-peptide15min-0 (MMTT) and C-peptide incremental AUC (iAUC)0-10min (clamp), and 2nd phase responses, including C-peptide iAUC0-120min (MMTT) and average C-peptide (C-peptideavg) during the steady state (clamp), were compared using paired t-tests or Wilcoxon tests.
MMTTs and clamps were performed in 15 euglycemic (A1c<5.7%) FDR- and control pairs (34.3yrs ±7.7; 20% male; BMI 25.6kg/m2 ±4.4). There were no differences in 1st phase or 2nd phase-stimulated responses. For the FDR- vs. control group, C-peptide15min-0 was 1.2ng/mL (0.9,1.9) vs. 1.62(1.1,2.2), p=0.62, C-peptide iAUC0-10min was 22.6ng/mL*min (19.4-51.6) vs. 24.4 (19.3-31), p=0.72, and C-peptide iAUC0-120min was 404 (369.3,435.5) vs. 383.3 (291.2,558), p=>0.99, C-peptideavg steady state was 12 (10.8-18.9) vs. 11.5 (8.9-14.5), p=0.98.
In this small cohort, no significant differences between stimulated 1st or 2nd phase responses were detected between FDR- and matched controls, suggesting that FDR- relatives may not have a defect in stimulated β cell response. Nondiabetic relatives are heterogeneous in their risk of autoimmunity; this could explain a lack of between-group differences. At-risk pediatric cohorts, which have increased risks of developing autoimmunity, could be more likely to show a difference in β cell response. Ongoing investigations will define β cell function in relatives with detectable Abs.
A. Neyman: None. K. Moors: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. L. DiMeglio: None. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. T.S. Hannon: None. E.K. Sims: None.