In individuals with new onset T1D, T2D-associated TCF7L2 genetic variants are associated with lower area-under-the curve (AUC) glucose and higher AUC C-peptide responses to a mixed meal. We aimed to test whether TCF7L2 variants affect glucose metabolism in nondiabetic islet autoantibody-positive (AbPos) individuals. We studied 1065 TrialNet Pathway to Prevention Study participants (AbPos relatives of persons with T1D) with TCF7L2 SNPs who underwent oral glucose tolerance tests (OGTT) (mean age 16.3 yrs, 63% <18 years old, 91.1% non-Hispanic, 47.7% male; T2D-associated TCF7L2 SNP: 48.1% 0 alleles, 43.9% 1 allele, 8% 2 alleles). We assessed the contribution of TCF7L2 SNP variants on Fasting (FIIS) and OGTT Index of Insulin Sensitivity (OIIS), Insulin Secretion (OIISec), and Disposition Index (ODI) with univariate and multivariate analyses. Then we studied the interaction between TCF7L2 SNP and BMI. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. Insulin sensitivity and secretion indices were significantly associated with age (FIIS, OIIS, OIISec), BMI Z-score (FIIS, OIIS, OIISec, ODI) and Hispanic ethnicity (FIIS, OIIS) but not sex in univariate analyses. TCF7L2 SNP was not significantly associated with these indices in univariate or multivariate analyses adjusting for BMI, age, sex and race-ethnicity. There was a significant interaction between BMI and presence of 2 (vs. 0) TCF7L2 SNP alleles on insulin sensitivity (OIIS) in children (p=0.0079) but not adults (p=0.94). After adjusting for age, ethnicity and sex, the difference did not reach statistical significance (p=0.0135). Restricting to non-obese participants, the results were similar. In sum, in nondiabetic AbPos individuals, the TCF7L2 variant does not appear to impact insulin sensitivity or secretion indices after accounting for BMI, age, sex and race-ethnicity.
M.J. Redondo: None. M.V. Warnock: None. L.E. Bocchino: None. S. Geyer: None. A. Pugliese: None. A. Steck: None. I. Libman: Consultant; Self; Novo Nordisk A/S. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. D.J. Becker: None. J. Sosenko: None. F. Bacha: Research Support; Self; AstraZeneca, Takeda Development Center Americas, Inc.
National Institute of Diabetes and Digestive and Kidney Diseases