<i>TCF7L2</i> Genetic Variants Do Not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-Positive Individuals at Risk for Type 1 Diabetes.

Abstract

We aimed to test whether type 2 diabetes (T2D)-associated <i>TCF7L2</i> genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D). We studied autoantibody-positive TrialNet Pathway to Prevention study participants (<i>N</i> = 1,061) (mean age 16.3 years) with <i>TCF7L2</i> single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, <i>P</i> values < 0.0086 were considered statistically significant. None, one, and two T2D-linked <i>TCF7L2</i> alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/I_F]) decreased with increasing BMI <i>z</i> score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI <i>z</i> score. Oral disposition index was negatively correlated with age, BMI <i>z</i> score, and Hispanic ethnicity. None of the indices were associated with <i>TCF7L2</i> SNPs. In multivariable analysis models with age, BMI <i>z</i> score, ethnicity, sex, and <i>TCF7L2</i> alleles as independent variables, C-peptide index increased with age, while BMI <i>z</i> score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/I_F), and lower disposition index; there was no significant effect of <i>TCF7L2</i> SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (<i>n</i> = 743; 70%), the results were similar. In nondiabetic autoantibody-positive individuals, <i>TCF7L2</i> SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI <i>z</i> score, age, sex, and ethnicity.