TCF7L2 Genetic Variants do not Influence Insulin Sensitivity or Secretion Indices in Autoantibody-positive Individuals at Risk for Type 1 Diabetes

<p><b>Objective</b>: 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).</p> <p><b>Research Design and Methods</b>: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with <i>TCF7L2</i> SNP information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, p-values <0.0086 were considered statistically significant. </p> <p><b>Results</b>: None, one and two T2D-linked <i>TCF7L2</i> alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/I_F) decreased with increasing BMI-Z-score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI-Z-score. Oral disposition index was negatively correlated with age, BMI-Z-score and Hispanic ethnicity. None of the indices were associated with <i>TCF7L2</i> SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and <i>TCF7L2 </i>alleles as independent variables, C-peptide index increased with age, while BMI Z-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 the <i>TCF7L2</i> SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar.</p> <p><b>Conclusions</b>: In non-diabetic autoantibody-positive individuals, <i>TCF7L2</i><i> </i>SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity. </p>