<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<sub>F</sub>) 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<sub>F</sub>)
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>
Distribution of C-Peptide and Its Determinants in North American Children at Risk for Type 1 Diabetes