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

posted on 12.08.2021, 20:17 by Maria J. Redondo, Megan V. Warnock, Ingrid M. Libman, Laura E. Bocchino, David Cuthbertson, Susan Geyer, Alberto Pugliese, Andrea K. Steck, Carmella Evans-Molina, Dorothy Becker, Jay M. Sosenko, Fida Bacha, the Type 1 diabetes TrialNet Study Group

Objective: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).

Research Design and Methods: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (n=1,061; mean age=16.3 years) with TCF7L2 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.

Results: None, one and two T2D-linked TCF7L2 alleles were present, respectively, in 48.1%, 43.9% and 8.0% of the participants. Insulin sensitivity (as reflected by 1/IF) 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 TCF7L2 SNPs. In multivariate analysis models with age, BMI Z-score, ethnicity, sex and TCF7L2 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/IF) and lower disposition index; there was no significant effect of the TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with normal OGTT (n=743, 70%), the results were similar.

Conclusions: In non-diabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI-Z-score, age, sex and ethnicity.


The sponsor of the trial was the Type 1 diabetes TrialNet Study Group. Type 1 diabetes TrialNet Study Group is a clinical trials network funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development, through the cooperative agreements U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085509, U01 DK103180, U01 DK103153, U01 DK085476, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106994, U01 DK107013, U01 DK107014, UC4 DK106993, and the JDRF. The contents of this Article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the JDRF.