TCF7L2 genetic variants do not influence insulin sensitivity or secretion indices in autoantibody-positive individuals at risk for type 1 diabetes

Authors: REDONDO, MARIA - Texas Children'S Hospital; WARNOCK, MEGAN - University Of South Florida; LIBMAN, INGRID - University Of Pittsburgh; BOCCHINO, LAURA - University Of South Florida; CUTHBERTSON, DAVID - University Of South Florida; GEYER, SUSAN - University Of South Florida; PUGLIESE, ALBERTO - University Of Miami; STECK, ANDREA - University Of Colorado; EVANS-MOLINA, CARMELLA - Indiana University School Of Medicine; BECKER, DOROTHY - University Of Pittsburgh; SOSENKO, JAY - University Of Miami; BACHA, FIDA - Children'S Nutrition Research Center (CNRC)

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2021
Publication Date: 8/26/2021
Citation: Redondo, M.J., Warnock, M.V., Libman, I.M., Bocchino, L.E., Cuthbertson, D., Geyer, S., Pugliese, A., Steck, A.K., Evans-Molina, C., Becker, D., Sosenko, J.M., Bacha, F., and the Type 1 Diabetes TrialNet Study Group. 2021. TCF7L2 genetic variants do not influence insulin sensitivity or secretion indices in autoantibody-positive individuals at risk for type 1 diabetes. Diabetes Care. 44(9):2039-2044. https://doi.org/10.2337/dc21-0531.
DOI: https://doi.org/10.2337/dc21-0531

Interpretive Summary: Type 1 diabetes is an autoimmune disease characterized by the presence of antibodies against the pancreatic tissue. Having antibodies in the blood increases the risk for future development of type1 diabetes. Some individuals with antibodies may have a genetic marker usually associated with obesity and type 2 diabetes. We tested if type 2 diabetes-associated TCF7L2 genetic variants affects insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes. We studied autoantibody-positive individuals. They had information on the genetic marker for TCF7L2 and oral glucose tolerance test (OGTT). We calculated indices of insulin sensitivity and secretion. We found that insulin sensitivity was inversely related to obesity and was lower in Hispanics. Insulin secretion was positively related to age and BMI. After accounting for age, BMI, ethnicity, sex, there was no significant effect of TCF7L2 genetic marker on insulin sensitivity or secretion. We conclude that the genetic marker TCF7L2 was not related to insulin sensitivity or secretion indices in individuals at high risk for type 1 diabetes. Future studies are needed to better understand how this genetic marker may affect the risk of diabetes.

Technical Abstract: 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). We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N=1,061) (mean age 16.3 years) with TCF7L2 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, P values < 0.0086 were considered statistically significant. None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [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 multivariable 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 TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar. In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI Z score, age, sex, and ethnicity.