Thyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study

Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization. Methods: We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits. Results: We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance. Conclusion: We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism.