Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance -: Evidence of interaction with the Trp64Arg variant of the β-3-adrenergic receptor

Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regulated by the deiodinases of which type 2 is expressed in humans in skeletal muscle and brown adipose tissue, where its transcription is stimulated by the beta-3 adrenergic pathway. We performed molecular scanning of the human type 2 deiodinase (DIO2) gene and evaluated a novel variant for associations with obesity and insulin resistance, assessing both the main effect and interaction with the Trp64Arg beta-3-adrenergic receptor (ADR133) variant. Molecular scanning of DIO2 in 50 obese Caucasians demonstrated a Thr92AIa variant. Association studies in 972 nondiabetic patients, 135 of whom underwent euglycemic-hyperinsulinemic clamps, showed that subjects with the Thr92Ala variant had lower glucose disposal rate (0.54 +/- 0.02 mg - min(-1) (.) kg(-1) fat-free mass Ala92 homozygotes vs. 0.44 +/- 0.02 Ala92 heterozygotes vs. 0.42 +/- 0.04 Thr92 homozygotes, P = 0.0088). Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92AIa DIO2 and Trp64Arg ADR133 variants on BMI (both variants 34.3 +/- 0.9 kg/m(2) vs. neither variant 33.1 +/- 0.4 kg/m(2), P = 0.04 for interaction). To our knowledge, Thr92AIa is the first description of a missense mutation of DIO2. This variant strongly associates with insulin resistance and, in subjects with the Trp64Arg ADR133 variant, an increased BMI, suggesting an interaction between these two common gene variants.