RESUMO
A common polymorphism of the type 2 deiodinase gene (Thr92Ala DIO2) was found to be associated with insulin resistance in a mixed Caucasian population. The aim of this study was to investigate the association of the Thr92Ala DIO2 variant to indices of insulin resistance in the Old Order Amish. A genotype-phenotype association study was performed at the research clinic in Strasburg, Pennsylvania, and the molecular genetics laboratory at the University of Maryland, Baltimore, Maryland, and the National Institutes of Health, Bethesda, Maryland. A total of 1,268 subjects participated in the Amish Family Diabetes Study. An association among the Thr92Ala DIO2 variant and type 2 diabetes, indices of insulin resistance (HOMA-IR), insulin secretion, free thyroid hormones, and thyrotropin (TSH) was found. No association was found among the Thr92Ala DIO2 variant and type 2 diabetes, impaired glucose tolerance, or body mass index (BMI) in the Amish. In nondiabetics (n = 747), the Ala92 allele tended to be associated with decreased rather then increased insulin secretion. No differences were observed in thyroid hormones or TSH. Contrary to prior findings, the Thr92Ala DIO2 variant tends to be associated with increased rather then decreased insulin sensitivity in the Amish. These findings could be secondary to a different genetic background or to environmental factors specific for this population.
Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Iodeto Peroxidase/genética , Adulto , Colesterol/sangue , Feminino , Genótipo , Glucose/metabolismo , Humanos , Insulina/sangue , Lipídeos/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Fenótipo , Polimorfismo Genético/genética , Hormônios Tireóideos/sangue , Iodotironina Desiodinase Tipo IIRESUMO
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 (ADRB3) variant. Molecular scanning of DIO2 in 50 obese Caucasians demonstrated a Thr92Ala 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 plus minus 0.02 mg center dot min(-1) center dot kg(-1) fat-free mass Ala92 homozygotes vs. 0.44 plus minus 0.02 Ala92 heterozygotes vs. 0.42 plus minus 0.04 Thr92 homozygotes, P = 0.0088). Association analysis of the entire group showed significant evidence for a synergistic effect between the Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 plus minus 0.9 kg/m(2) vs. neither variant 33.1 plus minus 0.4 kg/m(2), P = 0.04 for interaction). To our knowledge, Thr92Ala is the first description of a missense mutation of DIO2. This variant strongly associates with insulin resistance and, in subjects with the Trp64Arg ADRB3 variant, an increased BMI, suggesting an interaction between these two common gene variants.
