Brief Genetics Report 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 -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 -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 -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 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 Thr92Ala DIO2 and Trp64Arg ADRB3 variants on BMI (both variants 34.3 0.9 kg/m vs. neither variant 33.1 0.4 kg/m, 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. Diabetes 51:880–883, 2002 The cluster of obesity, hypertension, insulin resistance, and glucose intolerance/diabetes (Syndrome X) is a polygenic multifactorial condition in which the phenotype is the net result of the interaction between environmental factors and genetic predisposition deriving from variations in genes encoding proteins involved in metabolic pathways (1). In fact, polymorphisms in several candidate genes, such as the -3 adrenergic receptor (ADRB3) (2,3), insulin receptor substrate-1 (4), peroxisome proliferator–activated receptor(5), fatty acid binding protein-2 (6), and perhaps others, have shown association with various traits of Syndrome X. Thyroid hormones are important elements in the regulation of metabolic rate (7,8) and, although the molecular and cell biology of this process is not yet fully understood, evidence suggests that the thyroid hormones stimulate resting metabolic rate (RMR) by increasing ATP expenditure and through the regulation of expression of uncoupling proteins in the mitochondria of fat and muscle (9). Thyroid hormone also modulates adrenergic receptor number and thus responsiveness to catecholamines, which are also regulators of metabolic rate (10). Thus, thyroid hormone action is an extremely important determinant of the maintenance of the energy homeostasis. Furthermore, thyroid hormone influences carbohydrate metabolism in skeletal muscle and adipose tissue via the positive transcriptional regulation of the muscle/fat specific GLUT4 (11,12). The deiodinases play a key role in the maintenance of circulating and tissue levels of thyroid hormones. The pro-hormone T4 is converted in the periphery to its active form, T3, or to its inactive metabolite, reverse T3, by the action of these enzymes (13). The deiodinases are selenoenzymes characterized by a selenocysteine in the catalytic domain of the enzyme encoded by a UGA codon in the presence of a characteristic 3 untranslated region stem loop structure, the selenocysteine insertion sequence (SECIS) (14). Type 2 deiodinase appears to be a tissue-specific regulator of the intracellular T3 concentrations in brown fat, brain, and pituitary. In humans, type 2 deiodinase is From the Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, Baltimore, Maryland; the Graduate Program in Endocrinology, University of Rome “Tor Vergata,” Rome, Italy; the Department of Experimental Medicine and Pathology, University of Rome “La Sapienza,” Rome, Italy; Division of Nutrition, University of Rome “La Sapienza, Rome, Italy; the Department of Nutrition, University of Montreal, Montreal, Canada; the Baltimore Veterans Administration Geriatric Research and Education Clinical Center, Baltimore, Maryland. Address correspondence and reprint requests to Francesco Saverio Celi, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, 660 West Redwood St., Room 484, Baltimore, MD 21201. E-mail: [email protected] or [email protected]. Received for publication 1 October 2001 and accepted in revised form 5 December 2001. Additional information for this article can be accessed at http://diabetes. diabetesjournals.org. ADRB3, -3–adrenergic receptor; DIO2, human type 2 deiodinase; RFLP, restriction fragment–length polymorphism; RMR, resting metabolic rate; SECIS, selenocysteine insertion sequence; SSCP, single strand conformation polymorphism.