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Brief Genetics Report 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 Daniela Mentuccia,1,2 Laura Proietti-Pannunzi,3 Keith Tanner,1 Vincenzo Bacci,4 Toni I. Pollin,1 Eric T. Poehlman,5 Alan R. Shuldiner,1,6 and Francesco S. Celi3 Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regu- lated by the deiodinases of which type 2 is expressed in he cluster of obesity, hypertension, insulin resis- humans in skeletal muscle and brown adipose tissue, tance, and glucose intolerance/diabetes (Syn- where its transcription is stimulated by the ␤-3 adren- drome X) is a polygenic multifactorial condition ergic pathway. We performed molecular scanning of the in which the phenotype is the net result of the human type 2 deiodinase (DIO2) gene and evaluated a T interaction between environmental factors and genetic novel variant for associations with obesity and insulin resistance, assessing both the main effect and interac- predisposition deriving from variations in genes encoding tion with the Trp64Arg ␤-3–adrenergic receptor (ADRB3) proteins involved in metabolic pathways (1). In fact, variant. Molecular scanning of DIO2 in 50 obese Cauca- polymorphisms in several candidate genes, such as the ␤-3 sians demonstrated a Thr92Ala variant. Association adrenergic receptor (ADRB3) (2,3), insulin receptor sub- studies in 972 nondiabetic patients, 135 of whom under- strate-1 (4), peroxisome proliferator–activated receptor-␥ went euglycemic-hyperinsulinemic clamps, showed that (5), fatty acid binding protein-2 (6), and perhaps others, subjects with the Thr92Ala variant had lower glucose have shown association with various traits of Syndrome X. ⅐ ؊1 ⅐ ؊1 ؎ disposal rate (0.54 0.02 mg min kg fat-free mass Thyroid hormones are important elements in the regu- Ala92 homozygotes vs. 0.44 ؎ 0.02 Ala92 heterozygotes Asso- lation of metabolic rate (7,8) and, although the molecular .(0.0088 ؍ vs. 0.42 ؎ 0.04 Thr92 homozygotes, P ciation analysis of the entire group showed significant and cell biology of this process is not yet fully understood, evidence for a synergistic effect between the Thr92Ala evidence suggests that the thyroid hormones stimulate DIO2 and Trp64Arg ADRB3 variants on BMI (both vari- resting metabolic rate (RMR) by increasing ATP expendi- -ants 34.3 ؎ 0.9 kg/m2 vs. neither variant 33.1 ؎ 0.4 kg/m2, ture and through the regulation of expression of uncou .(for interaction). To our knowledge, Thr92Ala pling proteins in the mitochondria of fat and muscle (9 0.04 ؍ P is the first description of a missense mutation of DIO2. Thyroid hormone also modulates adrenergic receptor This variant strongly associates with insulin resistance number and thus responsiveness to catecholamines, and, in subjects with the Trp64Arg ADRB3 variant, an which are also regulators of metabolic rate (10). Thus, increased BMI, suggesting an interaction between these thyroid hormone action is an extremely important deter- two common gene variants. Diabetes 51:880–883, 2002 minant of the maintenance of the energy homeostasis. Furthermore, thyroid hormone influences carbohydrate From the 1Division of Endocrinology, Diabetes and Nutrition, Department of metabolism in skeletal muscle and adipose tissue via the Medicine, University of Maryland, Baltimore, Maryland; the 2Graduate Pro- positive transcriptional regulation of the muscle/fat spe- gram in Endocrinology, University of Rome “Tor Vergata,” Rome, Italy; the 3Department of Experimental Medicine and Pathology, University of Rome cific GLUT4 (11,12). “La Sapienza,” Rome, Italy; 4Division of Nutrition, University of Rome “La The deiodinases play a key role in the maintenance of Sapienza, Rome, Italy; the 5Department of Nutrition, University of Montreal, circulating and tissue levels of thyroid hormones. The Montreal, Canada; the 6Baltimore Veterans Administration Geriatric Research and Education Clinical Center, Baltimore, Maryland. pro-hormone T4 is converted in the periphery to its active Address correspondence and reprint requests to Francesco Saverio Celi, form, T3, or to its inactive metabolite, reverse T3, by the Division of Endocrinology, Diabetes and Nutrition, University of Maryland action of these enzymes (13). The deiodinases are seleno- School of Medicine, 660 West Redwood St., Room 484, Baltimore, MD 21201. E-mail: [email protected] or [email protected]. enzymes characterized by a selenocysteine in the catalytic Received for publication 1 October 2001 and accepted in revised form 5 domain of the enzyme encoded by a UGA codon in the pres- December 2001. Ј Additional information for this article can be accessed at http://diabetes. ence of a characteristic 3 untranslated region stem loop diabetesjournals.org. structure, the selenocysteine insertion sequence (SECIS) ADRB3, ␤-3–adrenergic receptor; DIO2, human type 2 deiodinase; RFLP, (14). Type 2 deiodinase appears to be a tissue-specific restriction fragment–length polymorphism; RMR, resting metabolic rate; SE- CIS, selenocysteine insertion sequence; SSCP, single strand conformation regulator of the intracellular T3 concentrations in brown polymorphism. fat, brain, and pituitary. In humans, type 2 deiodinase is 880 DIABETES, VOL. 51, MARCH 2002 D. MENTUCCIA AND ASSOCIATES TABLE 1 euglycemic clamp studies were performed in a subgroup Study population characteristics of 135 nondiabetic women. In this subgroup, there were no Age Men/ significant differences between genotypes in age, weight, n (years) BMI (kg/m2) Women BMI, fasting glucose levels, or RMR (Table 2). However, we observed a marked decrease in the glucose disposal Gene scanning 50 38.5 Ϯ 11 46.0 Ϯ 5 11/39 rate in subjects with the Thr92Ala variant (Ala92 homozy- Ϯ Ϯ Association analysis 972 56.0 13 32.8 8 71/901 gotes 17.2 Ϯ 1.6 mmol/min vs. Ala92 heterozygotes 18.2 Ϯ (total) Ϯ Association analysis 135 42.3 Ϯ 16.7 27.1 Ϯ 7.8 0/135 0.8 mmol/min vs. Thr92 homozygotes 22.6 0.9 mmol/min, (hyperinsulinemic P ϭ 0.0006), consistent with a dominant model (Table 2). clamp) A trend toward an increase of fasting insulin level was observed in carriers of the Ala92 DIO2 allele (Ala92 homo- Ϯ Data are means SD and n. zygotes 105.0 Ϯ 18.6 pmol/l vs. heterozygotes 72.0 Ϯ 9.6 pmol/l vs. Thr92 homozygotes 57.0 Ϯ 10.2 pmol/l, P ϭ also expressed in skeletal muscle (15). The type 2 deiodi- 0.0814) consistent with greater insulin resistance. nase gene (DIO2) is localized on chromosome 14q24.3, and In the larger group (n ϭ 922), the Thr92Ala DIO2 the entire gene is encoded by three exons (16). Experi- polymorphism did not associate with body weight or BMI. mental evidence demonstrates that DIO2 activity is regu- lated by metabolic stressors, such as cold exposure and However, significantly higher weight and BMI were ob- adrenergic stimulation, via the generation of intracellular served in carriers of both the Thr92Ala DIO2 and Trp64Arg cAMP (17,18). Furthermore, the action of this enzyme ADRB3 variants compared with subjects with neither or provides the supply of T3 for local use by the tissue itself, either variant alone, suggesting an interaction between the thus creating a type of autoregulatory, autocrine feedback two (Table 3). loop (19). We thus decided to study DIO2 as a candidate To our knowledge, this is the first description of a gene for obesity and insulin resistance in a population of missense variant of the human DIO2 gene. Although the morbidly obese Caucasians with normal thyroid function crystal structure of the type 2 deiodinine is not yet known, and to perform association studies of the gene variants in it is worth noting that this nonconservative amino acid a well-characterized nondiabetic Caucasian population change (aliphatic for polar group), which is not located (Table 1). within the conserved deiodinase catalytic domain, could By performing gene scanning of the entire coding region potentially affect its activity (21). However, this region of and the SECIS element of DIO2 with PCR–single strand the enzyme is not phylogenetically conserved. The homol- conformation polymorphism (SSCP) analysis, followed by ogous amino acid is represented by a proline in rodents DNA sequence analysis, we identified a common noncon- and by a glycine in chick. By contrast, humans and am- servative variant, 274 A3G, that predicts a nonconserva- phibians share a threonine in this position. The functional tive Thr92Ala substitution (Fig. 1). No other variants were consequences of this common missense mutation are not observed. The allele frequency of the Thr92Ala DIO2 yet known. variant was 0.35 in the study population with a distribution Our results indicate that the DIO2 Thr92Ala variant meeting Hardy-Weinberg equilibrium. This variant was strongly associates with insulin resistance as measured by common in various ethnic groups, particularly in Pima the hyperinsulinemic-euglycemic clamp. An inactivating Indians and Mexican-Americans with allele frequencies of mutation in DIO2 could lead to decreased intracellular 0.75 and 0.42, respectively (see online appendix at http:// availability of active thyroid hormone. A reduction in T3 diabetes.diabetesjournals.org). would, in turn, decrease the transcription of GLUT4 in Association studies were performed in a large, well- insulin-sensitive tissues, such as skeletal muscle and adi- characterized nondiabetic Caucasian population (20) re- pose tissue, contributing to insulin
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