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
- Daniela Mentuccia12,
- Laura Proietti-Pannunzi3,
- Keith Tanner1,
- Vincenzo Bacci4,
- Toni I. Pollin1,
- Eric T. Poehlman5,
- Alan R. Shuldiner16 and
- Francesco S. Celi3
- 1Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, Baltimore, Maryland
- 2Graduate Program in Endocrinology, University of Rome “Tor Vergata,” Rome, Italy
- 3Department of Experimental Medicine and Pathology, University of Rome “La Sapienza,” Rome, Italy
- 4Division of Nutrition, University of Rome “La Sapienza, Rome, Italy
- 5Department of Nutrition, University of Montreal, Montreal, Canada
- 6Baltimore Veterans Administration Geriatric Research and Education Clinical Center, Baltimore, Maryland
Abstract
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 β-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 β-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/m2 vs. neither variant 33.1 ± 0.4 kg/m2, 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.
Footnotes
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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: fceli{at}medicine.umaryland.edu or francescosaverio.celi{at}uniroma1.it.
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, β-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.
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