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
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
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DOI：
10.2337/diabetes.51.3.880
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发表时间：
2002-03-01
期刊：
影响因子：
7.7
通讯作者：
Celi, FS
中科院分区：
文献类型：
--
作者：
Mentuccia, D;Proietti-Pannunzi, L;Celi, FS
甲状腺激素的作用是能量和葡萄糖代谢的重要决定因素。T4代谢受脱碘酶调节，其中2型脱碘酶在人体骨骼肌和棕色脂肪组织中表达，其转录受β-3肾上腺素能途径刺激。我们对人类2型脱碘酶（DIO 2）基因进行了分子扫描，并评估了一种新的变体与肥胖和胰岛素抵抗的相关性，评估了主要效应以及与Trp 64 Arg β-3-肾上腺素能受体（ADR 133）变体的相互作用。50例肥胖白种人DIO 2的分子扫描显示Thr 92 AIa变异。在972名非糖尿病患者中进行的相关性研究，其中135名接受了正常血糖-高胰岛素钳夹试验，结果显示Thr 92 Ala变异的受试者葡萄糖处理率较低（0.54 +/- 0.02 mg·min（-1）（.）Ala 92纯合子与0.44 +/- 0.02 Ala 92杂合子与0.42 +/- 0.04 Thr 92纯合子的去脂质量分别为0.44 ± 0.02和0.42 ± 0.04 kg，P = 0.0088）。整个组的关联分析显示Thr 92 AIa DIO 2和Trp 64 Arg ADR 133变体之间对BMI的协同效应的显著证据（两种变体均为34.3 +/- 0.9 kg/m2 vs.两种变体均为33.1 +/- 0.4 kg/m2，相互作用P = 0.04）。据我们所知，Thr 92 AIa是DIO 2错义突变的第一个描述。该变体与胰岛素抵抗密切相关，并且在Trp 64 Arg ADR 133变体受试者中，BMI增加，表明这两种常见基因变体之间存在相互作用。
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.