Peeters Robin P, van den Beld Annewieke W, van Toor Hans, Uitterlinden Andre G, Janssen Joop A M J L, Lamberts Steven W J, Visser Theo J
Department of Internal Medicine, Room Ee 502, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2005 Jan;90(1):256-63. doi: 10.1210/jc.2004-1301. Epub 2004 Oct 13.
The interaction between the GH-IGF-I axis and thyroid hormone metabolism is complex and not fully understood. T(4) stimulates IGF-I activity in animals in the absence of GH. On the other hand, GH replacement therapy results in an increase in serum T(3) and a decrease in T(4) and rT(3) levels, suggesting a stimulation of type I deiodinase (D1) activity. Recently, we demonstrated the association of two polymorphisms in D1 (D1a-C/T; T = 34%, and D1b-A/G; G = 10%) with serum iodothyronine levels. Haplotype alleles were constructed, suggesting a lower activity of the D1 haplotype 2 allele (aT-bA) and a higher activity of the haplotype allele 3 (aC-bG). In this study, we investigated whether genetic variations in D1 are associated with the IGF-I system. In 156 blood donors and 350 elderly men, the association of the D1 haplotype alleles with circulating IGF-I and free IGF-I levels was studied. In addition, potential associations with muscle strength and body composition were investigated in the elderly population. Finally, the relation between serum iodothyronine levels and IGF-I levels was studied. In blood donors, haplotype allele 2 was associated with higher levels of free IGF-I (302.9 +/- 22.9 vs. 376.3 +/- 19.1 pg/ml, P = 0.02). In elderly men, haplotype allele 2 also showed an allele dose increase in free IGF-I levels (P(trend) = 0.01) and an allele dose decrease in serum T(3) levels (P(trend) = 0.01), independent of age. Carriers of the D1a-T variant also had a higher isometric grip strength (P = 0.047) and maximum leg extensor strength (P = 0.07) as well as a higher lean body mass (P = 0.03). In blood donors, T(4) and free T(4) were negatively correlated with total IGF-I levels (R = -0.18, P = 0.03 and R = -0.24, P = 0.003), whereas T(3) to T(4) and T(3) to reverse T(3) ratios were positively correlated with total IGF-I (R = 0.31, P < 0.001 and R = 0.18, P = 0.03). Free IGF-I showed a negative correlation with T(4) (R = -0.26, P = 0.001) and T(4)-binding globulin (R = -0.31, P < 0.001) and a positive correlation with T(3) to T(4) ratio (R = 0.21, P = 0.01). In conclusion, a polymorphism that results in a decreased D1 activity is associated with an increase in free IGF-I levels. The pathophysiological significance of this association with IGF-I is supported by an increased muscle strength and muscle mass in carriers of the D1 haplotype 2 allele in a population of elderly men. The association of D1 haplotype allele 2 with serum T(3) levels in the elderly population suggests a relative increase in its contribution to circulating T(3) in old age.
生长激素（GH）-胰岛素样生长因子-I（IGF-I）轴与甲状腺激素代谢之间的相互作用复杂且尚未完全明确。在缺乏GH的情况下，T4可刺激动物体内IGF-I的活性。另一方面，GH替代疗法会导致血清T3升高，T4和反T3水平降低，提示I型脱碘酶（D1）活性增强。最近，我们证实了D1基因的两个多态性（D1a-C/T；T = 34%，以及D1b-A/G；G = 10%）与血清甲状腺素水平相关。构建了单倍型等位基因，提示D1单倍型2等位基因（aT-bA）活性较低，而单倍型等位基因3（aC-bG）活性较高。在本研究中，我们调查了D1基因的遗传变异是否与IGF-I系统相关。在156名献血者和350名老年男性中，研究了D1单倍型等位基因与循环IGF-I和游离IGF-I水平的相关性。此外，在老年人群中调查了其与肌肉力量和身体组成的潜在关联。最后，研究了血清甲状腺素水平与IGF-I水平之间的关系。在献血者中，单倍型等位基因2与较高的游离IGF-I水平相关（302.9±22.9 vs. 376.3±19.1 pg/ml，P = 0.02）。在老年男性中，单倍型等位基因2也显示出游离IGF-I水平的等位基因剂量增加（P趋势 = 0.01）以及血清T3水平的等位基因剂量降低（P趋势 = 0.01），且与年龄无关。D1a-T变异的携带者还具有较高的等长握力（P = 0.047）和最大腿部伸肌力量（P = 0.07）以及较高的瘦体重（P = 0.03）。在献血者中，T4和游离T4与总IGF-I水平呈负相关（R = -0.18，P = 0.03和R = -0.24，P = 0.003），而T3/T4和T3/反T3比值与总IGF-I呈正相关（R = 0.31，P < 0.001和R = 0.18，P = 0.03）。游离IGF-I与T4（R = -0.26，P = 0.001）和T4结合球蛋白（R = -0.31，P < 0.001）呈负相关，与T3/T4比值呈正相关（R = 0.21，P = 0.01）。总之，导致D1活性降低的一种多态性与游离IGF-I水平升高相关。在老年男性人群中，D1单倍型2等位基因携带者的肌肉力量和肌肉量增加，支持了这种与IGF-I关联的病理生理意义。老年人群中D1单倍型等位基因2与血清T3水平的关联提示其在老年时对循环T3的贡献相对增加。
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