甲状腺肿形成过程中胰岛素受体底物-1的双相调节

Grozovsky R, Morales M M, Carvalho D P

Laboratório de Fisiologia Endócrina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.

Braz J Med Biol Res. 2007 May;40(5):679-86. doi: 10.1590/s0100-879x2007000500011.

Insulin receptor substrate-1 (IRS-1) is the main intracellular substrate for both insulin and insulin-like growth factor I (IGF-I) receptors and is critical for cell mitogenesis. Thyrotropin is able to induce thyroid cell proliferation through the cyclic AMP intracellular cascade; however, the presence of either insulin or IGF-I is required for the mitogenic effect of thyroid-stimulating hormone (TSH) to occur. The aim of the present study was to determine whether thyroid IRS-1 content is modulated by TSH in vivo. Strikingly, hypothyroid goitrous rats, which have chronically high serum TSH levels (control, C = 2.31 +/- 0.28; methimazole (MMI) 21d = 51.02 +/- 6.02 ng/mL, N = 12 rats), when treated with 0.03% MMI in drinking water for 21 days, showed significantly reduced thyroid IRS-1 mRNA content. Since goiter was already established in these animals by MMI for 21 days, we also evaluated IRS-1 expression during goitrogenesis. Animals treated with MMI for different periods of time showed a progressive increase in thyroid weight (C = 22.18 +/- 1.21; MMI 5d = 32.83 +/- 1.48; MMI 7d = 31.1 +/- 3.25; MMI 10d = 33.8 +/- 1.25; MMI 14d = 45.5 +/- 2.56; MMI 18d = 53.0 +/- 3.01; MMI 21d = 61.9 +/- 3.92 mg, N = 9-15 animals per group) and serum TSH levels (C = 1.57 +/- 0.2; MMI 5d = 9.95 +/- 0.74; MMI 7d = 10.38 +/- 0.84; MMI 10d = 17.72 +/- 1.47; MMI 14d = 25.65 +/- 1.23; MMI 18d = 35.38 +/- 3.69; MMI 21d = 31.3 +/- 2.7 ng/mL, N = 9-15 animals per group). Thyroid IRS-1 mRNA expression increased progressively during goitrogenesis, being significantly higher by the 14th day of MMI treatment, and then started to decline, reaching the lowest values by the 21st day, when a significant reduction was detected. In the liver of these animals, however, a significant decrease of IRS-1 mRNA was detected after 14 days of MMI treatment, a mechanism probably involved in the insulin resistance that occurs in hypothyroidism. The increase in IRS-1 expression during goitrogenesis may represent an important event associated with the increased rate of cell mitosis promoted by TSH and indicates that insulin and IGF-I are important co-mitogenic factors in vivo, possibly acting through the activation of IRS-1.

胰岛素受体底物-1（IRS-1）是胰岛素和胰岛素样生长因子I（IGF-I）受体共同的主要细胞内底物，对细胞有丝分裂至关重要。促甲状腺激素能够通过环磷酸腺苷细胞内级联反应诱导甲状腺细胞增殖；然而，促甲状腺激素（TSH）产生促有丝分裂作用需要胰岛素或IGF-I的存在。本研究的目的是确定TSH在体内是否会调节甲状腺IRS-1的含量。令人惊讶的是，患有慢性高血清TSH水平的甲状腺功能减退性甲状腺肿大鼠（对照组，C = 2.31±0.28；甲巯咪唑（MMI）处理21天组 = 51.02±6.02 ng/mL，N = 12只大鼠），当用0.03% MMI饮用水处理21天时，甲状腺IRS-1 mRNA含量显著降低。由于这些动物已经用MMI处理21天形成了甲状腺肿，我们还评估了甲状腺肿形成过程中IRS-1的表达。用MMI处理不同时间的动物甲状腺重量逐渐增加（对照组，C = 22.18±1.21；MMI处理5天组 = 32.83±1.48；MMI处理7天组 = 31.1±3.25；MMI处理10天组 = 33.8±1.25；MMI处理14天组 = 45.5±2.56；MMI处理18天组 = 53.0±3.01；MMI处理21天组 = 61.9±3.92 mg，每组N = 9 - 15只动物）以及血清TSH水平逐渐升高（对照组，C = 1.57±0.2；MMI处理5天组 = 9.95±0.74；MMI处理7天组 = 10.38±0.84；MMI处理10天组 = 17.72±1.47；MMI处理14天组 = 25.65±1.2；MMI处理18天组 = 35.38±3.69；MMI处理21天组 = 31.3±2.7 ng/mL，每组N = 9 - 15只动物）。甲状腺IRS-1 mRNA表达在甲状腺肿形成过程中逐渐增加，在MMI处理第14天时显著升高，然后开始下降，到第21天时达到最低值，此时检测到显著降低。然而，在这些动物的肝脏中，MMI处理14天后检测到IRS-1 mRNA显著下降，这一机制可能与甲状腺功能减退时出现的胰岛素抵抗有关。甲状腺肿形成过程中IRS-1表达的增加可能代表了与TSH促进的细胞有丝分裂速率增加相关的一个重要事件，表明胰岛素和IGF-I在体内是重要的协同促有丝分裂因子，可能通过激活IRS-1发挥作用。