Ordóñez P, Moreno M, Alonso A, Llaneza P, Díaz F, González C
Department of Functional Biology, Physiology Area, University of Oviedo, C/ Julián Clavería s/n 33006, Oviedo, Spain.
J Steroid Biochem Mol Biol. 2008 Sep;111(3-5):287-94. doi: 10.1016/j.jsbmb.2008.07.001. Epub 2008 Jul 9.
Recent clinical and experimental evidences suggest that sex steroids protect from insulin resistance associated with diabetes. Therefore, we have assessed the influence of E2 and/or P4 on insulin sensitivity by euglicaemic-hyperinsulinaemic clamp in ovariectomized streptozotocin-induced diabetic rats, focusing on key proteins of insulin signaling in skeletal muscle. Although low plasma levels of E2 (days 6 and 11) increased Glut-4 plasma membrane content and subsequent improved insulin sensitivity, they could not fully reverse hyperglycaemia negative effects on p85alpha-IRS-1 association and IRS-1 content during 11 days. However, high plasma levels of E2 (day 16) could reverse hyperglycaemia effects not only on Glut-4 plasma membrane content but also on p85alpha-IRS-1 association and IRS-1 protein content level. In contrast, P4 treatment only improved insulin sensitivity when its plasma concentration was low (days 6 and 11) and its effects were not associated with any proteins study in this paper. The combined therapy had a synergic effect on insulin sensitivity when their plasma levels were low (day 6) or high (day 16), that could be associated with Glut-4 plasma membrane content modulation, p85alpha-IRS-1 association and IRS-1 amount. These new findings improve our understanding of biochemical basis of insulin resistance due to hyperglycaemia and could open up new possibilities of treatment in uncontrolled type 1 DM.
近期的临床和实验证据表明，性类固醇可预防与糖尿病相关的胰岛素抵抗。因此，我们通过正常血糖-高胰岛素钳夹技术，评估了雌二醇（E2）和/或孕酮（P4）对去卵巢链脲佐菌素诱导的糖尿病大鼠胰岛素敏感性的影响，重点关注骨骼肌中胰岛素信号传导的关键蛋白。尽管低血浆E2水平（第6天和第11天）增加了葡萄糖转运蛋白4（Glut-4）的质膜含量，随后改善了胰岛素敏感性，但在11天内它们无法完全逆转高血糖对p85α-胰岛素受体底物1（IRS-1）结合及IRS-1含量的负面影响。然而，高血浆E2水平（第16天）不仅可以逆转高血糖对Glut-4质膜含量的影响，还能逆转其对p85α-IRS-1结合及IRS-1蛋白含量水平的影响。相比之下，P4治疗仅在其血浆浓度较低时（第6天和第11天）改善胰岛素敏感性，且其作用与本文研究的任何蛋白均无关。当血浆水平较低（第6天）或较高（第16天）时，联合治疗对胰岛素敏感性具有协同作用，这可能与Glut-4质膜含量调节、p85α-IRS-1结合及IRS-1数量有关。这些新发现增进了我们对高血糖所致胰岛素抵抗生化基础的理解，并可能为1型糖尿病控制不佳的治疗开辟新的途径。
