Instituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, Mendel Laboratory, Italy.
Endocr Rev. 2012 Aug;33(4):526-46. doi: 10.1210/er.2011-1042. Epub 2012 May 10.
Insulin signaling plays a physiological role in traditional insulin target tissues controlling glucose homeostasis as well as in pancreatic β-cells and in the endothelium. Insulin signaling abnormalities may, therefore, be pathogenic for insulin resistance, impaired insulin secretion, endothelial dysfunction, and eventually, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Tribbles homolog 3 (TRIB3) is a 45-kDa pseudokinase binding to and inhibiting Akt, a key mediator of insulin signaling. Akt-mediated effects of TRIB3 in the liver, pancreatic β-cells, and skeletal muscle result in impaired glucose homeostasis. TRIB3 effects are also modulated by its direct interaction with other signaling molecules. In humans, TRIB3 overactivity, due to TRIB3 overexpression or to Q84R genetic polymorphism, with R84 being a gain-of-function variant, may be involved in shaping the risk of insulin resistance, T2DM, and cardiovascular disease. TRIB3 overexpression has been observed in the liver, adipose tissue, skeletal muscle, and pancreatic β-cells of individuals with insulin resistance and/or T2DM. The R84 variant has also proved to be associated with insulin resistance, T2DM, and cardiovascular disease. TRIB3 direct effects on the endothelium might also play a role in increasing the risk of atherosclerosis, as indicated by studies on human endothelial cells carrying the R84 variant that are dysfunctional in terms of Akt activation, NO production, and other proatherogenic changes. In conclusion, studies on TRIB3 have unraveled new molecular mechanisms underlying metabolic and cardiovascular abnormalities. Additional investigations are needed to verify whether such acquired knowledge will be relevant for improving care delivery to patients with metabolic and cardiovascular alterations.
胰岛素信号在传统的胰岛素靶组织中发挥生理作用，控制葡萄糖稳态，以及在胰岛β细胞和内皮细胞中发挥作用。因此，胰岛素信号异常可能导致胰岛素抵抗、胰岛素分泌受损、内皮功能障碍，最终导致 2 型糖尿病（T2DM）和心血管疾病。TRIBS 同源物 3（TRIB3）是一种 45kDa 的假激酶，可与 Akt 结合并抑制 Akt，Akt 是胰岛素信号的关键介质。TRIB3 在肝脏、胰岛β细胞和骨骼肌中的 Akt 介导作用导致葡萄糖稳态受损。TRIB3 的作用也受其与其他信号分子的直接相互作用调节。在人类中，TRIB3 过度活跃，由于 TRIB3 过表达或 Q84R 遗传多态性，其中 R84 是一种功能获得性变体，可能参与塑造胰岛素抵抗、T2DM 和心血管疾病的风险。在胰岛素抵抗和/或 T2DM 个体的肝脏、脂肪组织、骨骼肌和胰岛β细胞中观察到 TRIB3 过表达。R84 变体也已被证明与胰岛素抵抗、T2DM 和心血管疾病相关。TRIB3 对内皮细胞的直接作用也可能在增加动脉粥样硬化风险方面发挥作用，这一点可以通过携带 R84 变体的人内皮细胞的研究来证明，这些细胞在 Akt 激活、NO 产生和其他促动脉粥样硬化变化方面存在功能障碍。总之，TRIB3 的研究揭示了代谢和心血管异常的新分子机制。需要进一步的研究来验证这些获得的知识是否与改善代谢和心血管改变患者的护理提供相关。
