Clinical Research Center for Diabetes, Tokushima University Hospital, Kuramoto-cho, Tokushima 770-8503, Japan.
Mol Cell Endocrinol. 2013 Jan 5;365(1):25-35. doi: 10.1016/j.mce.2012.08.022. Epub 2012 Sep 10.
Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.
血清素（5-羟色胺，5-HT）在糖尿病患者的血清中被发现升高。在这项研究中，我们研究了 5-HT 引起胰岛素失敏的机制。在 3T3-L1 脂肪细胞中，5-HT 处理诱导胰岛素受体底物-1（IRS-1）从低密微体（LDM）易位，LDM 是其功能的重要细胞内隔室，导致 IRS-1 泛素化和降解。此外，通过 ketanserin（一种特异性 5-HT2A 受体拮抗剂）或敲低 5-HT2A 受体的表达抑制 5-HT 刺激的 Akt 激活，促进了 5-HT 刺激的 IRS-1 从 LDM 中的 14-3-3β解离，导致剧烈的泛素化。有趣的是，另一种 5-HT2A 受体拮抗剂 sarpogrelate 通过激活 Akt 保护 IRS-1 免于降解。这表明 Akt 激活在通过将 IRS-1 维持在最佳亚细胞位置到脂肪细胞中，从而延长 IRS-1 的寿命方面非常重要。综上所述，这项研究表明，Akt 的激活可能能够通过稳定 LDM 中的 IRS-1 来补偿 5-HT 的不利影响。
