Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary.
Neurochem Res. 2021 Jun;46(6):1350-1358. doi: 10.1007/s11064-021-03269-2. Epub 2021 Feb 22.
Recently neuronal insulin resistance was suggested playing a role in Alzheimer's disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration-response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.
最近有研究表明，神经元胰岛素抵抗在阿尔茨海默病中起作用。链脲佐菌素（STZ）常用于诱导胰岛素代谢损伤。在我们之前对未分化的 SH-SY5Y 细胞的研究中，该化合物表现出细胞毒性而不改变胰岛素敏感性。然而，细胞向更成熟的神经元样表型分化可能会极大地影响胰岛素信号及其对 STZ 的敏感性。我们旨在研究 STZ 处理对 RA 分化的 SH-SY5Y 细胞中胰岛素信号的影响。比较了 STZ 或低血清（LS）条件对 RA 分化的 SH-SY5Y 细胞的细胞毒性以及胰岛素的保护作用。还通过评估糖原合酶激酶-3（GSK-3）磷酸化来研究胰岛素和肠降血糖素类似物 exendin-4 对胰岛素信号的影响。与我们之前在未分化的 SH-SY5Y 细胞中的结果相比，STZ 在分化细胞中的细胞毒性较低。胰岛素的细胞保护浓度在 STZ 和 LS 组中相似。然而，STZ 处理的分化细胞中胰岛素诱导的 GSK-3 磷酸化的浓度反应曲线右移提示发生了胰岛素抵抗，这进一步被 exendin-4 增强胰岛素作用所证实。分化降低了 SH-SY5Y 细胞对 STZ 非特异性细胞毒性的敏感性，并增强了胰岛素抵抗发展的相对重要性。因此，分化后的细胞可作为研究胰岛素信号在神经元存活中的作用的更好模型。然而，STZ 的直接细胞毒性也导致细胞死亡。
