Santos R X, Correia S C, Alves M G, Oliveira P F, Cardoso S, Carvalho C, Duarte A I, Santos M S, Moreira P I
Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra, Coimbra, Portugal.
Biochim Biophys Acta. 2014 Jul;1842(7):1154-66. doi: 10.1016/j.bbadis.2014.04.011. Epub 2014 Apr 18.
The main purpose of this study was to examine whether streptozotocin (STZ)-induced type 1 diabetes (T1D) and insulin (INS) treatment affect mitochondrial function, fission/fusion and biogenesis, autophagy and tau protein phosphorylation in cerebral cortex from diabetic rats treated or not with INS. No significant alterations were observed in mitochondrial function as well as pyruvate levels, despite the significant increase in glucose levels observed in INS-treated diabetic rats. A significant increase in DRP1 protein phosphorylated at Ser616 residue was observed in the brain cortex of STZ rats. Also an increase in NRF2 protein levels and in the number of copies of mtDNA were observed in STZ diabetic rats, these alterations being normalized by INS. A slight decrease in LC3-II levels was observed in INS-treated rats when compared to STZ diabetic animals. An increase in tau protein phosphorylation at Ser396 residue was observed in STZ diabetic rats while INS treatment partially reversed that effect. Accordingly, a modest reduction in the activation of GSK3β and a significant increase in the activity of phosphatase 2A were found in INS-treated rats when compared to STZ diabetic animals. No significant alterations were observed in caspases 9 and 3 activity and synaptophysin and PSD95 levels. Altogether our results show that mitochondrial alterations induced by T1D seem to involve compensation mechanisms since no significant changes in mitochondrial function and synaptic integrity were observed in diabetic animals. In addition, INS treatment is able to normalize the alterations induced by T1D supporting the importance of INS signaling in the brain.
本研究的主要目的是探讨链脲佐菌素（STZ）诱导的1型糖尿病（T1D）及胰岛素（INS）治疗是否会影响糖尿病大鼠（无论是否接受INS治疗）大脑皮层中的线粒体功能、裂变/融合及生物发生、自噬和tau蛋白磷酸化。尽管在接受INS治疗的糖尿病大鼠中观察到血糖水平显著升高，但线粒体功能以及丙酮酸水平未观察到显著改变。在STZ诱导的糖尿病大鼠大脑皮层中，观察到丝氨酸616位点磷酸化的动力相关蛋白1（DRP1）蛋白显著增加。此外，在STZ诱导的糖尿病大鼠中还观察到核因子E2相关因子2（NRF2）蛋白水平及线粒体DNA（mtDNA）拷贝数增加，这些改变通过INS治疗得以恢复正常。与STZ诱导的糖尿病动物相比，在接受INS治疗的大鼠中观察到微管相关蛋白1轻链3-II（LC3-II）水平略有下降。在STZ诱导的糖尿病大鼠中观察到丝氨酸396位点tau蛋白磷酸化增加，而INS治疗可部分逆转该效应。相应地，与STZ诱导的糖尿病动物相比，在接受INS治疗的大鼠中发现糖原合成酶激酶3β（GSK3β）的激活适度降低，蛋白磷酸酶2A（PP2A）的活性显著增加。半胱天冬酶9和3的活性以及突触素和突触后致密物95（PSD95）水平未观察到显著改变。总之，我们的结果表明，T1D诱导的线粒体改变似乎涉及代偿机制，因为在糖尿病动物中未观察到线粒体功能和突触完整性的显著变化。此外，INS治疗能够使T1D诱导的改变恢复正常，这支持了INS信号在大脑中的重要性。
