Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Physiology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Biochim Biophys Acta Mol Basis Dis. 2021 Apr 1;1867(4):166075. doi: 10.1016/j.bbadis.2021.166075. Epub 2021 Jan 12.
Although it is well established that diabetes impairs mitochondrial respiratory chain activity, little is known of the effects of intranasal insulin (INI) on the mitochondrial respiratory chain and structure-function of mitoBK channel in diabetes. We have investigated this mechanism in an STZ-induced early type 2 diabetic model. Single ATP-sensitive mitoBK channel activity was considered in diabetic and INI-treated rats using a channel incorporated into the bilayer lipid membrane. Because mitoBK channels have been involved in mitochondrial respiratory chain activity, a study was undertaken to investigate whether the NADH, complexes I and IV, mitochondrial ROS production, and ΔΨ are altered in an early diabetic model. In this work, we provide evidence for a significant decrease in channel open probability and conductance in diabetic rats. Evidence has been shown that BK channel β2 subunits induce a left shift in the BK channel voltage dependent curve in low Ca conditions,; our results indicated a significant decrease in mitoBK β2 subunits using Western blot analysis. Importantly, INI treatment improved mitoBK channel behaviors and β2 subunits expression up to ~70%. We found that early diabetes decreased activities of complex I and IV and increased NADH, ROS production, and ΔΨ. Surprisingly, INI modified the mitochondrial respiratory chain, ROS production, and ΔΨ up to ~70%. Our results thus demonstrate an INI improvement in respiratory chain activity and ROS production in brain mitochondrial preparations coming from the STZ early diabetic rat model, an effect potentially linked to INI improvement in mitoBK channel activity and channel β2 subunit expression.
尽管糖尿病确实会损害线粒体呼吸链的活性，但人们对鼻内胰岛素（INI）对糖尿病中线粒体呼吸链和 mitoBK 通道结构功能的影响知之甚少。我们在 STZ 诱导的早期 2 型糖尿病模型中研究了这种机制。使用整合到双层脂质膜中的通道，研究了糖尿病和 INI 治疗大鼠中单一 ATP 敏感的 mitoBK 通道活性。由于 mitoBK 通道已参与线粒体呼吸链活性，因此进行了一项研究以调查早期糖尿病模型中 NADH、复合物 I 和 IV、线粒体 ROS 产生和 ΔΨ 是否发生改变。在这项工作中，我们提供了证据表明糖尿病大鼠通道开放概率和电导率显着降低。有证据表明，BK 通道β2 亚基在低钙条件下诱导 BK 通道电压依赖性曲线向左移动；我们的结果表明，使用 Western blot 分析，mitoBK β2 亚基显着减少。重要的是，INI 治疗将 mitoBK 通道行为和β2 亚基表达改善至约 70%。我们发现，早期糖尿病降低了复合物 I 和 IV 的活性，增加了 NADH、ROS 产生和ΔΨ。令人惊讶的是，INI 修饰了线粒体呼吸链、ROS 产生和ΔΨ，最高可达约 70%。因此，我们的研究结果表明，INI 改善了来自 STZ 早期糖尿病大鼠模型的脑线粒体制剂中的呼吸链活性和 ROS 产生，这种作用可能与 INI 改善 mitoBK 通道活性和通道β2 亚基表达有关。
