Lehrer Steven, Rheinstein Peter H
Fermata Pharma. Inc New York New York USA.
Severn Health Solutions Severna Park Maryland USA.
Chronic Dis Transl Med. 2024 Jun 30;11(2):148-155. doi: 10.1002/cdt3.141. eCollection 2025 Jun.
Type 2 diabetes (T2D), but not type 1, protected against amyotrophic lateral sclerosis (ALS). In T2D serum insulin is normal or elevated in the early stages. Type 1 diabetes, characterized by a total lack of insulin, is associated with an increased risk of ALS. The antidiabetic metformin also protects against ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open channel via which toxic substances from astrocytes reach motor neurons to cause ALS.
In the current study we analyzed FDA MedWatch data to determine whether insulin or metformin could reduce the risk of ALS. We performed in silico molecular docking studies and molecular dynamics simulation with Cx43 to determine if insulin or metformin dock within the Cx43 channel and can block it effectively, again reducing risk of ALS.
In MedWatch, Insulin use is associated with a significantly reduced risk of ALS (Proportional Reporting Ratio 0.401). Metformin use is associated with a significantly reduced risk of ALS (PRR 0.567). The Human insulin heterodimer docked within center of the Cx43 channel, effectively blocking it. Molecular dynamics simulation showed that the block is highly stable and may be responsible for the protective effect of T2D on ALS. Metformin docks within the Cx43 channel, but the relatively small size of the metformin molecule may not allow it to obstruct the passage of toxic substances from astrocytes to motor neurons.
MedWatch data indicate that both insulin and metformin reduce risk of ALS. The results of our in silico docking study and molecular dynamics simulation corroborate our previous findings with Cx31. Insulin docks within the open hemichannel of hexameric Cx43, potentially blocking it. Molecular dynamics simulation showed that the block is stable and may be responsible for the protective effect of T2D and insulin on ALS.
2型糖尿病（T2D）而非1型糖尿病可预防肌萎缩侧索硬化症（ALS）。在T2D早期，血清胰岛素正常或升高。1型糖尿病的特征是完全缺乏胰岛素，与ALS风险增加有关。抗糖尿病药物二甲双胍也可预防ALS。连接蛋白43（Cx43）是一种星形胶质细胞蛋白，作为一个开放通道，星形胶质细胞的有毒物质通过该通道到达运动神经元，从而导致ALS。
在本研究中，我们分析了美国食品药品监督管理局（FDA）不良事件报告系统（MedWatch）的数据，以确定胰岛素或二甲双胍是否能降低ALS风险。我们对Cx43进行了计算机模拟分子对接研究和分子动力学模拟，以确定胰岛素或二甲双胍是否能对接在Cx43通道内并有效阻断它，从而再次降低ALS风险。
在MedWatch中，使用胰岛素与ALS风险显著降低相关（比例报告比值为0.401）。使用二甲双胍与ALS风险显著降低相关（PRR为0.567）。人胰岛素异二聚体对接在Cx43通道中心，有效阻断了该通道。分子动力学模拟表明，这种阻断非常稳定，可能是T2D对ALS具有保护作用的原因。二甲双胍对接在Cx43通道内，但二甲双胍分子相对较小，可能无法阻止星形胶质细胞的有毒物质向运动神经元的传递。
MedWatch数据表明，胰岛素和二甲双胍均可降低ALS风险。我们的计算机模拟对接研究和分子动力学模拟结果证实了我们先前关于Cx31的研究结果。胰岛素对接在六聚体Cx43的开放半通道内，可能会阻断它。分子动力学模拟表明，这种阻断是稳定的，可能是T2D和胰岛素对ALS具有保护作用的原因。
