Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA.
J Diabetes Res. 2018 Mar 18;2018:9163052. doi: 10.1155/2018/9163052. eCollection 2018.
Metformin is considered the first-line treatment for type 2 diabetes. While metformin primarily increases insulin sensitivity, evidence also suggests that metformin affects the activity of insulin-secreting pancreatic islets. This study was designed to systematically examine the direct effects of metformin by measuring insulin secretion and the kinetics of the calcium response to glucose stimulation in isolated mouse islets using varying concentrations (20 M, 200 M, and 1 mM) and durations (~1, 2, and 3 days) of metformin exposure. We observed both concentration- and duration-dependent inhibitory effects of metformin. Concentrations as little as 20 M (nearing circulating therapeutic levels) were sufficient to reduce insulin secretion following 3-day treatment. Concentrations of 200 M and 1 mM produced more pronounced effects more rapidly. With 1 mM metformin, islets showed severe impairments in calcium handling, inhibition of insulin secretion, and increased cell death. No stimulatory effects of metformin were observed for any experimental endpoint. We conclude that the direct effects of metformin on islets are inhibitory at near-physiological concentrations. Beneficial effects of metformin observed on islets under various stressors may occur by "resting" fatigued cellular processes. However, metformin may have unintended consequences on normally functioning islets within the circulating range that require further evaluation.
二甲双胍被认为是 2 型糖尿病的一线治疗药物。虽然二甲双胍主要增加胰岛素敏感性，但有证据表明二甲双胍还会影响胰岛分泌胰岛素的活性。本研究旨在通过测量在不同浓度（20μM、200μM 和 1mM）和暴露时间（~1、2 和 3 天）下，葡萄糖刺激时分离的小鼠胰岛中胰岛素分泌和钙反应动力学，来系统地检测二甲双胍的直接作用。我们观察到二甲双胍具有浓度和时间依赖性的抑制作用。仅 20μM（接近循环治疗水平）的浓度就足以在 3 天治疗后减少胰岛素分泌。浓度为 200μM 和 1mM 时，作用更为迅速。使用 1mM 二甲双胍时，胰岛钙处理严重受损，胰岛素分泌受到抑制，细胞死亡增加。对于任何实验终点，都没有观察到二甲双胍的刺激作用。我们得出结论，在接近生理浓度时，二甲双胍对胰岛的直接作用是抑制性的。在各种应激条件下，二甲双胍对胰岛的有益作用可能是通过“休息”疲劳的细胞过程来实现的。然而，二甲双胍可能会对循环范围内正常功能的胰岛产生意想不到的后果，需要进一步评估。
