PDF(Pubmed)
Abstract：
Sildenafil, a phosphodiesterase-5 (PDE5) inhibitor, has been shown to improve insulin sensitivity in animal models and prediabetic patients. However, its other metabolic effects remain poorly investigated. This study examines the impact of sildenafil on insulin secretion in MIN6-K8 mouse clonal β cells. Sildenafil amplified insulin secretion by enhancing Ca2+ influx. These effects required other depolarizing stimuli in MIN6-K8 cells but not in KATP channel-deficient β cells, which were already depolarized, indicating that sildenafil-amplified insulin secretion is depolarization-dependent and KATP channel-independent. Interestingly, sildenafil-amplified insulin secretion was inhibited by pharmacological inhibition of R-type channels, but not of other types of voltage-dependent Ca2+ channels (VDCCs). Furthermore, sildenafil-amplified insulin secretion was barely affected when its effect on cyclic GMP was inhibited by PDE5 knockdown. Thus, sildenafil stimulates insulin secretion and Ca2+ influx through R-type VDCCs independently of the PDE5/cGMP pathway, a mechanism that differs from the known pharmacology of sildenafil and conventional insulin secretory pathways. Our results reposition sildenafil as an insulinotropic agent that can be used as a potential antidiabetic medicine and a tool to elucidate the novel mechanism of insulin secretion.
摘要：
西地那非,磷酸二酯酶-5（PDE5）抑制剂，已被证明可以改善动物模型和糖尿病前期患者的胰岛素敏感性。然而,它的其他代谢作用仍然缺乏研究。这项研究检查了西地那非对MIN6-K8小鼠克隆β细胞胰岛素分泌的影响。西地那非通过增强Ca2+内流来增强胰岛素分泌。这些效应在MIN6-K8细胞中需要其他去极化刺激，但在缺乏KATP通道的β细胞中不需要。已经去极化了，表明西地那非扩增的胰岛素分泌是去极化依赖性和KATP通道非依赖性的。有趣的是,西地那非增强的胰岛素分泌被R型通道的药理学抑制抑制，但不是其他类型的电压依赖性Ca2+通道(VDCC)。此外，当PDE5敲低抑制其对环GMP的作用时，西地那非扩增的胰岛素分泌几乎没有受到影响。因此，西地那非通过R型VDCC独立于PDE5/cGMP途径刺激胰岛素分泌和Ca2流入，一种不同于西地那非已知药理学和常规胰岛素分泌途径的机制。我们的结果将西地那非重新定位为促胰岛素药，可用作潜在的抗糖尿病药物和阐明胰岛素分泌新机制的工具。
