Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
Department of Urology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
Life Sci. 2022 Jun 1;298:120504. doi: 10.1016/j.lfs.2022.120504. Epub 2022 Mar 31.
Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively.
OLETF and LETO rats were treated with oral tadalafil (100 μg/kg/day) or vehicle for 12 wks from at the age of 36 wks.
Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-β); especially IL-6, TNF-α, IGF-1, bFGF and TGF-β increased with T2D. Tadalafil suppressed these cytokines and growth factors.
These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D.
高胰岛素血症是 2 型糖尿病（T2D）前列腺增大的一个重要致病因素，然而，临床上在胰岛素缺乏的情况下前列腺重量会增加。为了研究前列腺增大的发病机制和磷酸二酯酶 5 抑制剂（PDE5i）的作用，使用 Otsuka Long-Evans Tokushima Fatty（OLETF）和 Long-Evans Tokushima Otsuka（LETO）大鼠作为 T2D 和对照。
OLETF 和 LETO 大鼠从 36 周龄开始，每天口服他达拉非（100μg/kg）或载体 12 周。
OLETF 大鼠的前列腺重量明显高于 LETO 大鼠，在 48 周时增加。在 OLETF 大鼠中，48 周时前列腺血流量明显低于 36 周时。12 周他达拉非治疗增加了两种菌株的前列腺血流量并抑制了前列腺重量的增加。这种变化与前列腺缺氧诱导因子-1α（HIF-1α）和 8-羟基-2'-脱氧鸟苷（8-OHdG）表达的变化呈负相关。随着年龄的增长，细胞因子白细胞介素（IL）-6、IL-8 和肿瘤坏死因子-α（TNF-α）以及细胞生长因子胰岛素样生长因子-1（IGF-1）、碱性成纤维细胞生长因子（bFGF）和转化生长因子-β（TGF-β）的 mRNA 和/或蛋白水平均升高；特别是 IL-6、TNF-α、IGF-1、bFGF 和 TGF-β随 T2D 而增加。他达拉非抑制这些细胞因子和生长因子。
这些数据表明，T2D 引起的慢性缺血导致氧化应激，通过上调几种细胞因子和生长因子导致前列腺增大。PDE5i 的治疗可改善前列腺缺血，并可能通过抑制 T2D 中的细胞因子和生长因子来预防增大。
