Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity.
Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity.
复制标题
DOI：
10.1530/joe-14-0335
复制
发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Egan JM
中科院分区：
文献类型：
--
作者：
Rouse M;Younès A;Egan JM
白藜芦醇（RES）和姜黄素（CUR）是在水果和姜黄中发现的多酚，具有对各种疾病有益的药用特性，如心脏病，癌症和2型糖尿病（T2 DM）。最近的研究结果表明，它们的治疗特性可归因于它们的抗炎作用。由于有报道称它们可以防止β细胞功能障碍，我们研究了它们在β细胞中的作用机制。在T2 DM中，cAMP在葡萄糖和肠促胰岛素刺激的胰岛素分泌以及整体胰腺β细胞健康中起关键作用。T2 DM管理的潜在治疗靶点在于调节磷酸二酯酶（PDE）的活性，其降解cAMP。据报道，RES和CUR在各种细胞类型中都是PDE抑制剂，但它们是否在胰腺β细胞中起作用仍不清楚。在我们目前的研究中，我们发现RES（0.1-10 μmol/l）和CUR（1-100 pmol/l）都能调节葡萄糖刺激条件下的胰岛素分泌。 此外，用这些多酚处理β细胞系和人类胰岛导致细胞内cAMP水平增加，其方式类似于3-异丁基-1-甲基黄嘌呤（一种经典的PDE抑制剂）。当我们研究RES和CUR对PDE的影响时，我们发现治疗显著下调了11种PDE同工酶中大多数的mRNA表达，包括PDE 3B，PDE 8A和PDE 10A，这些同工酶以前与胰岛中胰岛素分泌的调节有关。此外，RES和CUR在β细胞系和人胰岛中以剂量依赖性方式抑制PDE活性。总的来说，我们证明了天然多酚作为PDE抑制剂增强胰腺β细胞功能的新作用。
Resveratrol (RES) and curcumin (CUR) are polyphenols that are found in fruits and turmeric, and possess medicinal properties that are beneficial in various diseases, such as heart disease, cancer, and type 2 diabetes mellitus (T2DM). Results from recent studies have indicated that their therapeutic properties can be attributed to their anti-inflammatory effects. Owing to reports stating that they protect against β-cell dysfunction, we studied their mechanism(s) of action in β-cells. In T2DM, cAMP plays a critical role in glucose- and incretin-stimulated insulin secretion as well as overall pancreatic β-cell health. A potential therapeutic target in the management of T2DM lies in regulating the activity of phosphodiesterases (PDEs), which degrade cAMP. Both RES and CUR have been reported to act as PDE inhibitors in various cell types, but it remains unknown if they do so in pancreatic β-cells. In our current study, we found that both RES (0.1–10 μmol/l) and CUR (1–100 pmol/l)-regulated insulin secretion under glucose-stimulated conditions. Additionally, treating β-cell lines and human islets with these polyphenols led to increased intracellular cAMP levels in a manner similar to 3-isobutyl-1-methylxanthine, a classic PDE inhibitor. When we investigated the effects of RES and CUR on PDEs, we found that treatment significantly downregulated the mRNA expression of most of the 11 PDE isozymes, including PDE3B, PDE8A, and PDE10A, which have been linked previously to regulation of insulin secretion in islets. Furthermore, RES and CUR inhibited PDE activity in a dose-dependent manner in β-cell lines and human islets. Collectively, we demonstrate a novel role for natural-occurring polyphenols as PDE inhibitors that enhance pancreatic β-cell function.