2INSERM U1060/University Lyon 1/Inra 1235, Lyon-Sud Medicine, Faculty, 165 Chemin du Grand Revoyet-BP 12, 69921 Oullins Cedex, France.
FASEB J. 2013 Dec;27(12):5122-30. doi: 10.1096/fj.13-234104. Epub 2013 Sep 5.
As shown in a large clinical prospective trial, inhibition of the renin-angiotensin system (RAS) can delay the onset of type 2 diabetes in high-risk individuals. We evaluated the beneficial effects of RAS inhibition on β-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 mM (controls) or 16.7 mM glucose [high glucose (HG)] for 4 d with or without losartan (5 μM), a selective AT1R blocker, and/or U73122 (2 μM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R (P<0.05) and angiotensinogen (P<0.001) mRNAs. HG increased endoplasmic reticulum (ER) stress markers (P<0.001) such as GRP78, sXBP1, and ATF4 mRNAs and Grp78 protein levels (P<0.01). HG also decreased reticular calcium concentration (P<0.0001) and modified protein expressions of ER calcium pumps with reduction of SERCA2b (P<0.01) and increase of IP3R2 (P<0.05). Losartan prevented these deleterious effects and was associated with improved insulin secretion despite HG exposure. AT1R activation triggers the PLC-IP3-calcium pathway. Losartan prevented the increase of PLC β1 and γ1 protein levels induced by HG (P<0.05). U73122 reproduced all the protective effects of losartan. AT1R blockade protects human islets from the deleterious effects of glucose through inhibition of the PLC-IP3-calcium pathway.
在一项大型临床前瞻性试验中，肾素-血管紧张素系统 (RAS) 的抑制可延迟高危个体 2 型糖尿病的发生。我们评估了 RAS 抑制在糖毒性条件下对β细胞功能的有益影响。从 13 位供体中分离的胰岛在 5.5 mM（对照）或 16.7 mM 葡萄糖（高糖，HG）中培养 4 天，在最后 2 天用或不用氯沙坦（5 μM），一种选择性 AT1R 阻断剂，和/或 U73122（2 μM），一种选择性 PLC 抑制剂。HG 诱导 RAS 激活，导致 AT1R（P<0.05）和血管紧张素原（P<0.001）mRNA 的过表达。HG 增加内质网（ER）应激标志物（P<0.001），如 GRP78、sXBP1 和 ATF4 mRNA 以及 Grp78 蛋白水平（P<0.01）。HG 还降低了网状钙浓度（P<0.0001），并改变了 ER 钙泵的蛋白表达，减少了 SERCA2b（P<0.01）和增加了 IP3R2（P<0.05）。氯沙坦防止了这些有害作用，并与尽管暴露于 HG 但胰岛素分泌改善有关。AT1R 激活触发 PLC-IP3-钙途径。氯沙坦防止了 HG 诱导的 PLCβ1 和γ1 蛋白水平的增加（P<0.05）。U73122 复制了氯沙坦的所有保护作用。AT1R 阻断通过抑制 PLC-IP3-钙途径保护人胰岛免受葡萄糖的有害影响。
