背景:糖尿病(DM)通过糖基化增加引起心脏和脑微血管功能障碍,氧化应激和内皮激活。利拉鲁肽,胰高血糖素样肽-1类似物,抑制分离的内皮细胞中的NOX2和粘附分子。这里,我们研究了利拉鲁肽如何影响晚期糖基化,NOX表达和心脏炎症,糖尿病大鼠的脑和肾微血管系统。
方法:通过腹膜内注射链脲佐菌素(STZ)(60mg/kg体重)在Sprague-Dawley大鼠(n=15)中诱导DM。10只对照大鼠保持非糖尿病。从STZ注射后第9天开始,每天皮下注射利拉鲁肽(200μg/kg体重;n=7)或载体(n=8)直至第29天终止。糖基化终产物N-ε-(羧甲基)赖氨酸(CML),随后对NOX2、NOX4、ICAM-1和VCAM-1进行免疫组织化学分析和定量,以比较利拉鲁肽治疗与安慰剂。
结果:在心脏,利拉鲁肽治疗可显着降低CML在两个心室(从253±53至72±12;p=.003)和心房(343±29至122±8;p=.0001)以及NOX2,ICAM-1和VCAM-1,但对于NOX4则没有。同样在大脑的大脑和小脑中,利拉鲁肽显著降低了CML的分数/cm2(至60±7(p=0.0005)和47±13(p=.02),分别),以及NOX2和NOX4。在肾脏,利拉鲁肽治疗可降低DM诱导的血管和肾小球中ICAM-1和VCAM-1的表达。利拉鲁肽不影响血糖水平或体重。
结论:我们的研究表明,利拉鲁肽保护心脏,大脑和肾脏微血管系统对抗糖尿病引起的功能障碍,在1型糖尿病大鼠模型中独立于降低血糖。
BACKGROUND: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon-like peptide-1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats.
METHODS: DM was induced in Sprague-Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post-STZ injection, Liraglutide (200 μg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N-ε-(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM-1 and VCAM-1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo.
RESULTS: In the heart, Liraglutide treatment significantly reduced the DM-increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p = .003) and atria (343 ± 29 to 122 ± 8; p = .0001) and for NOX2, ICAM-1 and VCAM-1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p = .0005) and 47 ± 13 (p = .02), respectively), and for NOX2 and NOX4. In the kidney, the DM-induced expression of ICAM-1 and VCAM-1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight.
CONCLUSIONS: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes-induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model.