Department of Pathology, Amsterdam UMC location VUmc, Amsterdam, the Netherlands.
Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
Eur J Clin Invest. 2022 Sep;52(9):e13807. doi: 10.1111/eci.13807. Epub 2022 May 7.
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.
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.
In the heart, Liraglutide treatment significantly reduced the DM-increased scores/cm 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/cm 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.
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.
糖尿病（DM）通过增加糖基化、氧化应激和内皮激活导致心脏和脑微血管功能障碍。利拉鲁肽是一种胰高血糖素样肽-1 类似物，可抑制分离的内皮细胞中的 NOX2 和粘附分子。在这里，我们研究了利拉鲁肽如何影响糖尿病大鼠心脏、大脑和肾脏微血管的晚期糖基化、NOX 表达和炎症。
通过腹腔内链脲佐菌素（STZ）注射（60mg/kg 体重）诱导 Sprague-Dawley 大鼠（n=15）发生 DM。10 只对照大鼠保持非糖尿病状态。自 STZ 注射后第 9 天起，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 天结束。随后通过免疫组织化学分析和定量比较利拉鲁肽治疗与安慰剂，分析比较晚期糖基化终产物 N-ε-（羧甲基）赖氨酸（CML）、NOX2、NOX4、ICAM-1 和 VCAM-1。
在心脏中，利拉鲁肽治疗显著降低了 DM 增加的心室（从 253±53 降至 72±12；p=0.003）和心房（从 343±29 降至 122±8；p=0.0001）中 CML 的每厘米评分，以及 NOX2、ICAM-1 和 VCAM-1，但对 NOX4 没有影响。在大脑的大脑和小脑中，利拉鲁肽也显著降低了 CML 的每厘米评分（分别降至 60±7（p=0.0005）和 47±13（p=0.02））和 NOX2 和 NOX4。在肾脏中，利拉鲁肽降低了糖尿病诱导的血管和肾小球中 ICAM-1 和 VCAM-1 的表达。利拉鲁肽对血糖水平或体重没有影响。
我们的研究表明，利拉鲁肽在 1 型糖尿病大鼠模型中独立于降低血糖水平，保护心脏、大脑和肾脏微血管免受糖尿病引起的功能障碍。
