Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, PO Box 616, 6200, MD Maastricht, The Netherlands.
Cardiovasc Diabetol. 2013 Dec 5;12:175. doi: 10.1186/1475-2840-12-175.
The anti-diabetic drug metformin has been demonstrated to exert a protective effect against vascular complications in diabetes independent of its glucose lowering action. Since the endothelial glycocalyx has been indicated to have important vasculoprotective properties and to be vulnerable to degradation by hyperglycemic conditions, we evaluated in the current study the effect of short-term metformin treatment on whole-body glycocalyx barrier properties in a mouse model of non-insulin dependent diabetes mellitus (db/db mouse).
Glycocalyx barrier properties were measured in an acute experiment in three groups of mice: 1) db/db mice without treatment serving as controls, 2) db/db mice which received metformin for two weeks in the drinking water serving as experimental group, and 3) C57Bl/6 mice serving as reference group. Animals were put under anesthesia (ketamine, medetomidine, and atropine) and carotid artery blood pressure was continuously monitored. To probe the glycocalyx a mixture of the tracers FITC-labeled 70 kDa dextrans (Dex70) or fluorescein-labeled red blood cells (RBCs) versus Texas Red-labeled 40 kDa dextrans (Dex40) was infused and blood samples subsequently collected for 30 min to determine the initial vascular distribution volume and clearance of these tracers. Urine was collected and dry-to-wet weight of heart and kidney were determined after the experiment. Group differences were tested using unpaired t-tests.
Metformin treatment did not affect body weight, fasting blood glucose and arterial blood pressure. Compared to C57Bl/6 mice, db/db mice showed a diminished initial exclusion and increased vascular clearance of Dex70 versus Dex40 (P < 0.05), and both were improved by the metformin treatment (P < 0.05). While urine production was higher in the db/db mice compared to C57Bl/6 (P < 0.05), heart and kidney of the metformin treated animals showed comparable dry-to-wet weights compared to the C57Bl/6 mice.
Two weeks of metformin in the drinking water is associated with an improvement in glycocalyx barrier properties in db/db mice, as evidence by an enhanced exclusion and retention of 70 kDa dextrans in the vasculature. In addition, metformin improved hydration of heart and kidney. Previous reported cardiovascular benefits of metformin may well involve an improvement of the endothelial glycocalyx.
抗糖尿病药物二甲双胍已被证明可在不降低血糖的情况下对糖尿病的血管并发症发挥保护作用。由于内皮糖萼已被证明具有重要的血管保护特性，并且容易受到高血糖条件的降解，因此我们在当前的研究中评估了短期二甲双胍治疗对非胰岛素依赖性糖尿病模型（db/db 小鼠）中全身糖萼屏障特性的影响。
在三组小鼠的急性实验中测量糖萼屏障特性：1）未治疗的 db/db 小鼠作为对照组，2）接受饮用水中二甲双胍治疗两周的 db/db 小鼠作为实验组，3）C57Bl/6 小鼠作为参考组。动物被置于麻醉下（氯胺酮、美托咪定和阿托品），并连续监测颈动脉血压。为了探测糖萼，将示踪剂 FITC 标记的 70 kDa 葡聚糖（Dex70）或荧光素标记的红细胞（RBC）与 Texas Red 标记的 40 kDa 葡聚糖（Dex40）混合注入，并在 30 分钟后收集血液样本以确定这些示踪剂的初始血管分布体积和清除率。实验后收集尿液，并测定心脏和肾脏的干重-湿重。使用未配对的 t 检验测试组间差异。
二甲双胍治疗并未影响体重、空腹血糖和动脉血压。与 C57Bl/6 小鼠相比，db/db 小鼠的 Dex70 与 Dex40 的初始排除率降低，血管清除率增加（P<0.05），而这些均被二甲双胍治疗改善（P<0.05）。与 C57Bl/6 小鼠相比，db/db 小鼠的尿液产量更高（P<0.05），但经二甲双胍治疗的动物的心脏和肾脏的干重-湿重与 C57Bl/6 小鼠相当。
饮用水中两周的二甲双胍治疗与 db/db 小鼠糖萼屏障特性的改善相关，这表现为血管中 70 kDa 葡聚糖的排除和保留增加。此外，二甲双胍改善了心脏和肾脏的水合作用。先前报道的二甲双胍的心血管益处可能涉及改善内皮糖萼。
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