Abstract
BackgroundThe 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).MethodsGlycocalyx 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.ResultsMetformin 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.ConclusionsTwo 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.
Highlights
The anti-diabetic drug metformin has been demonstrated to exert a protective effect against vascular complications in diabetes independent of its glucose lowering action
At an age of 7 weeks, db/db mice were divided in a control group which continued with normal drinking water for two weeks and an experimental group which received metformin at a concentration of 0.33 mg/ml in the drinking water for the same period
Blood glucose during the experiment was found to be elevated in both groups of db/db mice compared to the earlier measurements in the awake animals (Figure 1), likely as a result of the anesthesia
Summary
The anti-diabetic drug metformin has been demonstrated to exert a protective effect against vascular complications in diabetes independent of its glucose lowering action. Metformin (dimethylbiguanide) is an orally administered insulin-sensitizing drug used to lower blood glucose concentrations in patients with non-insulin dependent diabetes mellitus (NIDDM) [1,2]. Metformin expresses the best balance of potent activity and low toxicity. It is the most popular antidiabetic drug in the United States and one of the most prescribed drugs in this country. The insulin-sensitizing effect of metformin has been suggested to be the result of many actions, including an increased insulin-mediated glucose disposal, increased translocation of glucose transporters, suppressed hepatic glucose output, increased intestinal glucose use and decreased fatty-acid oxidation [1,3,4]. It is considered that metformin has vasculoprotective properties [12], but the mechanisms behind these actions are not completely understood at the moment
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