Treatment with sulodexide, an endothelial glycocalyx‐mimetic, restores glucose tolerance in high fat diet‐fed mice

We tested if treatment with sulodexide, a glycocalyx‐mimetic, restores glycocalyx dimensions and whole‐body glucose tolerance induced by a high fat diet (HFD) in mice. C57Bl/6 mice were fed normal chow (n=5) or a HFD for 6 weeks (n=16), and half of these HFD‐fed mice were treated with sulodexide in their drinking water (15mg/100mL) for the final two weeks of the feeding period. At the day of experiment, the microcirculation of the hindlimb muscle was measured with a Sidestream Dark‐field camera under anesthesia, and dynamic variations in RBC column width in all visible microvessels were determined. Further, glucose tolerance was measured by i.p. injection of 1g/kg glucose and determining the area under the curve of blood glucose (AUCgluc). While median perfused RBC column diameter (± 6 μm) did not change, HFD mice were associated with increased outward movement of RBCs into glycocalyx (2.5 ± 0.3 μm vs 1.6 ± 0.3 μm in control, P<0.05), and this effect was impaired after sulodexide treatment (2.1 ± 0.3 μm; NS vs control). The AUCgluc was also increased in HFD‐fed mice versus control (1005.2 ± 59.8 mmol/L*90min. vs 773.7.1 ± 55.0 mmol/L*90min, P<0.05) and this effect was prevented after sulodexide treatment (780.4 ± 31.8 mmol/L*90min., NS vs control). In conclusion, two week sulodexide treatment partially restores glycocalyx dimensions and appears to reverse the HFD‐induced decline in whole‐body glucose tolerance in mice. Supported by DFN 2006.00.027, and CTMM work package 01C‐ 104‐04‐PREDICCT