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Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 ؎ 0.2 vs. 1.7 ؎ 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 ؎ 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 ؎ 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 ؎ 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 ؎ 6 to 112 ؎ 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 ؉ 2: from 0.4 ؎ 0.1 to 1.1 ؎ 0.2 nmol/l; D-dimer: from 0.27 ؎ 0.1 to 0.55 ؎ 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia. Diabetes 55:480 -486, 2006 P atients with diabetes have increased vascular vulnerability to atherogenic insults, leading to accelerated atherogenesis. Although atherogenesis is in part due to the increased prevalence of traditional cardiovascular risk factors, these factors cannot fully explain the propensity toward vascular complications in diabetic patients (1). Hyperglycemia itself has been shown to induce a wide array of downstream effects that adversely affect the protective capacity of the vessel wall (2). Hyperglycemia has been associated with enhanced endothelial permeability, increased leukocyte-endothelium adhesion, and impaired nitric oxide (NO) bioavailability (3-5). Despite clear progress in understanding the underlying pathophysiological mechanisms contributing to this vascular dysfunction, it has proven difficult to unravel a final common pathway for the increased vascular vulnerability under hyperglycemic conditions (6).The glycocalyx covers the endothelium and consists of endothelial cell-derived proteoglycans, glycoproteins, and adsorbed plasma proteins. This layer has been shown to orchestrate vascular homeostasis (7). Its thickness (up to 1 m) may explain its potent antiadhesive effects on leukocytes and platelets (8,9). Hyaluronan glycosaminoglycans, one of the major constituents of the glycocalyx, are crucial for maintaining endothelial barrier properties for plasma macromolecules (10). The glycocalyx also serves as a mechanosensor of shear stress, mediating shear-induced release of NO by endothelial cells (11-13). In fact, selective perturbation of the g...

Chronic hyperglycemia underlies microvascular complications in patients with type 1 diabetes. The mechanisms leading to these vascular complications are not fully understood. Recently, we observed that acute hyperglycemia results in endothelial glycocalyx damage. To establish whether glycocalyx is associated with microvascular damage, we performed glycocalyx perturbation volume measurements in type 1 diabetic patients with microalbuminuria (DM1-MA group; n ‫؍‬ 7), without microalbuminuria (DM1-NA group; n ‫؍‬ 7), and in age-matched control subjects (CON; n ‫؍‬ 7). Systemic glycocalyx volume was determined comparing intravascular distribution volume of a glycocalyxpermeable tracer (dextran 40) to that of a glycocalyximpermeable tracer (labeled erythrocytes). Sublingual capillaries were visualized using orthogonal polarization spectral microscopy to estimate microvascular glycocalyx. Patients and control subjects were matched according to age and BMI. Glycocalyx volume decreased in a stepwise fashion from CON, DM1-NA, and finally DM1-MA subjects (1.5 ؎ 0.1, 0.8 ؎ 0.4, and 0.2 ؎ 0.1 l, respectively, P < 0.05). Microvascular glycocalyx in sublingual capillaries was also decreased in type 1 diabetes versus the control group (0.5 ؎ 0.1 vs. 0.9 ؎ 0.1 m, P < 0.05). Plasma hyaluronan, a principal glycocalyx constituent, and hyaluronidase were increased in type 1 diabetes. In conclusion, type 1 diabetic patients are characterized by endothelial glycocalyx damage, the severity of which is increased in presence of microalbuminuria.

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Overall lowering of glucose is of pivotal importance in the treatment of diabetes, with proven beneficial effects on microvascular and macrovascular outcomes. Still, patients with similar glycosylated hemoglobin levels and mean glucose values can have markedly different daily glucose excursions. The role of this glucose variability in pathophysiological pathways is the subject of debate. It is strongly related to oxidative stress in in vitro, animal, and human studies in an experimental setting. However, in real-life human studies including type 1 and type 2 diabetes patients, there is neither a reproducible relation with oxidative stress nor a correlation between short-term glucose variability and retinopathy, nephropathy, or neuropathy. On the other hand, there is some evidence that long-term glycemic variability might be related to microvascular complications in type 1 and type 2 diabetes. Regarding mortality, a convincing relationship with short-term glucose variability has only been demonstrated in nondiabetic, critically ill patients. Also, glucose variability may have a role in the prediction of severe hypoglycemia. In this review, we first provide an overview of the various methods to measure glucose variability. Second, we review current literature regarding glucose variability and its relation to oxidative stress, long-term diabetic complications, and hypoglycemia. Finally, we make recommendations on whether and how to target glucose variability, concluding that at present we lack both the compelling evidence and the means to target glucose variability separately from all efforts to lower mean glucose while avoiding hypoglycemia.