glucuronyl-glucosamine-glycan-sulfate and Diabetic-Angiopathies

Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.. Male participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TER(alb)) and hyaluronan catabolism were assessed as measures of vascular permeability.. Both sublingual dimensions (0.64 [0.57-0.75] μm vs 0.78 [0.71-0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88-6.59] μm vs 8.89 [4.74-11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TER(alb) was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83-0.99] μm and to 5.88 [5.33-6.26] μm, respectively, p < 0.05). In line, a trend towards TER(alb) normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.. Type 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.. www.trialregister.nl NTR780/ http://isrctn.org ISRCTN82695186. An unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037).

Topics: Adult; Albumins; Capillary Permeability; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium; Endothelium, Vascular; Glycocalyx; Glycosaminoglycans; Humans; Male; Middle Aged; Mouth Mucosa

Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans (GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, i.v. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.

Topics: Acetylcholine; Animals; Aorta; Aortic Diseases; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Drug Evaluation, Preclinical; Endothelium, Vascular; Glycosaminoglycans; Hypoglycemic Agents; Male; Nitroprusside; Rats; Rats, Sprague-Dawley; Tunica Intima; Vasodilation

Diabetes mellitus is associated with many complications including retinopathy, nephropathy, neuropathy and angiopathy. Increased cardiovascular risk is accompanied with diabetes-induced endothelial dysfunction. Pharmacological agents with endothelium-protective effects may decrease cardiovascular complications. In present study sulodexide (glycosaminoglycans composed from heparin-like and dermatan fractions) was chosen to evaluate its protective properties on endothelial dysfunction in diabetes. Effect of sulodexide treatment (SLX, 100 UI/kg/day, i.p.) in 5 and 10 weeks lasting streptozotocin-induced diabetes (30 mg/kg/day, i.p. administered for three consecutive days) was investigated. Animals were divided into four groups: control (injected with saline solution), control-treated with sulodexide (SLX), diabetic (DM) and diabetic-treated with sulodexide (DM+SLX). The pre-prandial and postprandial plasma glucose levels, number of circulating endothelial cells (EC) and acetylcholine-induced relaxation of isolated aorta and mesenteric artery were evaluated. Streptozotocin elicited hyperglycemia irrespective of SLX treatment. Streptozotocin-induced diabetes enhanced the number of circulating endothelial cells compared to controls. SLX treatment decreased the number of EC in 10-week diabetes. Acetylcholine-induced relaxation of mesenteric arteries was significantly impaired in 5 and 10-week diabetes. SLX administration improved relaxation to acetylcholine in 5 and 10-week diabetes. Diabetes impaired acetylcholine-induced relaxation of rat aorta irrespective of SLX treatment. Our results demonstrate that SLX treatment lowers the number of circulating endothelial cells and improves endothelium-dependent relaxation in small arteries. These findings suggest endothelium-protective effect of sulodexide in streptozotocin-induced diabetes.

Topics: Acetylcholine; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelium, Vascular; Glycosaminoglycans; Hypoglycemic Agents; Male; Rats; Rats, Wistar; Time Factors; Vasodilation; Vasodilator Agents

Glycosaminoglycan sulodexide may influence morphology and functional properties of the basement membranes in microvessels. The aim of this study was to evaluate the effect of sulodexide administration on albuminuria and on different biochemical variables indicating endothelial dysfunction, oxidative stress and fibrinolysis in diabetic patients. Twenty diabetic patients of both types with micro- or macroalbuminuria were selected for sulodexide treatment. Daily dose of 600 U (60 mg) was injected intramuscularly five days a week. Fifteen doses were applied during 3 weeks. The patients were examined before and after treatment as well as 6 months later. No changes of diabetes control were observed during the study and after 6 months of wash-out period. Significant decrease of albuminuria (p < 0.001) was observed during the sulodexide administration with the following increase to pretreated values during the wash-out period. A decrease of serum N-acetyl-beta-glucosaminidase (NAG) activity (p < 0.03) at the end of treatment as compared to pretreated values was found in the whole group of diabetic patients. Slight reduction of oxidative stress expressed by malondialdehyde and superoxide dismutase was apparent after treatment but no simultaneous change in fibrinolysis was observed. Sulodexide may have some protective effects influencing functional properties of the basement membrane as manifested by lowered albuminuria. In addition, it may slightly decrease oxidative stress in diabetic patients and it could stabilize endothelial cells.

Topics: Acetylglucosaminidase; Adult; Aged; Albuminuria; Diabetes Mellitus; Diabetic Angiopathies; Female; Fibrinolysis; Glycosaminoglycans; Humans; Hypoglycemic Agents; Injections, Intramuscular; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Superoxide Dismutase

A total of nine patients with diabetes type I and II and with claudications due to macro- and microangiopathies of the lower extremities took sulodexide (Vessel Due F) by the i.m. route for a period of 20 days and then as capsules for 90 days. In all a favourable therapeutic effect was recorded, in particular as regards delay of claudications. The authors recorded lower blood sugar values, lower levels of cholesterol, triglycerides, fibrinogen and plasma viscosity. In the authors' view sulodexide is an important advance in the treatment of diabetics with claudications.

Topics: Arteriosclerosis; Blood Viscosity; Diabetic Angiopathies; Glycosaminoglycans; Humans; Hypolipidemic Agents; Ischemia; Leg; Male; Middle Aged

Topics: Aged; Diabetic Angiopathies; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Risk