glucuronyl-glucosamine-glycan-sulfate and Diabetes-Mellitus

Micro- and macrovascular complications of diabetes are leading morbidities in the world population. They are responsible not only for increased mortality but also severe disabilities, which jeopardize quality of life (e.g., blindness, walking limitations, and renal failure requiring dialysis). The new antidiabetic agents (e.g., glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter inhibitors) are increasingly recognized as breakthrough agents in the treatment of diabetes and prevention of diabetic complications. However, drugs effective in preventing and treating diabetic disabilities are still needed and sulodexide could be one of those able to address the unmet clinical needs of the new antidiabetic agents.. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal. We also manually searched potentially relevant journals, conference proceedings, and journal supplements. Any study monitoring any effect of sulodexide in subjects with diabetes, in relation to renal, vascular, and ocular complication, was considered. Treatment effects were estimated using standardized mean differences (SMDs), mean differences (MDs), and risk ratios (RRs), as appropriate. We calculated 95% confidence interval (CIs) and heterogeneity (Q, tau, and I. The search found 45 studies with 2817 participants (mean age 57 years; 63% male). The 26 randomized controlled studies included 2074 participants (mean age 58.8 years; 66% male). Sulodexide reduced the impact of diabetic retinopathy; increased the pain-free and maximal walking distance in peripheral arterial disease; accelerated the healing of diabetes-associated trophic ulcers; and decreased the rate of albumin excretion in subjects with nephropathy. The risk of adverse events (AEs) was not different between sulodexide and controls.. Sulodexide has a beneficial effect on the ocular, peripheral arterial disease, trophic ulcers, and renal complications of diabetes without increasing the risk of AEs.

Topics: Diabetes Mellitus; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged; Quality of Life

Experimental and clinical studies showed a decrease in albuminuria, a marker of diabetic nephropathy after administration of heparin or other glycosaminoglycans (GAG).. To study the effect of sulodexide on albumin excretion rate (AER) in patients with type 1 or type 2 diabetes mellitus (DM).. Twenty patients (12 of type 1 DM) aged 33-63 yrs (median 45) with microalbuminuria (AER 20-200 micrograms/min) or macroalbuminuria (AER > 200 micrograms/min) were enrolled in open study and received sulodexide 60 mg/day i.m. for 3 weeks with further 6-week follow-up without treatment. In the 2nd phase, sulodexide 100 mg/day was given p.o. for 8 weeks with further 8-weeks follow-up. Albuminuria in overnight urine samples was analyzed by the RIA method and results (medians with lower and upper quartiles) were compared by the Wilcoxon test.. In the 1st phase, AER (microgram/min) decreased from 167 (54-378) at baseline to 118 (78-220) at week 1 (p < 0.05), 105 (68-341) at week 2 (p < 0.05), and to 114 (56-354) at week 3 (NS). After stopping the treatment, AER gradually raised to baseline values. During the oral phase, AER decreased from 253 (37-961) to 137 (35-323) after 1 month (p < 0.05) and to 144 (47-588) after 2 months (NS). This effect was prolonged for further 2 months after treatment withdrawal (AER 110 (65-363) micrograms/min, p < 0.05). In both phases, the decrease in AER was shown only in patients with macroalbuminuria, but not in those with microalbuminuria. Blood pressure, glomerular filtration rate and metabolic compensation of DM were not changed.. A short-term treatment with sulodexide i.m. or p.o. significantly decreased albuminuria in DM patients. This effect was prolonged for further 2 months after oral administration. Therefore, sulodexide could be useful in the treatment of diabetic nephropathy. (Tab. 3, Ref. 20.)

Topics: Adult; Albuminuria; Diabetes Mellitus; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged

Thirty vasculopathic subjects with hyperlipoproteinemia (18) and/or diabetes (22) underwent a clinical double-blind study in order to evaluate the effect of sulodexide on lipid and hemorheologic parameters. The experimental design consisted of a first 20-day i.m. therapeutic period with either sulodexide (300 Lipasemic Units twice daily via intramuscular route) or placebo and the following 70 days with the active compound for both groups at the same posology. Results obtained demonstrated that sulodexide yields a hypotriglyceridemic effect on type IV hyperlipoproteinemia and hypofibrinogenic effect, as well. Moreover, this compound exerted a beneficial effect on HDL Cholesterol levels and on the antithrombin III activity by increasing both parameters significantly. Signs and symptoms were alleviated, particularly in the most severe cases of peripheral vascular disease. Insignificant and slight changes were observed at the end of treatments as regards the efficacy of the two administration routes, the i.m. one being more efficacious on lipid parameters and faster acting. No side effects or intolerance were observed during the different periods of the trial.

Topics: Adult; Aged; Antithrombin III; Cholesterol, HDL; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Double-Blind Method; Female; Fibrinogen; Glycosaminoglycans; Humans; Hyperlipidemias; Male; Middle Aged; Triglycerides; Vascular Diseases

The activation of nuclear factor (NF)-κB by cytokines under hyperglycaemic conditions is a potential mechanism for complications in diabetes. We investigated whether small ubiquitin-like modifier 4 (SUMO4) regulates renal NF-κB signalling in diabetic rats.. Histological changes in kidney were analysed in diabetic GK rats. The expressions of tumour necrosis factor (TNF)-α, NF-κB (p65), IκBα and SUMO4 in renal tissues were examined by immunohistochemistry and Western blotting. Primary cultured glomerular endothelial cells from rats were stimulated by TNF-α or interleukin (IL)-2.. The renal expression of TNF-α, NF-κB (p65), IκBα and SUMO4 was significantly higher in diabetic GK rats than in control rats. In control rats, no nuclear translocation was observed for IκBα or NF-κB (p65). However, in diabetic GK rats, translocation of NF-κB (p65) and IκBα into the nucleus was observed, and the expression of SUMO4 and IκBα was up-regulated in the glomerular endothelial cells. SUMO4 was localised in both the cytoplasm and nucleus, while IκBα was predominantly located in the nucleus after stimulation with TNF-α. In contrast, SUMO4 was localised in the nucleus, and increased cytoplasm SUMO4 localisation was found after stimulation with IL-2.. SUMO4 plays a role in regulating NF-κB signalling in glomerular cells. Cytokines have a unique effect in regulating the sumoylation of NF-κB.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Diabetes Mellitus; Diabetic Nephropathies; Endothelial Cells; Glycosaminoglycans; I-kappa B Proteins; Interleukin-2; Kidney Glomerulus; Male; NF-kappa B; NF-KappaB Inhibitor alpha; Rats; Rats, Wistar; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Tumor Necrosis Factor-alpha

To investigate the renal protective effects of sulodexide and its anti-oxidative stress mechanism in diabetic rats.. Thirty male SD rats were randomized into 3 equal groups, namely the control group, diabetic group, and sulodexide treatment group. Twelve weeks after establishment of rat diabetic models and administration of sulodexide, the rats were sacrificed for measurement of the urine volume, body mass, kidney mass/body weight ratio, plasma glucose, and glycosylated hemoglobin (HbA1c). Malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) activities in the renal tissue or serum were tested. Electron microscopy was performed to observe the pathological changes in the kidneys.. The urine volume, renal mass/body mass ratio, serum glucose, HbA1C, and serum and renal MDA levels all significantly increased in the diabetic rats in comparison with the normal controls (P<0.05). But the body weight and activities of SOD, CAT, and GSH-PX in the renal tissue in the normal control group were significantly higher than those in the diabetic and sulodexide group. After 12 weeks of sulodexide treatment, SOD, CAT, and GSH-PX activities in the renal tissue of rats were significantly increased in comparison with those in the diabetic rats (P<0.05). Electron microscopy showed obvious irregular thickening of the glomerular capillary basement membrane in the diabetic group with vacuolization in the mitochondria in the epithelial cells, and such pathological changes were significantly alleviated in the sulodexide treatment group.. Sulodexide can effectively lower the urinary albumin excretion rate, improve the ultrastructural renal pathologies and prevent glomerular basement membrane thickening in diabetic rats, probably in association with the reduction of the MDA levels and enhancement of SOD, CAT, and GSH-PX activities.

Topics: Animals; Antioxidants; Body Weight; Catalase; Diabetes Mellitus; Glutathione Peroxidase; Glycosaminoglycans; Kidney; Male; Malondialdehyde; Organ Size; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

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

The authors administered to type 1 diabetics (n = 15) or type 2 diabetics (n = 20) with microalbuminuria or macroalbuminuria for a period of 15 days i.m. doses of sulodexide (Vessel Due F), 600 i.u. (i.e. 60 mg). The evaluation of the whole group revealed a statistically significant reduction of the original mean value of albuminuria (509 +/- 127 ug/min) already during the first week of sulodexide administration (382 +/- 105). A further decrease was recorded after the second and third week of treatment (326 +/- 89, 319 +/- 85 ug/min). While in diabetics with microalbuminuria < 100 micrograms/min the mean levels of excreted albumin were not affected, in diabetics with macroalbuminuria 200 ug/min a significant reduction of albuminuria persisted (p < 0.001) achieved during sulodexide treatment persisted for three weeks after completed treatment. No differences were found between the results of type 1 and type 2 diabetics.. Seventy-seven per cent type 1 and type 2 diabetics responded to parenteral sulodexide administration for 15 days by a statistically significant reduction of albumin.

Topics: Adult; Aged; Albuminuria; Diabetes Mellitus; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged