chondroitin-sulfates and Diabetes-Mellitus--Type-1

In diabetic patients, wound healing is impaired. We studied the pathogenesis behind this clinical observation by characterizing the pattern of deposition of extracellular matrix (ECM) molecules and the cellular infiltrate in chronic (>8 wk) diabetic wounds, compared with chronic venous ulcers and an acute wound healing model. Punch biopsies were obtained from the chronic ulcer margins and control samples were collected from upper leg skin 5, 19, 28 d and 12 and 18 mo postwounding (p.w.). T cells, B cells, plasma cells, granulocytes and macrophages, and the ECM molecules fibronectin (FN), chondroitin sulfate (CS), and tenascin (TN) were visualized using immunohistochemical techniques. Expression of FN, CS, and TN was detected in dermal tissue early in normal wound healing (5-19 d p.w.). Abundant staining was seen 3 mo p.w., returning to prewounding levels after 12-18 mo p.w. In the dermis of chronic diabetic and venous ulcers with a duration of 12 mo or more, a prolonged presence of these ECM molecules was noted. Compared with normal wound healing: (i) the CD4/CD8 ratio in chronic wounds was significantly lower (p < 0.0027) due to a relatively lower number of CD4+ T cells; (ii) a significantly higher number of macrophages was present in the edge of both type of chronic ulcers (p < 0.001 versus day 29 p.w.); and (iii) more B cells and plasma cells were detected in both type of chronic wounds compared with any day in the acute wound healing model (p < 0.04 for CD20+ and p < 0.01 for CD79a+ cells). These data indicate that important differences exist in the cellular infiltrate and ECM expression patterns of acute, healing versus chronic wounds, which may be related to the nonhealing status of chronic wounds.

Topics: Acute Disease; Adult; Aged; Basement Membrane; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes; Cell Count; Chondroitin Sulfates; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Foot; Extracellular Matrix; Female; Fibronectins; Granulocytes; Humans; Lymphocytes; Macrophages; Male; Middle Aged; Tenascin; Varicose Ulcer; Wound Healing; Wounds and Injuries

Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.

Topics: Adult; Chondroitin Sulfates; Cross-Over Studies; Dermatan Sulfate; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Drug Combinations; Female; Heparinoids; Heparitin Sulfate; Humans; Male; Middle Aged; Proteinuria; Treatment Outcome

Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.

Topics: Animals; Blood Glucose; Bone and Bones; Bone Density; Bone Marrow; Bone Remodeling; Chondroitin Sulfates; Cytokines; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Lipogenesis; Male; Osteoporosis; Osteoprotegerin; Oxidative Stress; RANK Ligand; Rats; X-Ray Microtomography

Diabetes mellitus is a global health problem representing the fifth leading cause of mortality and a major risk factor for cardiovascular diseases. In the last years, we reported an association among urinary trypsin inhibitor (UTI), a small proteoglycan that plays pleiotropic roles in many inflammatory processes, and both type 1 and 2 diabetes and developed a method for its direct quantitation and structural characterization.. Urine from 39 patients affected by type 1 diabetes, 32 patients with type 2 diabetes, and 52 controls were analysed. UTI was separated from the main glycosaminoglycans physiologically present in urine by anion exchange chromatography, treated for chondroitin sulphate (CS) chain complete depolymerisation, and analysed for both UTI content and CS structure. UTI identification was performed by nano-LC-MS/MS analysis.. We evidenced increased UTI levels, as well as reduced sulphation of its CS moiety in association with diabetes, regardless of both age and medium-term glycaemic control. Furthermore, no association between UTI and albumin excretion rate was found.. Evidences suggest that UTI levels are not directly correlated with renal function or, otherwise, that they may increase before the onset of renal impairment in diabetes, representing a potential marker for the underlying inflammatory condition.

Topics: Adolescent; Adult; Aged; Biomarkers; Carbohydrates; Case-Control Studies; Chondroitin Sulfates; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Electrophoresis; Female; Glycoproteins; Humans; Male; Middle Aged; Renal Insufficiency; Urinalysis; Young Adult

Microencapsulation of pancreatic islets with polymeric compounds constitutes an attractive alternative therapy for type 1 diabetes mellitus. The major limiting factor is the availability of a biocompatible and mechanically stable polymer. We investigated the potential of Biodritin, a novel polymer constituted of alginate and chondroitin sulfate, for islet microencapsulation.. Biodritin microcapsules were obtained using an air jet droplet generator and gelated with barium or calcium chloride. Microencapsulated rat insulinoma RINm5F cells were tested for viability using the [3-(4,5-dimetyl-thiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] [MTT] colorimetric assay. Microencapsulated rat pancreatic islets were coincubated with macrophages derived from mouse peritoneal liquid to assess the immunomodulatory potential of the microcapsules, using quantitative real time-PCR (qPCR). Biodritin biocompatibility was demonstrated by subcutaneous injection of empty microcapsules into immunocompetent Wistar rats. Insulin secretion by microencapsulated human pancreatic islets was evaluated using an electrochemoluminescent assay. Microencapsulated human islets transplanted into chemically induced diabetic mice were monitored for reversal of hyperglycemia.. The metabolic activity of microencapsulated RINm5F cells persisted for at least 15 days. Interleukin-1beta expression by macrophages was observed during coculture with islets microencapsulated with Biodritin-CaCl2, but not with Biodritin-BaCl2. No statistical difference in glucose-stimulated insulin secretion was observed between nonencapsulated and microencapsulated islets. Upon microencapsulated islet transplantation, the blood glucose level of diabetic mice normalized; they remained euglycemic for at least 60 days, displaying normal oral glucose tolerance tests.. This study demonstrated that Biodritin can be used for islet microencapsulation and reversal of diabetes; however, further investigations are required to assess its potential for long-term transplantation.

Topics: Alginates; Animals; Biocompatible Materials; Capsules; Cell Line, Tumor; Chondroitin Sulfates; Coculture Techniques; Diabetes Mellitus, Type 1; Humans; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Islets of Langerhans Transplantation; Macrophages; Rats

Pathogenesis, frequency, and management of heparin-induced thrombocytopaenia are well-known. They may be related with both unfractioned heparin and low-molecular weight heparin. Suspected heparin must be discontinued as soon as the diagnosis is established. Orgaran (danaparoid sodium) may be used for management of patients with heparin-associated thrombocytopaenia but can itself be associated with a thrombocytopaenia. Our case report allows us to catch in mind such a crossed complication.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Captopril; Carotid Stenosis; Chondroitin Sulfates; Dermatan Sulfate; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Drug Combinations; Female; Heparin; Heparitin Sulfate; Humans; Hypertension; Stroke; Thrombocytopenia

We have studied the growth kinetics of fibroblasts derived from uninjured skin and chronic wounds in non-diabetic and diabetic (IDDM) patients. DNA measurements during the first 24 h after cell starvation showed that fibroblasts derived from chronic wounds, both non-diabetic and diabetic, display a decreased adhesion and proliferation. When determining the rate of proliferation after another 48, 72 and 96 h, a significant decrease in the proliferation rate was found in the chronic wound fibroblasts compared to those from uninjured skin. Furthermore, we have investigated the effects of heparin, hyaluronic acid and other heparin-like substances on the proliferation of non-diabetic and diabetic fibroblasts. We found that these substances stimulated the proliferation of human fibroblasts derived from both normal skin and chronic wounds measured as DNA content. Stimulation with heparin normalized the proliferation of the diabetic chronic wound fibroblasts. This effect was independent of the presence of serum. The effect of heparin was dose-dependent and most pronounced during the first 24 h of stimulation. These results suggest that heparin may be of importance in the treatment of chronic diabetic wounds.

Topics: Anticoagulants; Cell Count; Cell Division; Chondroitin Sulfates; Diabetes Mellitus, Type 1; Diabetic Foot; DNA; Fibroblasts; Heparin; Humans; Hyaluronic Acid; Skin; Time Factors