Glycosaminoglycan therapy for long-term diabetic complications?

Abstract

Long-term complications are the most important cause of mortality of diabetic patiens in western countries and diabetic nephropathy has emerged as a major determinant of end-stage renal failure [1]. Moreover, patients with diabetes mellitus have a high probability of developing acute cardiovascular disease, in particular myocardial infarction and cerebrovascular stroke which are the cause of death in nearly 80 % of this population [2]. Although data from the Diabetes Control and Complications Trial establish that hyperglycaemia has a central role in diabetic complications, strict metabolic control can be difficult to achieve. The search for new and ancillary approaches to diabetic complications is therefore warranted and understanding the distal pathway of glucose toxicity assumes clinical and therapeutical significance. Thus, evidence has been provided [3,4] that the alterations of the glycosaminoglycan (GAG) structure and metabolism may be of major importance for the development of diabetic complications. The aim of this article is to stress the hypothesis that GAGs might play an important role in the pathogenesis of late diabetic complications and that their treatment may be useful in several of these complications. GAG structure and functionGAGs are highly glycosylated and sulphated glycoproteins, consisting of dimeric repeated units containing an uronic acid (iduronic or glucuronic acid) and an aminosugar (glucosamine or galattosamine) [5]. These molecules are widely distributed in the body and prominent in extracellular matrices [5].Three major classes of GAGs have been described: a predominant large chondroitin sulphate, a small dermatan sulphate and a polydisperse heparan sulphate (HS) [5]. GAGs are vital in maintaining the structural integrity of the tissue and studies have shown that basement membranes contain HS in the form of a proteoglycan unique to that tissue [5]. HS forms anionic sites in this matrix and are thought to restrict the passage of proteins through the basement membrane [5]. GAG metabolism and diabetes mellitusIn diabetic patients, the increased macromolecular permeability within the glomeruli that precedes the onset of established renal lesions and the increased vascular permeability to albumin seem to be related to structural alterations in the macromolecular pathway, i. e. the extracellular matrix, between the endothelial cells [4]. The nature of this alteration may be related to the loss of negatively charged molecules of extracellular matrix and of the endothelium, among which HS is highly represented. A number of reports indicate that HS metabolism is impaired in diabetes and this is responsible for the extracellular matrix negative charge loss [4]. HS is a strongly negatively charged molecule that is structurally similar to heparin but its base polymer has a lower degree of processing (sulphation, epimerization) (Fig. 1). The HS chain imparts a negative charge to the basement membrane and determines the molecular charge permselectivity of the glomerular basement membrane [4]. Th...

Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients

“…All three observations question the concept that abnormal charge permselectivity is the initial GBM disorder responsible for microalbuminuria. Therefore, the most plausible explanation of the improvement in microalbuminuria is sulodexide's wellknown favorable effect on the endothelium (13).…”

“…It has already been proposed that GAGs may reduce albuminuria in DN by favorably interfering with mechanisms responsible for the altered GBM and composition and function (permselectivity) of the mesangial extracellular matrix (13,35). Several observations suggest that sulodexide activity in the kidney is complex, possibly modulating the renal expression of genes involved in renal remodeling: first, the persistence of the hypoalbuminuric effect up to 4 mo after cessation of therapy with the higher doses of sulodexide; second, the number of responders increases over the 4 mo of treatment, suggesting the hypoalbuminuric effect of sulodexide increases over time; and third, the similar extent of the hypoalbuminuric effect in patients with/without concomitant ACEI-therapy and the sharp difference between the persistent, posttreatment urinary albumin lowering effect of sulodexide and the rapid rise in AER seen shortly after discontinuation of ACEI therapy (36).…”

“…A number of drugs are currently being investigated, glycosaminoglycans (GAGs; see Appendix) are particularly interesting because they theoretically can target the generalized endothelial dysfunction and the metabolic defect in matrix and basement membrane synthesis, which, according to the Steno hypothesis, are responsible for DN and possibly also for the high rate of cardiovascular mortality observed in DN patients (9,13).…”

“…Interestingly, we have demonstrated that these favorable effects accompany inhibition of renal TGF-␤ (17). Furthermore, GAGs have been shown to restore anionic charges lost from the endothelial surface (18) and a number of other endothelial dysfunctions relevant to diabetic micro-and macroangiopathy (13). Recent explorative studies have also described favorable results on albuminuria in DN patients treated with a LMW heparin (19,20), danaparoid, a mixture of sulfated GAGs consisting mainly of heparan sulfate (21), and sulodexide (22)(23)(24)(25)(26)(27)(28)(29).…”

“…It has also been shown to inhibit TGF-␤ overexpression and matrix synthesis induced by high concentrations of glucose in mesangial cells (Gambaro G and Schleicher E, manuscript in preparation) to the same extent as the single components and to rectify endothelial dysfunctions observed in DM (13).…”