Early- and advanced non-enzymatic glycation in diabetic vascular complications: the search for therapeutics

Casper G. Schalkwijk 0 1 Toshio Miyata 0 1 0 T. Miyata United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine , 2-1 Seiryo-Machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan 1 C. G. Schalkwijk (&) Department of Internal Medicine, University Hospital Maastricht , P. Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes. Because of the huge premature morbidity and mortality associated with diabetes, prevention of vascular complications is a key issue. Although the exact mechanism by which vascular damage occurs in diabetes in not fully understood, numerous studies support the hypothesis of a causal relationship of non-enzymatic glycation with vascular complications. In this review, data which point to an important role of Amadori-modified glycated proteins and advanced glycation endproducts in vascular disease are surveyed. Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, we also described recent developments of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes. - Cardiovascular disease is a common complication of diabetes and the leading cause of death among people with diabetes (Zimmet et al. 2001). Vascular complications in diabetes can be caused by micro- and macroangiopathy (Schalkwijk and Stehouwer 2005). Retinal and renal microangiopathy cause retinopathy and nephropathy, and microangiopathy of the vasa nervorum contributes to diabetic neuropathy. Macroangiopathy in diabetes consists mainly of an accelerated form of atherosclerosis and affects all clinically important sites, i.e. the coronary, the carotid and the peripheral arteries, thus increasing the risk of myocardial infarction, stroke and peripheral artery disease. Dysfunction of the vascular endothelium is regarded not only as an important factor in the initiation of vascular complications but also in its progression and clinical sequelae (Cines et al. 1998). The results of large studies in type 1 and type 2 diabetes provide strong evidence that hyperglycaemia plays an important role in the pathogenesis of nephropathy, retinopathy, neuropathy and accelerated atherosclerosis (The Diabetes Control Complications Trial Research Group 1993; The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group 2000; UK Prospective Diabetes Study (UKPDS) Group 1995, 1998). These studies also emphasised that hyperglycaemia is an independent risk factor for these vascular complications although the exact relationship between glucose control and macrovascular complications, especially in type 2 diabetes, is still a matter of debate (Skyler et al. 2009). A growing body of evidence suggests that many hyperglycaemia-induced changes that explain the pathogenesis of vascular complications are mediated by early glycated proteins and/or advanced glycation endproducts (AGEs) (Goh and Cooper 2008; Genuth et al. 2005) (Fig. 1). Nonenzymatic glycation involves the condensation reaction of the carbonyl group of sugar aldehydes with the N-terminus or free-amino groups of proteins via a nucleophilic addition, resulting first in the rapid formation of a Schiff base. Through acidbase catalysis, these labile adducts then undergo rearrangements to the more stable Amadoriproducts. Only a small part of these relatively stable Amadori-products undergo further irreversible chemical reactions leading to the formation of AGEs. An important distinction of AGEs, compared with their Amadori-products, is their irreversible nature. In the complex pathways leading to the formation of AGEs, it seems that oxidative stress plays an important role, and therefore, AGEs will also accumulate under conditions of oxidative stress and inflammation (Baynes and Thorpe 2000). Because of the potential role of early- and advanced non-enzymatic glycation in vascular complications, the development of pharmacological inhibitors that inhibit the formation of these glycated products or the biological consequences of glycation and thereby retard the development of vascular complications in diabetes is of particular interest. In this review, data which point to an important role of Amadori-glycated proteins and AGEs in the development of vascular complications and recent developments in therapeutic interventions in the glycation pathway will be described. Amadori-glycated proteins and vascular complications The majority of the glycated proteins in plasma exist as Amadori-glycated proteins rather than as AGEs. On the basis of proteomic profiling, it was found that glucose attaches at many different sites in human serum albumin in vivo as evidenced by the 31 glycation sites (Zhang et al. 2008). In addition to albumin, other high-abundance plasma proteins were identified glycated including serotransferrin, alpha-1-antitrypsin, alpha-2-macroglobulin, apolipoprotein A-I and A-II, fibrinogen and alpha-1-acid glycoprotein as well as several moderately abundant glycated proteins (Jaleel et al. 2005; Dolhofer and Wieland 1980). Although several studies have demonstrated that the amount of Amadori-modified proteins is increased in diabetic patients, only limited data are available on the association of the plasma concentrations of Amadori-albumin with the presence and severity of diabetic complications. In a rodent model of type 2 diabetes, plasma Amadorialbumin concentrations were elevated twofold and declined after administration of a monoclonal anti-Amadori albumin, and this decrease was accompanied by a decrease of fibronectin (Cohen et al. 1994) indicating for the first time in vivo that Amadori-albumin contributes causally to diabetic vasculopathy. Indeed, infusion of Amadori-albumin in animal model induced a generalised diabetic vasculopathy (Cohen et al. 1996). In support, in type 1 diabetic Fig. 1 Formation of Amadori-glycated proteins and advanced glycation endproducts (AGEs) and their putative role in vascular complications patients, Amadori-albumin correlated with the generally recognised plasma markers of endothelial or vascular dysfunction (Schalkwijk et al. 1999). Amadori-albumin exhibits potential deleterious effects in various vascular cells types, which can be associated with vascular complications. Amadori-albumin has been shown to affect the biology of endothelial cells, such as TNF-a and E-selectin expression, and modulation of nitric oxide (NO) synthase activity (Amore et al. 1997; Higai et al. 2006). In human glomerular endothelial cells, Amadori-albumin caused an increase in type IV collagen, fibronectin and transforming growth factor-b1 (TGF-b1) expression, with an essential role of PKC signalling and TGF-b1 acti (...truncated)