The critical role of methylglyoxal and glyoxalase 1 in diabetic nephropathy.

The discovery of increased formation of methylglyoxal (MG) by cell metabolism in high glucose concentration in vitro suggested possible relevance to diabetes and diabetes complications (1,2). MG is the precursor of quantitatively important advanced glycation end products (AGEs) of protein and DNAand MG-derived AGEs increase in experimental and clinical diabetes (3,4). Increased MG and its metabolism by glyoxalase 1 (Glo1) was linked to clinical microvascular complications (nephropathy, retinopathy, and neuropathy) (5). Current clinical treatment decreasing MG and MG-derived AGEs, such as insulin lispro (6,7), has some clinical benefit in diabetic nephropathy (8), although the decrease in MGderived AGE exposure is minor—;17% (7). Greater benefits may be achieved with specific and effective antiMG targeted therapy. An outstanding research problem is to gain unequivocal evidence that MG glycation is a key mediator of vascular complications and, if possible, provide some pointers as to how MG glycation could be effectively countered. In this issue, the study by Giacco et al. (9) provides key evidence by a functional genomic approach manipulating expression of Glo1 to increase or decrease endogenous MG glycation. The outcomes show that development of experimental diabetic nephropathy is driven by increased levels of MG glycation and increasing renal expression of Glo1 prevents this. Recent research has shown Glo1 expression may be increased by small molecule inducers (10). Taken together, these findings suggest that prevention and treatment of diabetic nephropathy and possibly other complications of diabetes may be improved by development of Glo1 inducers. MG is an endogenous a-oxoaldehyde or dicarbonyl metabolite formed mainly from the degradation of triose phosphates—a minor spontaneous “leak” from the metabolic flux through anaerobic glycolysis (Fig. 1). Other usually minor contributions to MG formation are from the oxidation of acetone—increased in diabetic ketoacidosis—catabolism of threonine, and nonenzymatic degradation of glucose and proteins glycated by glucose (11). MG is a highly potent glycating agent with specific reactivity ;20,000-fold higher than that of glucose. This is tolerable in vivo because efficient detoxification of MG by Glo1 maintains the concentration of MG in plasma approximately 50,000-fold lower than that of glucose. In diabetes, however, MG concentrations and MG-derived AGEs increase in plasma and at sites of complications development (4,12,13). MG is formed mainly inside cells but a minor fraction leaks out and so glycation of both cellular and extracellular proteins by MG increases (4,14,15). MG is unlike glucose in its glycation reaction with proteins. Glucose reacts with proteins on lysine side chain or N-terminal amino groups to initially form fructosamine adducts—such as glycated hemoglobin A1c. MG is rather an arginine-directed glycating agent mainly forming the hydroimidazolone adduct MG-H1 (16) (Fig. 1). As a consequence, the functional impairment of protein is more likely by MG glycation because arginine residues are more common in functional domains of protein than lysine residues (19.5 vs. 12.5%) (17). Moreover, arginine residues within functional domains are hot spots for MG modification. For example, arginine residues within the RGD and GFOGER motifs of integrin-binding domains of collagen IV lining the walls of blood vessels are hot spots for MG glycation and modification triggers detachment of endothelial cells (15). MG glycation has the potential to seek out and damage sensitive sites in tissues and blood vessels. Although the steady-state levels of MG-modified proteins is low, usually 1–5%, their physiological effects are amplified by a “gatekeeper” role in dysfunction, such as MG-modified mitochondrial