Methylglyoxal: possible link between hyperglycaemia and immune suppression? Claire L. Price and Stella C. Knight Antigen Presentation Research Group, Imperial College London Faculty of Medicine, Level 7W, NWLH campus, Watford Road, Harrow, Middlesex, HA1 3UJ, UK No matter the cause of diabetes, the result is always hyperglycaemia. This excess glucose metabolism drives several damage pathways and raises concentrations of the reactive dicarbonyl, methylglyoxal (MG). MG can modify the structure and function of target molecules by forming advanced glycation end-products (AGEs) that act through their receptor (RAGE) to perpetuate vascular and neuronal injury responsible for long-term complications of diabetes. Diabetes patients also suffer lower resistance to many common infections, although the cause(s) for this lower resistance remains elusive. Here, we review recent evidence concerning immune suppression in diabetes and discuss the effects of MG on components of the immune system. We suggest that MG could be a missing link between hyperglycaemia and immune suppression in diabetes. The diabetes burden With recent increasing levels of obesity and related meta- bolic disorders, including insulin resistance and type 2 diabetes, the need to understand consequences of these conditions becomes progressively more important. The result of diabetes is inevitably hyperglycaemia, which is accompanied by other metabolic dysfunctions, raised con- centrations of metabolic byproducts and tissue damage. In addition to these well-studied consequences, diabetes also predisposes individuals to greater susceptibility to com- mon infections, the cause(s) of which remains unclear. In this article, we present evidence that the glycolytic bypro- duct methylglyoxal (MG) is a potent modifier of immune components and function, and we propose that MG- induced immune damage might provide a link between hyperglycaemia and diabetes-related infection risk. MG and metabolic dysfunction in diabetes The reactive a-oxoaldehyde MG is formed as a natural byproduct of several metabolic pathways, mainly from glycolysis but also from lipid peroxidation and threonine catabolism (Figure 1) [1]. To prevent cellular damage, MG is usually swiftly detoxified by defence components, in- cluding the specialised glyoxalase system, which converts a-oxoaldehydes to their respective hydroxyacids [2]. In diabetes, the increased flux of glucose metabolism causes metabolic dysfunction. Higher rates of respiration through the electron transport chain within mitochondria lead to superoxide ‘leakage’, increased oxidative stress and acti- vation of the nuclear enzyme, poly(ADP-ribose) polymer- ase-1 (PARP). PARP activation depletes its substrate NAD + (slowing rate of glycolysis and electron transport) and inhibits glyceraldehyde-3-phosphate (G-3-P) dehydro- genase (GAPDH) [3]. By inhibiting the GAPDH conversion of G-3-P, glycolytic intermediates build up, compounded by increased glucose at the head of the chain (Figure 1). Glycolytic intermediates are pushed down their respective metabolic pathways (protein kinase C, polyol and hexosa- mine), altering cellular balance and causing damage through raised angiogenic factors, reduced nitric oxide, and altered gene expression and protein function (Figure 1) [4]. This damage, along with that from formation of advanced glycation end-products (AGEs, discussed below), lies behind the vascular and neuronal compli- cations of diabetes [5]. The glycolytic intermediates fructose-1,6-diphosphate, G-3-P and glycerol phosphate are direct precursors of MG; thus, in diabetes, MG production is vastly increased. Furthermore, the glyoxalase defence against MG becomes overwhelmed, with activity of glyoxalase I decreased by oxidative stress, and MG concentrations are able to rise [6]. As such, MG blood levels are 2–6 times higher in diabetes patients compared with controls [7]. Because MG initially binds reversibly to tissues in vivo [8], actual levels might be far higher than this measurement suggests, and concen- trations probably vary locally depending upon availability of precursors and activity of defences. MG is thought to be the most abundant and potent of the a-dicarbonyls, with MG-derived AGEs being quantitatively important [6]. Formation of AGEs Maillard first described the non-enzymatic reaction of glycine with glucose in 1912 [9], spurring diabetes researchers’ interest in the subject of advanced glycation. We now know that reducing sugars and other a-dicarbonyl compounds (glyoxal, MG and 3-deoxyglucosone) form a range of heterogeneous AGE adducts on free amine and thiol groups within proteins, lipoproteins and nucleic acids. These adducts alter the structure and function of their target molecules but also form ligands for the receptor for AGEs, RAGE [10] and other known AGE receptors (for review see Ref. [11]). RAGE ligation causes Opinion Corresponding author: Knight, S.C. (s.knight@imperial.ac.uk). 312 1043-2760/$ – see front matter . Crown Copyright ß 2009 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2009.03.010 Available online 24 August 2009