Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives

Abstract

Persistent hyperglycemic state in type 2 diabetes mellitus leads to the initiation and progression of non-enzymatic glycation reaction with proteins and lipids and nucleic acids. Glycation reaction leads to the generation of a heterogeneous group of chemical moieties known as advanced glycated end products (AGEs), which play a central role in the pathophysiology of diabetic complications. The engagement of AGEs with its chief cellular receptor, RAGE, activates a myriad of signaling pathways such as MAPK/ERK, TGF-β, JNK, and NF-κB, leading to enhanced oxidative stress and inflammation. The downstream consequences of the AGEs/RAGE axis involve compromised insulin signaling, perturbation of metabolic homeostasis, RAGE-induced pancreatic beta cell toxicity, and epigenetic modifications. The AGEs/RAGE signaling instigated modulation of gene transcription is profoundly associated with the progression of type 2 diabetes mellitus and pathogenesis of diabetic complications. In this review, we will summarize the exogenous and endogenous sources of AGEs, their role in metabolic dysfunction, and current understandings of AGEs/RAGE signaling cascade. The focus of this review is to recapitulate the role of the AGEs/RAGE axis in the pathogenesis of type 2 diabetes mellitus and its associated complications. Furthermore, we present an overview of future perspectives to offer new therapeutic interventions to intervene with the AGEs/RAGE signaling pathway and to slow down the progression of diabetes-related complications.

Keywords: advanced glycation end products (AGEs); diabetic complications; hyperglycemia; pancreatic beta cells; receptor for advanced glycation end products (RAGE); type 2 diabetes mellitus.

Figure 1

Pathways of AGEs formation. Maillard reaction is the classical pathway of advanced glycation end products (AGEs) formation. Metal catalyzed autooxidation of glucose (Wolff pathway) or reverse aldol reaction and autooxidation of the Schiff base (Namiki pathway) or non-oxidative Amadori product cleavage (Hodge pathway) forms reactive dicarbonyls and AGEs precursors that contribute significantly to AGEs formation. In the Polyol pathway, an excessive amount of glucose is reduced to sorbitol by the enzyme aldol reductase, which is then converted to fructose by sorbitol dehydrogenase. Fructose and its metabolites, being potent glycating agents, lead to the production of AGEs. The lipid peroxidation of polyunsaturated fatty acids leads to the formation of lipid peroxides, which first converts to reactive dicarbonyls and ultimately results in the formation of advanced lipid peroxidation end products (ALEs). The amino acid derived ketone body metabolism also generates AGEs by producing the intermediate AGEs precursor reactive dicarbonyls. The endogenous generation of methylglyoxal via the triose phosphate isomerase reaction of glycolysis is also an important source of AGEs. Some of the important reactive dicarbonyls involved in AGEs formation include methylglyoxal, glyoxal, and 3-deoxyglucosone.

Figure 2

AGEs/RAGE-induced pancreatic beta cell toxicity. The AGEs/RAGE mediated signaling causes enhanced oxidative stress and increased inflammation in pancreatic beta cells. The generation of damaging reactive oxygen species (ROS) during oxidative stress affects the amyloidogenicity of islet amyloid polypeptide (IAPP) and leads to the formation and aggregation of toxic IAPP species. RAGE binds with these toxic IAPP intermediates and leads to the formation of amyloid plaque resulting in pancreatic beta cell toxicity.

Figure 3

AGEs/RAGE axis and diabetic complications. The AGEs/RAGE interaction triggers several signaling cascades such as IKK/NF-κB, ERK/MAPK, PKC, JNK and JAK/STAT and activates transcription factors such as NFκB, CREB, AP-1, and STAT3, which results in oxidative stress and amplifies inflammatory responses. The AGEs/RAGE axis will stimulate macrophage infiltration, increase gene expression of inflammatory cytokines, adhesion molecules, and ECM proteins. It will result in overexpression of TGF-β, fibronectin, and collagen. The increase in ER stress will lead to enhanced oxidative stress which will further cause inflammatory responses and activate LDL oxidation. The RAGE expression will be upregulated in response to positive feedback by AGEs/RAGE axis induced NFκB activation. The AGEs/RAGE/NFκB-driven sustained inflammation and oxidative stress activation of signaling cascades play an important role in the pathogenesis of diabetic complications. AGE: advanced glycation end products; IL-1β: interleukin 1 beta; IL-6: interleukin 6; TNFα: tumor necrosis factor alpha; COX-2: cyclooxygenase-2; p27: cyclin-dependent kinase inhibitor 1B; TGFβ: transforming growth factor beta; NGF: nerve growth factor; ICAM-1: endothelial and leukocyte associated transmembrane protein; VCAM-1: vascular cell adhesion molecule 1; MCP-1: monocyte chemoattractant protein-1; MMP2: matrix metallopeptidase 2; ECM: extracellular matrix accumulation; IKβ: inhibitor of NFκB; IKK: inhibitor of IKβ; NFκB: nuclear factor kappa B; MAPK: mitogen-activated protein kinases; ERK: extracellular signal-regulated kinases; CREB: cAMP-response element binding protein; PKC: protein kinase C; JNK: Jun N-terminal kinase; AP-1: activator protein 1; JAK-STAT: janus kinase-signal transducer and activator of transcription.