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An update on the potential role of advanced glycation end products in glycolipid metabolism
Journal Pre-proof An update on the potential role of advanced glycation end products in glycolipid metabolism
Xiaolei Wang, Junjun Liu, Ying Yang, Xiandang Zhang PII:
S0024-3205(20)30091-6
DOI:
https://doi.org/10.1016/j.lfs.2020.117344
Reference:
LFS 117344
To appear in:
Life Sciences
Received date:
22 October 2019
Revised date:
17 January 2020
Accepted date:
18 January 2020
Please cite this article as: X. Wang, J. Liu, Y. Yang, et al., An update on the potential role of advanced glycation end products in glycolipid metabolism, Life Sciences(2020), https://doi.org/10.1016/j.lfs.2020.117344
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© 2020 Published by Elsevier.
Journal Pre-proof An update on the potential role of advanced glycation end products in glycolipid metabolism
Xiaolei Wang1*, Junjun Liu1, Ying Yang1, Xiandang Zhang1*
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Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, Jinan, 250014, China
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*Corresponding author Dr. Xiandang Zhang
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Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, 18877, Jing 10 Rd., Jinan, 250014, China. Email:
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[email protected]. Fax: 82919799 Dr. Xiaolei Wang
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Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, 18877, Jing 10 Rd., Jinan, 250014, China. Email: [email protected].
Acknowledgements We acknowledge Prof. Philippe Savarin (University Paris 13) for providing professional suggestions for the manuscript. This work was supported by the National Natural Science Foundation [81900736], Innovation Project of Shandong Academy of Medical Sciences, and Scientific and Technological Development Programme of Shandong Academy of Medical
Journal Pre-proof Sciences (2018-22). Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this article.
Total word count: 5087
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Number of figures: 3
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Number of tables: 1
Journal Pre-proof An update on the potential role of advanced glycation end products in glycolipid
metabolism
Abstract Advanced glycation end products (AGEs) play a crucial role in many major diseases, such as diabetes and atherosclerosis. AGE accumulation in the body is generally considered a consequence of hyperglycaemia. However, recent studies have shown that AGEs may also be an important
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cause of the initial pathogenesis of diabetes and atherosclerosis. The objective of the present review
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is to provide an update on the AGE-induced mechanisms involved in the pathophysiology of
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glucose and lipid metabolism, even though the unique mechanisms involved in these diseases are not well understood. AGE precursors (methylglyoxal) and AGE receptors have been demonstrated in
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animal models to mediate insulin resistance and lipid metabolism disorders. Although we have
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not yet achieved a complete understanding of the role of AGEs, emerging therapeutic
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interventions targeting AGE reduction and AGE-RAGE signalling have yielded some beneficial clinical outcomes. Additional studies are needed to evaluate the utility and mechanism of
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circulating and tissue AGEs to support the identification of efficient and specific interventions.
Keywords: Advanced glycation end products (AGEs), Receptor for AGEs (RAGE), Diabetes, Lipid metabolism, Glycolipid
Journal Pre-proof 1 Introduction of advanced glycation end products (AGEs) and AGE compounds AGEs are formed via a nonenzymatic reaction between reducing sugars and proteins, lipids or nucleic acids, also known as the Maillard reaction. AGEs can be obtained exogenously or endogenously, through diet or produced within the body, respectively. Accumulation of AGEs independently promotes oxidative stress and ageing, and AGEs are involved in the development of several pathologies, such as diabetes, atherosclerosis and cardiovascular diseases [1]. AGEs exert their pathogenic effects by (1) modifying extracellular and intracellular proteins (i.e.,
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crosslinking) and (2) activating signalling cascades by binding to cell surface receptors (RAGEs). (1) AGEs alter the
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physiological properties of extracellular matrix (ECM) proteins through the formation of intermolecular bonds or crosslinking. In addition, intracellular accumulation of AGEs may cause endoplasmic reticulum (ER) stress, usually
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leading to inflammation or apoptosis [2]. Moreover, AGEs can crosslink proteins in the mitochondrial respiratory
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chain, suppressing ATP synthesis and aggravating reactive oxygen species (ROS) production [3]. (2) RAGEs can be separated into two main types depending on the downstream effects of AGE binding and activation: RAGE initiates
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complex signalling pathways when activated by ligand binding, whereas AGER1 is associated with AGE
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endocytosis, breakdown, and removal from the circulation [4] (Fig. 1).
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Journal Pre-proof Fig. 1. Scheme of AGEs interaction with RAGE and AGER1 under conditions with different AGE loads. (A) A low AGEs burden and (B) an overload of AGEs. RAGE, receptor for AGEs; AGER1, AGE receptor 1; p38 MAPK, p38 mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; ERK 1/2, extracellular signal-regulated protein kinases 1 and 2; JAK/STAT, Janus kinase/signal transducers and activators of transcription; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; AP-1, activator protein 1; FOXO, forkhead box protein O subclass; SIRT1, sirtuin-1. Adapted from Chen et al. [4].
AGEs can be produced in the body or obtained from exogenous sources such as diet and smoking. AGE accumulation occurs during heat processing of food, and browning continues during storage. Many types of AGE
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precursors are formed during the initial, intermediate and final stages of the Maillard reaction. Different AGE
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compounds are created through a series of reactions depending on their composition and molecular size [4]. Such compounds include pyrraline, Nɛ-carboxymethyllysine (CML), Nɛ-carboxyethyllysine (CEL), pentosidine,
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argpyrimidine, derivatives of methylglyoxal (MG), hydroimidazolones derived from MG, glyoxal (GO), 3-
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deoxyglucosone (3-DG), and arginine-derived Nδ-ornithine and bis(lysyl)imidazolium derivatives, such as methylglyoxal-lysine dimer (MOLD) and glyoxal-lysine dimer (GOLD) [5,6].
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For decades, the effects of AGEs on diabetes and hyperlipidaemia have been extensively studied, and this
metabolism.
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review focuses on the potential role of AGEs in glycolipid
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2 Effects of AGEs on endocrinology and metabolic diseases
2.1 AGE: a potential endocrine disruptor Some studies have noted that the disruption of endocrine activity involves AGE-mediated disease progression. Humans are susceptible to systemic accumulation of endogenous and exogenous AGEs, which interfere with physiologically significant hormones, including insulin [7], adiponectin [8], androstenedione [9], progesterone, and oestradiol [10], among others. AGEs may block or entrap natural hormones in the body and affect their target actions. Moreover, AGEs can imitate or partly imitate hormones and cause excessive irritation. In addition to these
Journal Pre-proof effects, AGEs also bind to the cell surface or to nuclear receptors, inhibiting normal signals as hormone antagonists [11].
2.2 AGEs and glycolipid metabolism: effect or cause? Endogenous formation of AGEs is a normal consequence of metabolism. AGEs require weeks or years to form; however, the accumulation of high levels of AGEs or AGE compounds in tissues and the circulation can be
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pathogenic. For example, increased levels of MG (a major precursor of AGEs) can be generated in processes such as glycolysis, glucose oxidation, lipid peroxidation, and protein glycation [12] and directly react with lysine and
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arginine residues on proteins to produce AGEs [13]. Under certain conditions, such as hyperglycaemia and
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hyperlipidaemia, the formation of AGEs can be accelerated; indeed, elevated amounts of AGEs have been found to
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be associated with ageing and different diseases in vivo [14-18].
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2.2.1 Hyperglycaemia-induced AGE accumulation plays a crucial role in diabetic complications Various cells can be injured during the onset of diabetes, and one way that hyperglycaemia causes cell injury is by
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fostering AGE accumulation [19]. Both islet β-cell dysfunction and diabetic nephropathy are associated with the
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accumulation of AGEs [20-24], and the mechanism may be related to AGE-induced mitochondrial stress, ER stress, and downstream signalling pathway activation [25,26]. Extensive evidence demonstrates that AGEs contribute to
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long-term diabetic complications, especially microvascular complications [19]. The aetiology of diabetic retinopathy, another frequent microvascular complication in addition to diabetic nephropathy, is complex,
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one of the established mechanisms is AGE-induced proinflammatory signalling [27]. In addition, recent studies suggest the important role of AGEs, which are implicated in enhanced proliferation, inflammation and ECM degradation, in macrovascular complications [28].
2.2.2 Pathological outcomes of AGE accumulation in atherosclerosis Lipid peroxidation can result in AGE formation; this process is considered an alternative pathway of the Maillard reaction [29] and suggests a close relationship between AGEs and lipid metabolism. Glucose intolerance and
Journal Pre-proof hyperglycaemia, which are characterized by lipid accumulation and coronary artery disease (CAD), are associated with the pathogenesis of atherosclerosis [30,31]. Extracellular protein glycation can directly promote atherosclerosis. Furthermore, AGE receptor-activated signalling pathways can increase inflammation, calcium deposition, and vascular smooth muscle cell (SMC) apoptosis, contributing to the development of atherosclerosis [32].
2.3 New insight into AGEs should be valued Although the importance of AGEs in the pathogenesis of diabetic complications and lipid
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metabolism has been reinforced by many studies (Table 1), the exact mechanisms by which
accumulation has been reported to be an initial factor for diabetes onset [33].
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Interestingly, AGE
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AGEs function in the initial pathogenesis of diabetes and hyperlipidaemia are poorly understood.
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Nonetheless, clinical evidence has indicated that arterial stenosis and atherosclerosis are related to RAGE levels in patients either with or without diabetes [2], suggesting that the effect of AGEs on lipid metabolism may be
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independent of elevated blood glucose. Thus, AGE formation may be an important reason underlying disorders of
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glucose and lipid metabolism.
Table 1. Effects of AGEs on the pathophysiology of glucose and lipid metabolism Disease/tissue injury Pancreatic dysfunction
Mechanism/pathway p38/MAPK HSP60
Diabetic nephropathy
References You et al. [21] Guan et al. [20]
PI3K/Akt, MAPK/ERK, and NF-κB Inflammation PI3K-AKT, NF-κB
Sanajou et al. [22]
Ojima et al. [23] Sharma et al. [24]
Journal Pre-proof Endoplasmic reticulum stress
Fan et al. [26]
Diabetic retinopathy
Proinflammatory signalling
Zong et al. [27]
Coronary artery disease
Proliferation, ECM degradation Oxidative stress
Atherosclerosis
Kosmopoulos et al. [28]
Fishman et al. [2]
Calcium deposition, SMC apoptosis
Katakami [32]
SMC proliferation and migration, macrophage activation, inflammation
del Turco and Basta [18]
Granular calcification, predisposition to rupture
Pugliese et al. [34]
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3 AGEs and AGE compounds might be the cause of glycolipid metabolic disorders
3.1 Glycometabolism
considered to be the main factor in AGE formation, intensive control
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Because hyperglycaemia is
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of hyperglycaemia is expected to also mitigate the consequences of AGEs on diabetic
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complications. However, studies have failed to produce the anticipated results [35-37]. In fact, high systemic AGE levels are not always associated with high glucose levels because AGEs can be
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produced in the body, accumulate during ageing, and be absorbed from food [38]. AGEs are naturally present in raw
addition,
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animal-origin foods, and cooking accelerates the generation of additional AGEs within these foods. In
glucose exhibits the slowest glycation rate among reducing sugars [39]. The reported data even
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suggest that there is no correlation between serum levels of AGEs and glucose [40]. Moreover, food-derived AGEs have been indicated to contribute to cellular and tissue injury in chronic diabetes [19], and serum AGE levels are reportedly significantly increased in prediabetic rats [41]. Furthermore, clinical studies have shown that dietary AGEs can modulate the AGE load in subjects with diabetes, but studies in healthy subjects are limited [42]. Thus, the roles of AGEs in healthy and prediabetic subjects warrant further research because AGE accumulation alone might trigger the disease. Insulin resistance (IR) and hyperglycaemia are the underlying causes of type 2 diabetes
Journal Pre-proof (T2D), and MG levels increase due to elevated flux through glycolysis. Elevated levels of MG lead to AGEs accumulation, contributing to diabetic vascular complications such as nephropathy and cardiovascular diseases [43]. Additionally, MG formation includes the degradation of glycated proteins, lipid peroxidation of polyunsaturated fatty acids and oxidative protein metabolism [44]. Kim et al. [45] demonstrated that MG can induce angiogenic impairment of endothelial progenitor cells via alterations in the AGE/RAGE-VEGFR-2 pathway. MG also
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mediates streptozotocin-induced diabetic neuropathic pain by activating peripheral transient
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receptor potential channel ankyrin 1 (TRPA1) in rats [46]. Moraru et al. [47] found that elevated
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levels of MG cause flies to become obese, resistant to insulin, and hyperglycaemic. Moreover, MG leads to primary defects in insulin signalling and cellular abnormalities at the proteomic and
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metabolic levels in rat muscle cells [13]. These observations place MG not only downstream but
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also upstream of IR and hyperglycaemia in the development of diabetes. Identifying the
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3.2 Lipid metabolism
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therapy of this disease.
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underlying mechanisms of AGEs and MG in diabetes will be crucial for the early prevention and
AGEs should be considered major cardiometabolic risk factors [42]. How do AGEs specifically contribute to atherosclerosis or hyperlipidaemia? (1) Nonreceptor-mediated effects are direct cytotoxic mechanisms due to glycation and crosslinking modifications in the ECM, altered ECM architecture and the trapping of macromolecules against vessel walls [32]. (2) Receptor-mediated effects, including endothelial dysfunction, SMC proliferation and migration, macrophage activation, enhanced uptake of oxidized LDL (oxLDL), and foam cell formation [18], are closely related to abnormal lipid metabolism. Qualitatively, RAGE upregulation is associated with granular rather than diffuse calcification, exposing the lipid core of atheromatous plaques and resulting in instability and predisposition to rupture [34]. Moreover, AGE-RAGE interactions might amplify inflammatory responses through lipid deposit-induced metalloproteinases [18].
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3.3 A new function for AGEs in hepatic glycolipid metabolism The current paradigm states that IR is the early symptom and basic feature of T2D. IR occurs when insulin-mediated glucose uptake and utilization in the liver, muscle and adipose tissue decrease. Effective prevention of IR is thus an important approach to controlling and delaying the onset of diabetes. Insulin binds to the insulin receptor on the cell membrane, phosphorylates
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insulin receptor substrate (IRS1/2), activates related pathway molecules through PI3K/Akt,
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promotes both tissue uptake of glucose and glycogen synthesis, stimulates lipid synthesis and
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inhibits gluconeogenesis [48] (Fig. 2). According to a clinical study, IR was exacerbated in a high-AGE diet-fed group compared with a low-AGE diet-fed group [49], and animal
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experiments have confirmed that AGEs can cause islet β-cell insulin synthesis disorders and
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tissue IR. AGEs reduce insulin synthesis in islet β-cells by modulating the activity of FOXO [25],
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and muscle glucose uptake is reduced via the suppression of GLUT4 by AGEs [50]. The liver is considered to be the starting point of IR, and it plays a central regulatory role in glycolipid
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metabolism [51]. Regardless, the mechanism by which AGEs impact hepatic IR (pathways
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involved in GSK3β-induced glycogenesis and SREBP1c-induced lipid synthesis) remains unclear (Fig. 2). The AGE precursor MG was shown to decrease cholesterol biosynthesis and exacerbate IR in rat muscle cells [13], indicating the potential role of AGEs in glycolipid metabolism.
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Fig. 2. Mechanisms of AGEs-induced insulin resistance. The insulin signalling pathway: Insulin binds to the insulin receptor on
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the cell membrane, phosphorylates insulin receptor substrate (IRS1/2), activates related pathway molecules through PI3K/Akt,
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promotes both tissue uptake of glucose and glycogen synthesis, stimulates lipid synthesis and inhibits gluconeogenesis. AGEs in black represent mechanisms that have been confirmed (“+” represents stimulation, and “-” represents inhibition.). AGEs in red represent unclear mechanisms. IRS1/IRS2, insulin receptor substrate 1 and 2; PI3K, phosphatidylinositol 3-kinase; GLUT4, glucose transporter 4; SREBP1c, sterol regulatory element-binding protein 1c; GSK-3, glycogen synthase kinase 3.
AGEs and elevated levels of nonesterified fatty acids play important roles in oxidative stress and inflammation [52], which are the basic pathophysiological processes of liver diseases. The liver is a crucial centre of fatty acid metabolism, and hepatic AGE accumulation can cause liver damage and contribute to hepatotoxicity and liver injury [53]. Additionally, circulating levels of AGEs have been found to be elevated in patients with non-alcoholic fatty liver disease
Journal Pre-proof (NAFLD) [54] and liver cirrhosis [55]. Hepatic ROS levels in rats were found to increase in response to MG treatment [12], and another study reported that both hepatic expression of RAGE and plasma MG levels are increased in mice fed a high-fat diet compared with mice fed a low-fat diet [56]. Furthermore, fructose-mediated increase in MG flux can suppress hepatic AMPK activation, causing IR, fatty liver and dyslipidaemia, an association that has been overlooked to date [57]. Overall, a new mechanistic explanation has culminated from the results
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of these studies, suggesting that elevated AGEs or MG levels may be a root cause of hepatic
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glycolipid disorders (Fig. 3).
Fig. 3. Schematic diagram. The current dominant paradigm that insulin resistance andhyperglycaemia are root causes of tissue damage [47]. A new explanation culminates from this review, suggesting that elevated AGEs or MG levels may be the root cause of hepatic glycolipid disorders.
4 Perspective: interventions to reduce AGEs
Journal Pre-proof Despite the adverse effects of AGEs on diabetes recorded over the past two decades, measures necessary to limit AGE exposure and function (AGE/RAGE interactions and downstream pathway activation) are still not well understood. Dietary factors are an important reason for AGE accumulation that may be utilized in the development of potential therapeutic and preventive targets for diabetes. Bread, beer and carbonated drinks are rich sources of AGEs and MG. Dietary AGE interventions can prevent new formation of dietary AGEs, minimize the
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absorption of AGEs by the gastrointestinal tract and reduce levels of circulating AGEs [4]. Drug
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options are another way of reducing AGEs: (1) Aminoguanidine and pyridoxamine have
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antioxidant properties and are used to inhibit AGE formation and ameliorate coronary artery disease, but their use might be limited due to safety concerns encountered in clinical trials [2].
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Resveratrol can suppress hyperglycaemia and other related diseases, including atherosclerosis, in
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response to AGEs through mechanisms that also mainly target oxidative stress [58]. (2) In
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addition, rats and mice treated with a soluble RAGE (sRAGE) infusion or RAGE inhibitor displayed reduced rates of atherosclerosis [59-61]. Polygonum cuspidatum extract can
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significantly reduce AGE formation, lower blood glucose and normalize serum lipid parameters,
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including LDL-C, HDL-C, and triglycerides (TG), in diabetic rats [62]. Studies have shown that statins can increase the plasma levels of sRAGE and thus inhibit interaction between AGEs and RAGE [63,64]. Although some antidiabetic and antihypertensive drugs are already clinically approved, their specific mechanisms have not been fully elucidated, and clinical results concerning the AGE/RAGE axis are rare because the primary effects of these drugs are more important than are their secondary effects as AGE inhibitors or RAGE antagonists [65]. Given these results, additional basic research and clinical trials are needed to evaluate AGE intervention strategies and to investigate the potential mechanisms of AGEs in diabetes.
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5 Conclusions AGEs comprise a critical family of molecules with pivotal roles in the pathophysiology of metabolic diseases. As AGEs are directly implicated in diabetes and atherosclerosis through modulation of IR, oxidative stress and lipid synthesis, AGEs and RAGE should be considered major metabolic risk factors. Increasing evidence supports a role for AGEs and AGE/RAGE
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signalling in glycolipid metabolic abnormalities. The development of therapeutic interventions
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the prevention and treatment of metabolic diseases.
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aimed at reducing circulating AGEs or blocking RAGE activation may offer new perspectives on
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Acknowledgements
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We acknowledge Prof. Philippe Savarin (University Paris 13) for providing professional
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suggestions for the manuscript. This work was supported by the National Natural Science Foundation [81900736], the Innovation Project of Shandong Academy of Medical Sciences, and
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Sciences (2018-22).
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the Scientific and Technological Development Programme of Shandong Academy of Medical
Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this article.
Data availability The data used to support our findings in this study are available from the corresponding author upon request.
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Journal Pre-proof Conflict of Interest Policy Form The authors declare that there is no conflict of interest regarding the publication of this article. Author Contribution Acquisition of data, design and drafting of the manuscript and obtained funding: Xiaolei Wang Figure design and revision of the manuscript: Junjun Liu Revision of the manuscript: Ying Yang
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Obtained funding and study supervision: Xiandang Zhang
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Graphical abstract
Xiaolei Wang, Junjun Liu, Ying Yang, Xiandang Zhang PII:
S0024-3205(20)30091-6
DOI:
https://doi.org/10.1016/j.lfs.2020.117344
Reference:
LFS 117344
To appear in:
Life Sciences
Received date:
22 October 2019
Revised date:
17 January 2020
Accepted date:
18 January 2020
Please cite this article as: X. Wang, J. Liu, Y. Yang, et al., An update on the potential role of advanced glycation end products in glycolipid metabolism, Life Sciences(2020), https://doi.org/10.1016/j.lfs.2020.117344
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Journal Pre-proof An update on the potential role of advanced glycation end products in glycolipid metabolism
Xiaolei Wang1*, Junjun Liu1, Ying Yang1, Xiandang Zhang1*
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Shandong Institute of Endocrine & Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, Jinan, 250014, China
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*Corresponding author Dr. Xiandang Zhang
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Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, 18877, Jing 10 Rd., Jinan, 250014, China. Email:
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[email protected]. Fax: 82919799 Dr. Xiaolei Wang
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Shandong Institute of Endocrine and Metabolic Diseases, Shandong First Medical University &
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Shandong Academy of Medical Sciences, 18877, Jing 10 Rd., Jinan, 250014, China. Email: [email protected].
Acknowledgements We acknowledge Prof. Philippe Savarin (University Paris 13) for providing professional suggestions for the manuscript. This work was supported by the National Natural Science Foundation [81900736], Innovation Project of Shandong Academy of Medical Sciences, and Scientific and Technological Development Programme of Shandong Academy of Medical
Journal Pre-proof Sciences (2018-22). Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this article.
Total word count: 5087
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Number of figures: 3
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Number of tables: 1
Journal Pre-proof An update on the potential role of advanced glycation end products in glycolipid
metabolism
Abstract Advanced glycation end products (AGEs) play a crucial role in many major diseases, such as diabetes and atherosclerosis. AGE accumulation in the body is generally considered a consequence of hyperglycaemia. However, recent studies have shown that AGEs may also be an important
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cause of the initial pathogenesis of diabetes and atherosclerosis. The objective of the present review
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is to provide an update on the AGE-induced mechanisms involved in the pathophysiology of
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glucose and lipid metabolism, even though the unique mechanisms involved in these diseases are not well understood. AGE precursors (methylglyoxal) and AGE receptors have been demonstrated in
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animal models to mediate insulin resistance and lipid metabolism disorders. Although we have
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not yet achieved a complete understanding of the role of AGEs, emerging therapeutic
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interventions targeting AGE reduction and AGE-RAGE signalling have yielded some beneficial clinical outcomes. Additional studies are needed to evaluate the utility and mechanism of
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circulating and tissue AGEs to support the identification of efficient and specific interventions.
Keywords: Advanced glycation end products (AGEs), Receptor for AGEs (RAGE), Diabetes, Lipid metabolism, Glycolipid
Journal Pre-proof 1 Introduction of advanced glycation end products (AGEs) and AGE compounds AGEs are formed via a nonenzymatic reaction between reducing sugars and proteins, lipids or nucleic acids, also known as the Maillard reaction. AGEs can be obtained exogenously or endogenously, through diet or produced within the body, respectively. Accumulation of AGEs independently promotes oxidative stress and ageing, and AGEs are involved in the development of several pathologies, such as diabetes, atherosclerosis and cardiovascular diseases [1]. AGEs exert their pathogenic effects by (1) modifying extracellular and intracellular proteins (i.e.,
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crosslinking) and (2) activating signalling cascades by binding to cell surface receptors (RAGEs). (1) AGEs alter the
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physiological properties of extracellular matrix (ECM) proteins through the formation of intermolecular bonds or crosslinking. In addition, intracellular accumulation of AGEs may cause endoplasmic reticulum (ER) stress, usually
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leading to inflammation or apoptosis [2]. Moreover, AGEs can crosslink proteins in the mitochondrial respiratory
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chain, suppressing ATP synthesis and aggravating reactive oxygen species (ROS) production [3]. (2) RAGEs can be separated into two main types depending on the downstream effects of AGE binding and activation: RAGE initiates
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complex signalling pathways when activated by ligand binding, whereas AGER1 is associated with AGE
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endocytosis, breakdown, and removal from the circulation [4] (Fig. 1).
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Journal Pre-proof Fig. 1. Scheme of AGEs interaction with RAGE and AGER1 under conditions with different AGE loads. (A) A low AGEs burden and (B) an overload of AGEs. RAGE, receptor for AGEs; AGER1, AGE receptor 1; p38 MAPK, p38 mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; ERK 1/2, extracellular signal-regulated protein kinases 1 and 2; JAK/STAT, Janus kinase/signal transducers and activators of transcription; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; AP-1, activator protein 1; FOXO, forkhead box protein O subclass; SIRT1, sirtuin-1. Adapted from Chen et al. [4].
AGEs can be produced in the body or obtained from exogenous sources such as diet and smoking. AGE accumulation occurs during heat processing of food, and browning continues during storage. Many types of AGE
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precursors are formed during the initial, intermediate and final stages of the Maillard reaction. Different AGE
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compounds are created through a series of reactions depending on their composition and molecular size [4]. Such compounds include pyrraline, Nɛ-carboxymethyllysine (CML), Nɛ-carboxyethyllysine (CEL), pentosidine,
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argpyrimidine, derivatives of methylglyoxal (MG), hydroimidazolones derived from MG, glyoxal (GO), 3-
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deoxyglucosone (3-DG), and arginine-derived Nδ-ornithine and bis(lysyl)imidazolium derivatives, such as methylglyoxal-lysine dimer (MOLD) and glyoxal-lysine dimer (GOLD) [5,6].
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For decades, the effects of AGEs on diabetes and hyperlipidaemia have been extensively studied, and this
metabolism.
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review focuses on the potential role of AGEs in glycolipid
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2 Effects of AGEs on endocrinology and metabolic diseases
2.1 AGE: a potential endocrine disruptor Some studies have noted that the disruption of endocrine activity involves AGE-mediated disease progression. Humans are susceptible to systemic accumulation of endogenous and exogenous AGEs, which interfere with physiologically significant hormones, including insulin [7], adiponectin [8], androstenedione [9], progesterone, and oestradiol [10], among others. AGEs may block or entrap natural hormones in the body and affect their target actions. Moreover, AGEs can imitate or partly imitate hormones and cause excessive irritation. In addition to these
Journal Pre-proof effects, AGEs also bind to the cell surface or to nuclear receptors, inhibiting normal signals as hormone antagonists [11].
2.2 AGEs and glycolipid metabolism: effect or cause? Endogenous formation of AGEs is a normal consequence of metabolism. AGEs require weeks or years to form; however, the accumulation of high levels of AGEs or AGE compounds in tissues and the circulation can be
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pathogenic. For example, increased levels of MG (a major precursor of AGEs) can be generated in processes such as glycolysis, glucose oxidation, lipid peroxidation, and protein glycation [12] and directly react with lysine and
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arginine residues on proteins to produce AGEs [13]. Under certain conditions, such as hyperglycaemia and
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hyperlipidaemia, the formation of AGEs can be accelerated; indeed, elevated amounts of AGEs have been found to
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be associated with ageing and different diseases in vivo [14-18].
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2.2.1 Hyperglycaemia-induced AGE accumulation plays a crucial role in diabetic complications Various cells can be injured during the onset of diabetes, and one way that hyperglycaemia causes cell injury is by
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fostering AGE accumulation [19]. Both islet β-cell dysfunction and diabetic nephropathy are associated with the
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accumulation of AGEs [20-24], and the mechanism may be related to AGE-induced mitochondrial stress, ER stress, and downstream signalling pathway activation [25,26]. Extensive evidence demonstrates that AGEs contribute to
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long-term diabetic complications, especially microvascular complications [19]. The aetiology of diabetic retinopathy, another frequent microvascular complication in addition to diabetic nephropathy, is complex,
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one of the established mechanisms is AGE-induced proinflammatory signalling [27]. In addition, recent studies suggest the important role of AGEs, which are implicated in enhanced proliferation, inflammation and ECM degradation, in macrovascular complications [28].
2.2.2 Pathological outcomes of AGE accumulation in atherosclerosis Lipid peroxidation can result in AGE formation; this process is considered an alternative pathway of the Maillard reaction [29] and suggests a close relationship between AGEs and lipid metabolism. Glucose intolerance and
Journal Pre-proof hyperglycaemia, which are characterized by lipid accumulation and coronary artery disease (CAD), are associated with the pathogenesis of atherosclerosis [30,31]. Extracellular protein glycation can directly promote atherosclerosis. Furthermore, AGE receptor-activated signalling pathways can increase inflammation, calcium deposition, and vascular smooth muscle cell (SMC) apoptosis, contributing to the development of atherosclerosis [32].
2.3 New insight into AGEs should be valued Although the importance of AGEs in the pathogenesis of diabetic complications and lipid
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metabolism has been reinforced by many studies (Table 1), the exact mechanisms by which
accumulation has been reported to be an initial factor for diabetes onset [33].
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Interestingly, AGE
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AGEs function in the initial pathogenesis of diabetes and hyperlipidaemia are poorly understood.
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Nonetheless, clinical evidence has indicated that arterial stenosis and atherosclerosis are related to RAGE levels in patients either with or without diabetes [2], suggesting that the effect of AGEs on lipid metabolism may be
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independent of elevated blood glucose. Thus, AGE formation may be an important reason underlying disorders of
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glucose and lipid metabolism.
Table 1. Effects of AGEs on the pathophysiology of glucose and lipid metabolism Disease/tissue injury Pancreatic dysfunction
Mechanism/pathway p38/MAPK HSP60
Diabetic nephropathy
References You et al. [21] Guan et al. [20]
PI3K/Akt, MAPK/ERK, and NF-κB Inflammation PI3K-AKT, NF-κB
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Fan et al. [26]
Diabetic retinopathy
Proinflammatory signalling
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Coronary artery disease
Proliferation, ECM degradation Oxidative stress
Atherosclerosis
Kosmopoulos et al. [28]
Fishman et al. [2]
Calcium deposition, SMC apoptosis
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SMC proliferation and migration, macrophage activation, inflammation
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3 AGEs and AGE compounds might be the cause of glycolipid metabolic disorders
3.1 Glycometabolism
considered to be the main factor in AGE formation, intensive control
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Because hyperglycaemia is
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of hyperglycaemia is expected to also mitigate the consequences of AGEs on diabetic
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complications. However, studies have failed to produce the anticipated results [35-37]. In fact, high systemic AGE levels are not always associated with high glucose levels because AGEs can be
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produced in the body, accumulate during ageing, and be absorbed from food [38]. AGEs are naturally present in raw
addition,
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animal-origin foods, and cooking accelerates the generation of additional AGEs within these foods. In
glucose exhibits the slowest glycation rate among reducing sugars [39]. The reported data even
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suggest that there is no correlation between serum levels of AGEs and glucose [40]. Moreover, food-derived AGEs have been indicated to contribute to cellular and tissue injury in chronic diabetes [19], and serum AGE levels are reportedly significantly increased in prediabetic rats [41]. Furthermore, clinical studies have shown that dietary AGEs can modulate the AGE load in subjects with diabetes, but studies in healthy subjects are limited [42]. Thus, the roles of AGEs in healthy and prediabetic subjects warrant further research because AGE accumulation alone might trigger the disease. Insulin resistance (IR) and hyperglycaemia are the underlying causes of type 2 diabetes
Journal Pre-proof (T2D), and MG levels increase due to elevated flux through glycolysis. Elevated levels of MG lead to AGEs accumulation, contributing to diabetic vascular complications such as nephropathy and cardiovascular diseases [43]. Additionally, MG formation includes the degradation of glycated proteins, lipid peroxidation of polyunsaturated fatty acids and oxidative protein metabolism [44]. Kim et al. [45] demonstrated that MG can induce angiogenic impairment of endothelial progenitor cells via alterations in the AGE/RAGE-VEGFR-2 pathway. MG also
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mediates streptozotocin-induced diabetic neuropathic pain by activating peripheral transient
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receptor potential channel ankyrin 1 (TRPA1) in rats [46]. Moraru et al. [47] found that elevated
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levels of MG cause flies to become obese, resistant to insulin, and hyperglycaemic. Moreover, MG leads to primary defects in insulin signalling and cellular abnormalities at the proteomic and
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metabolic levels in rat muscle cells [13]. These observations place MG not only downstream but
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also upstream of IR and hyperglycaemia in the development of diabetes. Identifying the
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3.2 Lipid metabolism
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therapy of this disease.
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underlying mechanisms of AGEs and MG in diabetes will be crucial for the early prevention and
AGEs should be considered major cardiometabolic risk factors [42]. How do AGEs specifically contribute to atherosclerosis or hyperlipidaemia? (1) Nonreceptor-mediated effects are direct cytotoxic mechanisms due to glycation and crosslinking modifications in the ECM, altered ECM architecture and the trapping of macromolecules against vessel walls [32]. (2) Receptor-mediated effects, including endothelial dysfunction, SMC proliferation and migration, macrophage activation, enhanced uptake of oxidized LDL (oxLDL), and foam cell formation [18], are closely related to abnormal lipid metabolism. Qualitatively, RAGE upregulation is associated with granular rather than diffuse calcification, exposing the lipid core of atheromatous plaques and resulting in instability and predisposition to rupture [34]. Moreover, AGE-RAGE interactions might amplify inflammatory responses through lipid deposit-induced metalloproteinases [18].
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3.3 A new function for AGEs in hepatic glycolipid metabolism The current paradigm states that IR is the early symptom and basic feature of T2D. IR occurs when insulin-mediated glucose uptake and utilization in the liver, muscle and adipose tissue decrease. Effective prevention of IR is thus an important approach to controlling and delaying the onset of diabetes. Insulin binds to the insulin receptor on the cell membrane, phosphorylates
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insulin receptor substrate (IRS1/2), activates related pathway molecules through PI3K/Akt,
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promotes both tissue uptake of glucose and glycogen synthesis, stimulates lipid synthesis and
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inhibits gluconeogenesis [48] (Fig. 2). According to a clinical study, IR was exacerbated in a high-AGE diet-fed group compared with a low-AGE diet-fed group [49], and animal
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experiments have confirmed that AGEs can cause islet β-cell insulin synthesis disorders and
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tissue IR. AGEs reduce insulin synthesis in islet β-cells by modulating the activity of FOXO [25],
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and muscle glucose uptake is reduced via the suppression of GLUT4 by AGEs [50]. The liver is considered to be the starting point of IR, and it plays a central regulatory role in glycolipid
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metabolism [51]. Regardless, the mechanism by which AGEs impact hepatic IR (pathways
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involved in GSK3β-induced glycogenesis and SREBP1c-induced lipid synthesis) remains unclear (Fig. 2). The AGE precursor MG was shown to decrease cholesterol biosynthesis and exacerbate IR in rat muscle cells [13], indicating the potential role of AGEs in glycolipid metabolism.
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Fig. 2. Mechanisms of AGEs-induced insulin resistance. The insulin signalling pathway: Insulin binds to the insulin receptor on
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the cell membrane, phosphorylates insulin receptor substrate (IRS1/2), activates related pathway molecules through PI3K/Akt,
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promotes both tissue uptake of glucose and glycogen synthesis, stimulates lipid synthesis and inhibits gluconeogenesis. AGEs in black represent mechanisms that have been confirmed (“+” represents stimulation, and “-” represents inhibition.). AGEs in red represent unclear mechanisms. IRS1/IRS2, insulin receptor substrate 1 and 2; PI3K, phosphatidylinositol 3-kinase; GLUT4, glucose transporter 4; SREBP1c, sterol regulatory element-binding protein 1c; GSK-3, glycogen synthase kinase 3.
AGEs and elevated levels of nonesterified fatty acids play important roles in oxidative stress and inflammation [52], which are the basic pathophysiological processes of liver diseases. The liver is a crucial centre of fatty acid metabolism, and hepatic AGE accumulation can cause liver damage and contribute to hepatotoxicity and liver injury [53]. Additionally, circulating levels of AGEs have been found to be elevated in patients with non-alcoholic fatty liver disease
Journal Pre-proof (NAFLD) [54] and liver cirrhosis [55]. Hepatic ROS levels in rats were found to increase in response to MG treatment [12], and another study reported that both hepatic expression of RAGE and plasma MG levels are increased in mice fed a high-fat diet compared with mice fed a low-fat diet [56]. Furthermore, fructose-mediated increase in MG flux can suppress hepatic AMPK activation, causing IR, fatty liver and dyslipidaemia, an association that has been overlooked to date [57]. Overall, a new mechanistic explanation has culminated from the results
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of these studies, suggesting that elevated AGEs or MG levels may be a root cause of hepatic
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glycolipid disorders (Fig. 3).
Fig. 3. Schematic diagram. The current dominant paradigm that insulin resistance andhyperglycaemia are root causes of tissue damage [47]. A new explanation culminates from this review, suggesting that elevated AGEs or MG levels may be the root cause of hepatic glycolipid disorders.
4 Perspective: interventions to reduce AGEs
Journal Pre-proof Despite the adverse effects of AGEs on diabetes recorded over the past two decades, measures necessary to limit AGE exposure and function (AGE/RAGE interactions and downstream pathway activation) are still not well understood. Dietary factors are an important reason for AGE accumulation that may be utilized in the development of potential therapeutic and preventive targets for diabetes. Bread, beer and carbonated drinks are rich sources of AGEs and MG. Dietary AGE interventions can prevent new formation of dietary AGEs, minimize the
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absorption of AGEs by the gastrointestinal tract and reduce levels of circulating AGEs [4]. Drug
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options are another way of reducing AGEs: (1) Aminoguanidine and pyridoxamine have
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antioxidant properties and are used to inhibit AGE formation and ameliorate coronary artery disease, but their use might be limited due to safety concerns encountered in clinical trials [2].
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Resveratrol can suppress hyperglycaemia and other related diseases, including atherosclerosis, in
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response to AGEs through mechanisms that also mainly target oxidative stress [58]. (2) In
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addition, rats and mice treated with a soluble RAGE (sRAGE) infusion or RAGE inhibitor displayed reduced rates of atherosclerosis [59-61]. Polygonum cuspidatum extract can
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significantly reduce AGE formation, lower blood glucose and normalize serum lipid parameters,
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including LDL-C, HDL-C, and triglycerides (TG), in diabetic rats [62]. Studies have shown that statins can increase the plasma levels of sRAGE and thus inhibit interaction between AGEs and RAGE [63,64]. Although some antidiabetic and antihypertensive drugs are already clinically approved, their specific mechanisms have not been fully elucidated, and clinical results concerning the AGE/RAGE axis are rare because the primary effects of these drugs are more important than are their secondary effects as AGE inhibitors or RAGE antagonists [65]. Given these results, additional basic research and clinical trials are needed to evaluate AGE intervention strategies and to investigate the potential mechanisms of AGEs in diabetes.
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5 Conclusions AGEs comprise a critical family of molecules with pivotal roles in the pathophysiology of metabolic diseases. As AGEs are directly implicated in diabetes and atherosclerosis through modulation of IR, oxidative stress and lipid synthesis, AGEs and RAGE should be considered major metabolic risk factors. Increasing evidence supports a role for AGEs and AGE/RAGE
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signalling in glycolipid metabolic abnormalities. The development of therapeutic interventions
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the prevention and treatment of metabolic diseases.
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aimed at reducing circulating AGEs or blocking RAGE activation may offer new perspectives on
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Acknowledgements
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We acknowledge Prof. Philippe Savarin (University Paris 13) for providing professional
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suggestions for the manuscript. This work was supported by the National Natural Science Foundation [81900736], the Innovation Project of Shandong Academy of Medical Sciences, and
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Sciences (2018-22).
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the Scientific and Technological Development Programme of Shandong Academy of Medical
Conflict of interest statement The authors declare that there is no conflict of interest regarding the publication of this article.
Data availability The data used to support our findings in this study are available from the corresponding author upon request.
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Journal Pre-proof Conflict of Interest Policy Form The authors declare that there is no conflict of interest regarding the publication of this article. Author Contribution Acquisition of data, design and drafting of the manuscript and obtained funding: Xiaolei Wang Figure design and revision of the manuscript: Junjun Liu Revision of the manuscript: Ying Yang
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Obtained funding and study supervision: Xiandang Zhang
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Graphical abstract