Metformin and Inflammation

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Metformin and Inflammation: Its Potential Beyond Glucose-lowering Effect Yoshifumi Saisho* Department of Internal Medicine, Keio University School of Medicine Abstract: Metformin is an oral hypoglycemic agent which is most widely used as first-line therapy for type 2 diabetes. Metformin improves hyperglycemia by suppressing hepatic glucose production and increasing glucose uptake in muscle. Metformin also has been shown to reduce cardiovascular events in randomized controlled trials; however, the underlying mechanism remains to be established. Recent preclinical and clinical studies have suggested that metformin not only improves chronic inflammation through the improvement of metabolic parameters such as hyperglycemia, insulin resistance and atherogenic dyslipidemia, but also has a direct anti-inflammatory action. Studies have Y. Saisho suggested that metformin suppresses inflammatory response by inhibition of nuclear factor κB (NFκB) via AMP-activated protein kinase (AMPK)-dependent and independent pathways. This review summarizes the basic and clinical evidence of the anti-inflammatory action of metformin and discusses its clinical implication.

Keywords: AMPK, anti-inflammatory effect, biguanide, NFκB, type 2 diabetes. 1. INTRODUCTION The prevalence of type 2 diabetes (T2DM) is rapidly increasing worldwide [1]. Metformin is an oral hypoglycemic agent that is widely used for the treatment of T2DM. Current guidelines for the treatment of T2DM recommend metformin as a first-line drug [2-6]. Metformin and other biguanides are derived from French Lilac Galega officinalis (Fig. 1). Their utility as oral hypoglycemic agents became well known in the 1950s, and the two main biguanides, metformin and phenformin, were introduced in the late 1950s. However, phenformin had to be withdrawn because of a strong association with lactic acidosis [7], whereas cases of lactic acidosis associated with metformin are very rare [8]. Metformin has been shown to lower fasting plasma glucose by decreasing hepatic glucose production and improving muscle insulin sensitivity [9]. Despite its long use, however, its mechanism of action remains to be fully elucidated. Moreover, recent basic and clinical studies have shown it to possess various beneficial effects beyond its hypoglycemic effect, such as anti-inflammatory, anti-cancer and anti-aging effects. This review focuses on the antiinflammatory effect of metformin, among these various potential effects, and discusses its clinical relevance. 2. GLUCOSE-LOWERING EFFECT OF METFORMIN 2.1. Mechanism Metformin has been used clinically for over 50 years. However, its molecular mechanism of action is not well *Address correspondence to this author at the Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan; Tel: +81-3-3353-1211, x62383; Fax: +81-3-33592745; E-mail: [email protected] 1871-5303/15 $58.00+.00

understood. Several mechanisms of the glucose-lowering effect of metformin have been proposed. Metformin mainly lowers plasma glucose level via suppression of hepatic glucose production, mainly as a result of reduction in gluconeogenesis [9, 10]. Metformin also increases glucose uptake in muscle [11-13]. An important possible target of metformin is AMPactivated protein kinase (AMPK), a cellular energy sensor activated under metabolic stress [14, 15]. The activation of AMPK inhibits hepatic glucose production, improves insulin sensitivity and glucose uptake by muscle, and induces fatty acid oxidation. Threonine 172 phosphorylation is necessary for this activation, and the tumor suppressor gene liver kinase B1 (LKB1) is the main responsible kinase [16]. The major downstream target of AMPK is mammalian target of rapamycin (mTOR), a kinase whose activity is important in cellular growth processes and protein synthesis [17, 18]. Metformin activates AMPK in a dose- and timedependent manner, with a decrease in ATP and a concomitant increase in AMP concentration. It has also been reported that the activation of AMPK by metformin is independent of changes in AMP/ATP ratio, and occurs through inhibition of mitochondrial respiratory chain complex I and an increase in reactive nitrogen species (RNS) [19, 20]. On the other hand, Foretz et al. have reported that metformin showed a similar glucose-lowering effect in mice lacking hepatic AMPK compared with wild-type mice [21], suggesting that suppression of hepatic glucose production by metformin is independent of AMPK. A recent study has shown that metformin reduced levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, and blocked glucagondependent glucose output from mouse hepatocytes [22]. Current knowledge regarding the molecular mechanism of metformin’s action in the liver has been well summarized by Rena et al. (Fig. 2) [15]. More recently, Madiraju et al. have proposed another mechanism by which metformin © 2015 Bentham Science Publishers

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Fig. (1). Chemical structures of galegine, an alkaloid from French Lilac Galega officinalis, and metformin.

Fig. (2). Molecular mechanism of anti-hyperglycemic action of metformin on liver cell. Adapted and modified from ref [15]. Metformin is transported into hepatocytes mainly via OCT1, resulting in inhibition of the mitochondrial respiratory chain (complex I). The resulting deficit in energy production is balanced by reducing the consumption of energy in the cell, particularly reduced gluconeogenesis in the liver. This is mediated in two main ways. First, a decrease in ATP level and a concomitant increase in AMP level occur, which is thought to contribute to the inhibition of gluconeogenesis directly (because of the energy/ATP deficit). Second, the increased AMP level functions as a key signaling mediator that has been proposed to 1) allosterically inhibit cAMP-PKA signaling through suppression of adenylate cyclase, 2) allosterically inhibit FBPase, a key gluconeogenic enzyme, and 3) activate AMPK. This leads to inhibition of gluconeogenesis (1 and 2) and lipid/cholesterol synthesis (3). Recently, another mechanism by which metformin suppresses gluconeogenesis, by inhibiting mitochondrial glycerophosphate dehydrogenase (mGPD), has been reported [23]. OCT1; organic cation transporter 1, FBPase; fructose-1,6-bisphosphatase.

suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase [23].

Even though the molecular mechanism of metformin’s action remains to be fully understood, the glucose-lowering

Metformin and Inflammation

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 2

effect of metformin is mainly through suppression of hepatic glucose production. Other possible mechanisms of metformin’s action include alteration of bile acid metabolism [24, 25] and enhancement of the incretin pathway [26, 27]. 2.2. Clinical Studies Metformin has been shown to reduce glycated hemoglobin (HbA1c) level by ~1.5%, which is comparable or even superior to that by other oral hypoglycemic agents (OHAs) [2, 3, 28-30]. Metformin mainly reduces fasting plasma glucose level rather than postprandial glucose excursion, through suppression of hepatic glucose production [9]. In contrast to sulfonylureas, the effect of metformin on body weight is neutral or modestly beneficial, and the risk of hypoglycemia from metformin is low [3, 29, 30]. Metformin has been also shown to be effective for prevention of T2DM. In the Diabetes Prevention Program (DPP), treatment with metformin reduced the incidence of T2DM by 31% compared with placebo in patients with impaired glucose tolerance (IGT) [31]. 2.3. Effect on Cardiovascular Outcome In the United Kingdom Prospective Diabetes Study (UKPDS), intensive glucose control with metformin showed a risk reduction of 39% for myocardial infarction (p = 0.01), 30% for all macrovascular complications (p = 0.02), 32% for any diabetes-related endpoint (p = 0.002), 42% for diabetesrelated death (p = 0.017) and 36% for all-cause mortality (p = 0.011) compared with conventional therapy [32]. This effect of metformin was greater than that of intensive therapy with a sulfonylurea or insulin, and persisted after a post-study follow-up of 10 years[33]. Other studies have shown the efficacy of metformin in secondary prevention of cardiovascular disease in patients with T2DM [34, 35]. Based on this evidence and meta-analyses [36, 37], current guidelines for treatment of T2DM propose metformin as first-line pharmacotherapy [3-6], although recent meta-analyses have raised a question on the cardioprotective effect of metformin [38, 39]. The underlying mechanism by which metformin reduces the incidence of cardiovascular events and all-cause mortality has been actively investigated. Metformin not only improves hyperglycemia and insulin resistance [9, 40], but also has been shown to improve other cardiovascular risk factors, such as an overweight state or obesity, atherogenic dyslipidemia, blood pressure, pro-coagulant state and thrombosis, and carotid intima-media thickness (IMT) [37, 41-44]. It has been reported that metformin improved endothelial function in patients with normal glucose tolerance (NGT), suggesting glucose-independent effects of metformin [45]. Chronic inflammation is also associated with the progression of atherosclerosis [46]. Recent studies have suggested that metformin has an anti-inflammatory effect by direct and indirect mechanisms. 3. ANTI-INFLAMMATORY EFFECT OF METFORMIN 3.1. Mechanism Metformin has been shown to restore endothelial function in high-fat-fed diabetic rats [47]. In that study,

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metformin treatment also significantly improved nitric oxide (NO) bioavailability, glycation, oxidative stress, and chemokine CCL2 (monocyte chemoattractant protein-1) level in the aorta. It has also been reported that metformin increased NO synthesis via activation of AMPK [48] and decreased reactive oxygen species (ROS) production through inhibition of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and the respiratory mitochondrial chain in bovine aortic endothelial cells [49]. Another study showed that metformin inhibited nuclear factor κB (NFκB) activation in the vessel wall and decreased serum C-reactive protein (CRP) level in high-fat-fed atherogenic rabbits [50]. Using human umbilical vein endothelial cells (HUVEC), Hattori et al. have shown that metformin inhibited cytokineinduced NFκB activation via AMPK activation [51]. Recently, Lu et al. have also shown that metformin attenuated ballooninjury-induced neointimal hyperplasia in fructose-induced insulin-resistant rats by suppressing c-jun N-terminal kinase (JNK) and NFκB [52]. Cao et al. have reported that metformin inhibited vascular calcification in rat aortic smooth muscle cells (SMC) through activation of the AMPK-endothelial NO synthase (eNOS)-NO pathway [53]. These studies suggest that inhibition of NFκB by activation of AMPK is important for the anti-inflammatory action of metformin. On the other hand, Isoda et al. have reported that metformin inhibited NFκB activation through blockade of the phosphoinositide 3-kinase (PI3K)-Akt pathway in human vascular SMC [54]. Kim et al. have recently reported that metformin inhibited inflammatory response via AMPK-phosphatase and the tensin homolog (PTEN) pathway in rat SMC[55]. PTEN, a tumor suppressor gene, antagonizes PI3K and affects cell survival, growth and proliferation. They showed that AMPK and PTEN interact to regulate inflammation in the anti-inflammatory action of metformin. Poly [ADP ribose] polymerase 1 (PARP-1) acts as a coactivator of NFκB-mediated transcription to activate proinflammatory pathways such as p38 mitogen-activated protein kinase (MAPK) and JNK and inhibit B-cell lymphoma-6 (Bcl-6)-exerted anti-inflammatory function[5658]. Gongol et al. have reported that AMPK activation with metformin treatment induced PARP-1 dissociation from Bcl6 intron 1 and increased Bcl-6 expression, and inhibited expression of inflammatory mediators in HUVEC [59]. A recent study by Zheng et al. has shown that sirtuin 1 (SIRT1) regulated inflammation and apoptosis through LKB1/ AMPK-dependent pathways in bovine retinal capillary endothelial cells (BREC) and the retina of diabetic rats, and metformin upregulated the SIRT1/LKB1/AMPK pathway and inhibited cellular metabolic memory through suppression of reactive oxygen species (ROS)/PARP signaling [60]. Another possible mechanism of the anti-inflammatory action of metformin is inhibition of advanced glycation endproducts (AGEs) formation. Metformin inhibits the formation of AGEs [61, 62] which promote inflammation and ROS (glycoxidation) [63-65]. Hyperglycemia increases the formation of AGEs, and metformin reduces the levels of these molecules via a chemical reaction between the metformin molecule and dicarbonyl precursors of AGEs such as methylglyoxal. A recent study has also shown that metformin inhibited AGEs-induced apoptosis and inflammatory and fibrotic reactions in tubular cells by


reducing ROS generation via suppression of receptor for AGEs (RAGE) expression through AMPK activation [66]. The potential molecular mechanisms of the anti-inflammatory action of metformin are summarized in Fig. 3. The anti-inflammatory action of metformin is reported in not only vascular endothelial cells and SMC, but also other cell types. It has been reported that metformin reduced the production of NO, prostaglandin E2 (PGE2) and proinflammatory cytokines (interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α) through inhibition of NFκB activation in macrophages [67]. The level of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates active glucocorticoids, is elevated in adipose tissue in human obesity and metabolic syndrome, and is associated with chronic inflammation [68]. Esteves et al. have reported that metformin suppressed pro-inflammatory cytokine-induced 11β-HSD1 expression in human adipocytes via inhibition of the NFκB pathway [69]. In mouse lung tissue, metformin also suppressed ROS and allergic eosinophilic inflammation via AMPK activation [70, 71], suggesting that metformin could be a pharmacological strategy to control asthma. It has also been reported that metformin suppressed endotoxininduced uveitis in rats [72]. Li et al. have reported that hepatic activation of AMPK inhibited sterol regulatory element binding proteins (SREBP-1c and -2)-dependent lipogenesis and attenuated hepatic steatosis and atherosclerosis

Yoshifumi Saisho

in diet-induced insulin-resistant LDL receptor-deficient mice [73]. Kita et al. have reported that metformin prevented and reversed steatosis and inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis (NASH), although this effect of metformin seemed independent of the AMPK pathway [74]. 3.2. Indirect Effects The indirect anti-inflammatory action of metformin is associated with metabolic consequences. Improvement of hyperglycemia and weight loss with metformin treatment results in favorable effects on chronic inflammation and atherosclerosis, as described above. Metformin has also been reported to decrease triglycerides and low density lipoprotein (LDL) cholesterol and improve atherogenic dyslipidemia [37], which also results in favorable effects on chronic inflammation and atherosclerosis. Potential mechanisms of the cardiovascular protection by metformin are summarized in Fig. 4. 3.3. Clinical Studies In the DPP study, the effect of lifestyle intervention or metformin on inflammation was investigated [75]. A total of 3,234 adults with IGT were randomized to an intensive lifestyle intervention group, metformin treatment group or

Fig. (3). Potential molecular mechanism of anti-inflammatory action of metformin. Metformin suppresses inflammatory response by inhibition of NFκB through AMPK-dependent and independent pathways. Metformin also increases nitric oxide (NO) production and inhibits the poly [ADP ribose] polymerase 1 (PARP-1) pathway through AMPK activation, leading to suppression of inflammatory response. In addition, metformin also suppresses inflammatory response through inhibition of advanced glycation endproducts (AGEs) formation and receptor for AGE (RAGE) expression.



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Fig. (4). Mechanism of atherogenesis in type 2 diabetes. Adapted and modified from ref [106]. Filled boxes denote potentially antiatherogenic actions of metformin supported by evidence from clinical studies; shaded boxes denote potentially anti-atherogenic actions of metformin demonstrated in experimental studies.

placebo group, and C-reactive protein (CRP) and fibrinogen were measured at baseline and after 12 months. Metformin reduced CRP compared with that in the placebo group at 12 months (-7% vs. +5% for men and -14% vs. 0% for women), while a greater reduction in CRP was observed in the lifestyle intervention group (-33% for men and -29% for women). The anti-inflammatory effect of metformin has also been evaluated in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial [42]. In this trial, a total of 2,368 patients with T2DM and coronary artery disease were randomized to treatment with either an insulinsensitizing strategy or insulin-providing strategy and followed for an average of 5 years. The insulin-sensitizing strategy employed primarily metformin and/or a thiazolidinedione, while the insulin-providing strategy employed primarily a sulfonylurea or meglitinide. In contrast to the insulinproviding strategy, the insulin-sensitizing strategy led to lower plasma insulin, lower plasminogen activator inhibitor type 1 (PAI-1) antigen, lower CRP and lower fibrinogen levels during the trial. The effects of initiating insulin glargine or metformin on inflammatory biomarkers in patients with T2DM and an elevated CRP level (≥2.0 mg/L) have been investigated in the Lantus for C-reactive Protein Reduction in Early Treatment of T2DM (LANCET) trial [76]. The primary

outcome of this trial was change in CRP level from baseline to 14 weeks, and the secondary outcome was changes in IL-6 and soluble TNF receptor 2 (sTNFr2) levels. Five-hundred patients were enrolled in this trial; however, no significant reduction in either CRP or other inflammatory biomarkers was observed with treatment with metformin or insulin. Krysiak et al. have studied the effect of metformin on monocyte secretory function in patients with impaired fasting glucose, and reported that metformin reduced monocyte release of TNF-α, IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1) and IL-8, as well as plasma CRP level [77]. The same group has also reported a similar suppressive effect of metformin on lymphocyte release of proinflammatory cytokines such as IL-2, interferon (IFN)-γ and TNF-α [78]. Ersoy et al. have reported that metformin treatment decreased PAI-1 and vascular endothelial growth factor (VEGF) in obese patients with T2DM [79]. It has also been reported that metformin decreased plasma resistin concentration in pediatric patients with IGT [80] and increased thrombospondin-1 (TSP-1), a novel antiangiogenic adipokine, in women with polycystic ovary syndrome (PCOS) [81]. Derosa et al. have reported that the combination of metformin and exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduced inflammatory markers such as vaspin, chemerin and resistin in patients with T2DM compared with metformin plus placebo [82],


suggesting that combination therapy is more effective to control inflammation. Taking these results together, metformin seems to have a modest anti-inflammatory effect in patients with IGT or T2DM. However, it has been reported that metformin treatment did not change CRP or 8-iso-prostaglandin F2α (8-iso-PGF2α) level in subjects with NGT [83, 84]; thus, it still remains uncertain whether the anti-inflammatory effect of metformin is due to its direct action or an indirect effect through the improvement of insulin sensitivity and hyperglycemia. 4. OTHER EFFECTS OF METFORMIN 4.1. Anti-cancer Effect In 2005, Evans et al. reported a significant 23% reduction in the incidence of any cancer with metformin use [85]. Since then, many preclinical and observational studies have shown an anti-cancer effect of metformin [86-90], and several randomized controlled trials of the effect of metformin in prevention and treatment of cancer are currently underway. Currently, the molecular mechanism by which metformin suppresses tumor growth is thought to be mediated by the

Yoshifumi Saisho

inhibition of mTOR through AMPK-dependent and independent pathways, which has been reviewed by several authors (Fig. 5) [18, 91]. Moreover, since metformin can regulate inflammation, it may also play a role in the tumor microenvironment [18]. Metformin may also suppress tumor growth through ameliorating hyperinsulinemia. On the other hand, a meta-analysis of 14 randomized controlled trials (RCT) has shown no significant reduction in either cancer risk or cancer mortality with the use of metformin [92]. Recently, Suissa et al. have pointed out the presence of time-related biases in the previously published observational studies, which might flaw the results of those studies [93], and they reported no association between metformin use and risk of lung or colorectal cancer in patients with T2DM [94, 95]. 4.2. Anti-aging Effect In addition to the possible anti-cancer effect of metformin, anti-aging effects of metformin have recently been attracting attention. Martin-Montalvo et al. have reported that metformin improved healthspan and lifespan in mice [96]. They observed that treatment with metformin mimicked some of the benefits of calorie restriction, such as

Fig. (5). Potential molecular mechanism of anti-cancer action of metformin. Adapted and modified from ref [18]. Direct effects: metformin inhibits complex I and mTORC1 via AMPK-dependent and independent pathways (through REDD1 or Rag GTPase). Metformin also decreases insulinemia and, thereby, indirectly modulates proliferative pathways: AKT and ERK. mTORC1; mTOR complex 1, REDD1; regulated in development and DNA damage responses 1, ERK; extracellular signal-regulated kinases.



improved physical performance, increased insulin sensitivity and reduced LDL cholesterol level, without a decrease in caloric intake. At a molecular level, metformin increased AMPK activity and antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Cabreiro et al. have reported that metformin increased lifespan in Caenorhabditis elegans [97]. Interestingly, they showed that metformin did not extend lifespan in C. elegans in the absence of their microbial trophic partner, Escherichia coli. They showed that metformin extended lifespan in worms by altering microbial folate and methionine metabolism, indicating the importance of microbial metabolism for the effects of metformin on its eukaryote partner. It remains unclear whether metformin alters human microbiota metabolism as well as that of worms. 5. CONCLUSION: IMPLICATIONS FOR CLINICAL PRACTICE Metformin is a widely prescribed oral antihyperglycemic agent as first line therapy for T2DM. The merits of use of metformin include low risk of hypoglycemia, favorable effect on body weight and lower cost. Metformin has been shown to reduce cardiovascular events and all-cause mortality in UKPDS; however, the mechanism of metformin’s action remains to be completely clarified. Although clinical studies have reported conflicting results, direct and indirect antiinflammatory effects of metformin have been reported in in vitro and in vivo studies, and this effect may be associated with cardiovascular protection independent of its hypoglycemic effect. Several mechanisms of the direct antiinflammatory effect of metformin have been proposed, including suppression of NFκB activation through AMPKdependent and independent pathways. Indirect effects may result from improvement of insulin resistance, obesity and dyslipidemia by metformin treatment. From a clinical point of view, the low risk of hypoglycemia, which is the most frequent and serious adverse event in anti-diabetic therapy, with metformin treatment is also important for cardiovascular protection. Hypoglycemia could affect cardiovascular events by inducing inflammation, blood coagulation abnormality, sympathoadrenal response and endothelial dysfunction [98, 99]. Recent clinical trials have failed to show the efficacy of strict glycemic control on cardiovascular outcome in patients with T2DM [100-102], in which strict glycemic control was associated with increased incidence of hypoglycemia, indicating the importance of avoiding hypoglycemia, especially severe hypoglycemia, in the treatment of T2DM. As described above, various beneficial effects of metformin beyond its hypoglycemic effect are gaining attention, including anti-cancer and anti-aging effects. However, an association between metformin use and increased risk of cognitive impairment has recently been reported [103]. Metformin-induced vitamin B12 malabsorption may mediate this association. Other adverse effects of metformin include gastrointestinal disturbance and lactic acidosis. Lactic acidosis is the most serious adverse event of metformin. Although the incidence of lactic acidosis with

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metformin treatment is very low (4.3 cases per 100,000 patient-years) [8], caution is needed in the use of metformin in patients at risk of lactic acidosis such as the elderly and patients with renal impairment or liver failure [104, 105]. In conclusion, metformin is an oral hypoglycemic agent that is expected to have various beneficial effects beyond its hypoglycemic effects. Preclinical studies suggest that metformin has direct and indirect anti-inflammatory effects; however, its clinical relevance remains to be established. Further research is warranted to clarify the mechanism of the anti-inflammatory effect of metformin in humans. CONFLICT OF INTEREST The author(s) confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS The author is grateful to Dr. Akira Shimada for his critical review of the manuscript and Dr. Wendy Gray for editing the manuscript. I apologize to the many authors of original research whose publications I could not cite owing to space restrictions. REFERENCES [1] [2]

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Received: 19 May, 2014

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Yoshifumi Saisho Chan JC, Deerochanawong C, Shera AS, et al. Role of metformin in the initiation of pharmacotherapy for type 2 diabetes: an AsianPacific perspective. Diabetes Res Clin Pract 2007; 75: 255-266.

Accepted: 11 March, 2015

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.

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