Asthma is a major burden on global health care system which is encumbering all regions in the world. Several risk factors can induce and exacerbate asthma. Recent compelling evidences have associated metabolic syndrome with the incidence of asthma. The abdominal obesity, hypertension and insulin resistance are metabolic syndrome criteria which are substantially involved in inducing and exacerbating asthma. Several mechanisms are involved in the association between metabolic syndrome and asthma. It could be due to mechanical reason, genetic factors, inflammatory effect, hormonal effect, insulin resistance and the effect of other co-morbidities associated with obesity

Ibrahim, Baharudin

Mostafa, Arwa Mohamed Amin

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&*(&*#'&$%#&(/*'$#.&('%'-+*+((&0+$*. ' "(%.&#&)  ASTHMA AND METABOLIC SYNDROME - WHERE IS THE LINK?Baharudin Ibrahim, Arwa Mohamed Amin MostafaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, MalaysiaAbstract: Asthma is a major burden on global health care system which is encumbering all regions inthe world. Several risk factors can induce and exacerbate asthma. Recent compelling evidences haveassociated metabolic syndrome with the incidence of asthma. The abdominal obesity, hypertensionand insulin resistance are metabolic syndrome criteria which are substantially involved in inducingand exacerbating asthma. Several mechanisms are involved in the association between metabolicsyndrome and asthma. It could be due to mechanical reason, genetic factors, inflammatory effect,hormonal effect, insulin resistance and the effect of other co-morbidities associated with obesity. Inthis review, we discuss the mechanisms which link metabolic syndrome to asthma.Keywords: Asthma, metabolic syndromeIntroductionAsthma is a major global health issue which burdens people from all regions of the world. It was estimatedthat 334 million patients are suffering from asthma globally [1]. Using the Global Initiative for Asthma (GINA)definition, asthma is a chronic and heterogeneous airway inflammatory disease with symptoms that vary intime and intensity such as, wheeze, shortness of breath, chest tightness and cough [2]. Due to the airway hyperresponsiveness of asthma, the symptoms can be instigated by stimuli such as exercise, allergen, change inweather or viral respiratory infection. An exacerbation of asthma may lead to long hospitalization and death.Asthma can be exacerbated by several risk factors such as type two diabetes mellitus (T2-DM), obesity or highbody mass index (BMI), hypertension, gastroesophageal reflux and sleep-disorder breathing [3]. However, thepresence of clustering conditions such as, metabolic syndrome has strong association with asthma [4, 5]. Ratherthan one disease, metabolic syndrome is a group of simultaneous disease conditions which includehypertension, abdominal obesity (central obesity), atherogenic dyslipidemia and insulin resistance or glucoseintolerance [6]. According to the National Cholesterol Education Program’s Adult Treatment Panel III report(NCEP ATP III), metabolic syndrome can be clinically diagnosed with the presence of at least three out of fivecriteria which are waist circumference more than 40 inch in men and 35 inch in women, blood pressure morethan 130/85 mm Hg, fasting blood sugar more than 110 mg/dL, triglycerides (TG) more than 150 mg/dl andhigh density lipoprotein (HDL) less than 40 mg/dL in men and 50mg/dL in women [7, 8]. In metabolicsyndrome, some types of cells suffer from function perturbation such as vascular endothelial cells, glandularepithelium, renal epithelial cells and potentially the airway epithelial and sub epithelial cells [5]. Suchperturbations, make metabolic syndrome strong risk factor for cardiovascular diseases, stroke and diabetes.Adding to them, growing evidences have strengthened the association between asthma and metabolicsyndrome [4, 9-11]. Here, we discuss the association of metabolic syndrome with asthma and the mechanismslinking this association.Metabolic syndrome associated asthma, where is the link?The association between metabolic syndrome and asthma was investigated in several population studies. In inthe Korean health and genome study, the association between metabolic syndrome and asthma -like-symptomswas tested among 9942 adults who were 40 to 69 years of age [12]. Among asthma-like-symptoms, wheeze(p=0.0006), resting dyspnoea (p=0.0062) and post-exercise dyspnoea (p=0.0001) were significantly prevalentamong subjects with metabolic syndrome compared to subjects without metabolic syndrome. Among thecriteria of metabolic syndrome, abdominal obesity and elevated blood pressure were significantly associatedwith asthma-like syndrome. The metabolic syndrome and incidence of asthma study (The HUNT study) wasone of the largest population based studies that asserted the association between metabolic syndrome andasthma (adjusted OR 1.57, 95% CI 1.31 - 1.87) [4]. In this study, 23,191 asthma-free subjects were categorizedbased on metabolic syndrome and followed-up for asthma incidence. Among metabolic syndrome components,high waist circumference (adjusted OR 1.62, 95% CI 1.36–1.94) and elevated glucose or diabetes (adjusted('#&!&*(&*#'&$%#&( 	 OR 1.43, 95% CI 1.01–2.04) were significant. Furthermore, Assad et al (2013) indicated that asthma isassociated with three components of metabolic syndrome, the abdominal obesity, hypertension and elevatedfasting glucose or diabetes in an un-adjusted models [13]. However, upon adjusting the models to BMI, it wasfound that BMI rather than metabolic syndrome is strongly associated with asthma in women. From theaforementioned studies, it is understandable that the abdominal obesity, insulin resistance (elevated glucose)and hypertension are the main risk factors that associate metabolic syndrome with asthma. Based on these riskfactors, there are several suggestive mechanisms which explain the link between metabolic syndrome andasthma. It can be due to mechanical effect, genetic factors, epigenetic factors, inflammatory effect,mitochondrial dysfunction, hormonal effect and the effect of other co-morbidities [5, 11, 14].Abdominal obesity or visceral obesity component of the metabolic syndrome is actually a leading factor forhypertension and insulin resistance [15, 16]. Therefore, visceral obesity plays pivotal role in the metabolicsyndrome-asthma linkage. This link is bilateral. Accordingly, obese asthmatic patients are more likely todevelop metabolic syndrome and vice versa [11]. The obesity associated asthma is distinctive phenotype ofasthma (OAA) and it is more likely to have poorer therapeutic outcome than non-obese asthmatic [9, 14]. Thisappear in the mechanical, genetic, inflammatory and hormonal effects of obesity on asthma.The mechanical effect of abdominal obesity on lung volumes is manifested in the exponential reduction of thefunctional residual capacity (FRC) and the expiratory reserve volume (ERV) with the increase of BMI [17,18]. In other words, an increase of BMI would cause an increase in airway resistance [18]. Obesity is associatedwith several genetic variabilities that have substantial effect on asthma and its response to therapy. In fact,asthma and obesity have shared genetic factors [14]. For instance, the β2-adrenergic receptor gene (ADRβ2)and the glucocorticoid receptor gene (NR3C1) are related to asthma and obesity. The Gln27 polymorphism ofthe ADRβ2 gene was found significantly more frequent among obese patients compared to non-obese [19].This polymorphism interferes with the response to β2-agonists in asthma [20]. The polymorphism of theNR3C1 gene was found to be significantly associated with bronchial asthma [14]. Besides, abdominal obesityis highly affected by the genetic variation in glucocorticoid receptors [21]. Obesity is known to cause chronicpro-inflammatory status in the human body which is characterized by the perturbation of pro-inflammatorymediators [14]. The increased levels of high sensitivity C-reactive protein (hs-CRP), tumor necrosis factoralpha (TNF-α), interleukin (IL-6) and leptin were observed in obese-asthma patients [11, 14]. This pro-inflammatory status can lead to airway modulation, insulin resistance and hypertension. Obese asthmaticchildren had higher pro-inflammatory leptin and lower anti-inflammatory adiponectin compared to non-obeseasthmatic children [22]. The increase of leptin with the decrease of adiponectin has key role in airwayinflammation, lung dysfunction and the development of asthma [12, 23]. Besides, leptin can increase the levelsof other pro-inflammatory mediators such as TNF-α and IL-6 [11]. It is worthy to note that leptin can causerenal and sympathetic effects leading to hypertension which is associated with asthma as well [12]. Hormonal-differences has its implication on obesity linked asthma. Obesity reduces progesterone levels [24].Progesterone causes up-regulation of ADRβ2 receptor. Moreover, leptin present in higher concentration inwomen than men [14]. Thus, obese women are more likely to suffer from OAA than men.Insulin resistance (glucose intolerance) a key element of metabolic syndrome leads to hyperinsulinemia whichis an increased level of insulin due to the elevated glucose levels [5]. Hyperinsulinemia is associated withincreased airway contractility, cell proliferation and fibrosis of the airway smooth muscle [25]. Indeed,increased insulin activates the PI3K/Akt pathway in the bronchial epithelial cells which leads tobronchoconstriction. Furthermore, metabolic syndrome is associated with increased asymmetric dimethylarginine (ADMA) which impairs the arginine-nitric oxide metabolism and cell programing [26]. This causesan increase in arginine catabolism, as well as the formation of toxic reactive nitric oxide (peroxynitrite) whichcause bronchoconstriction and mitochondrial dysfunction. This impairment was found in both metabolicsyndrome and asthma as well.In addition to all the aforementioned mechanisms that link metabolic syndrome with asthma, there are severalobesity related co-morbid conditions which can induce or exacerbate asthma condition such as sleep disorderbreathing (SDB), gastroesophageal reflux disease (GERD), T2-DM, hypertension and dyslipidemia [14]. TheSDB has been found significantly associated in asthma [27]. Similarly, GERD is associated with chestcongestion, lung inflammation and cough which may cause asthma and bronchitis [28]. The associationbetween hypertension and asthma is understandable with the effect of leptin on the renal and sympatheticactivity [12]. Elevated serum triglycerides and low HDL were associated with wheezing in large populationstudy of 85,555 Spanish adults [29]. T2-DM is highly associated with declined lung function [30]. Noteworthy,the impaired arginine-nitric oxide metabolism and mitochondrial dysfunction which link metabolic syndromewith asthma, are apparently manifested in T2-DM [31, 32].&*(&*#'&$%#&(/*'$#.&('%'-+*+((&0+$*. ' "(%.&#&)  ConclusionIt could be concluded that the association between asthma and metabolic syndrome is supported bygrowing body of evidences. This association is multifactorial rather than one direct linkage betweenthe two conditions. Asthmatic patients suffering from metabolic syndrome should not be treated forasthma in isolation from their metabolic syndrome status to avoid poor therapeutic outcome.   Apersonalized therapeutic regimen that includes weight management, asthma type phenotyping, as wellas drug response phenotyping may have better outcome.References1. The Global Asthma Network (GAN) Steering Group. The Global Asthma Report 2014. 2014  [cited 201624/07/2016]; Available from: http://www.globalasthmareport.org/resources/ Global_Asthma_Report_2014.pdf.2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention 2016.2016  [cited 2016; Available from: www.ginasthma.org.3. Shore, S.A., Obesity and asthma: Possible mechanisms. Journal of Allergy and Clinical Immunology,2008. 121(5): p. 1087-1093.4. Brumpton, B.M., et al., Metabolic syndrome and incidence of asthma in adults: the HUNT study. EurRespir J, 2013. 42(6): p. 1495-502.5. Agrawal, A., et al., Emerging Interface between Metabolic Syndrome and Asthma. American Journal ofRespiratory Cell and Molecular Biology, 2011. 44(3): p. 270-275.6. 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Asthma and Metabolic Syndrome - Where is the Link?

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Asthma and Metabolic Syndrome - Where is the Link?

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