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Principal component analysis of adipocytokines and insulin associate with risk factors of cardiovascular diseases



Obesity plays an important role in the development of chronic diseases like cardiovascular diseases and diabetes. The possible underlying mechanism for this connection is that adipose tissue secretes an array of chemical messenger adipokines proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta). This study aimed to investigate the linkage between adipocytokines and insulin with the cardiovascular disease risk, with particular reference to the adipokines galectin-3, plasminogen activator inhibitor-1, and interleukin-1-beta, C-reactive protein, and monocyte chemoattractant protein.


Two patterns were identified. The first pattern was galectin-3, plasminogen activator inhibitor-1 and interleukin-1-beta and the second one was C-reactive protein, insulin and monocyte chemoattractant protein-1. The second pattern was strongly associated with the higher scores for resting metabolic rate, diastolic blood pressure, homeostasis model insulin resistance index, lipid profile (except low density lipoprotein, total cholesterol), and body composition parameters (except fat free mass index and waist hip ratio), while negatively associated with age and high density lipoprotein level (all p < 0.05). The first pattern was, however, significantly associated with body fat mass, obesity degree percentage, waist circumference, fat mass index, and waist hip ratio (p < 0.05 for all).

This is a retrospective study. Ethics approval (IR.TUMS.VCR.REC.1395.1597).


Cardiovascular diseases (CVDs) is an umbrella term that includes diseases affecting the heart and blood vessels [1]. There are a number of modifiable (smoking, alcohol consumption, diet, exercise) and non-modifiable (genes) that may contribute to the onset and progression of CVD [2], with strong evidence suggesting obesity is a major risk factor for CVD. Relevant reports also demonstrated that obesity is predominant in CVD patients [3]. one possible underlying mechanism for this connection is that adipose tissue secretes an array of chemical messenger adipokines including leptin and proinflammatory cytokines [tumor necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1- beta (IL-1β)] [4]. Indeed, abnormal levels of adipokines may predispose obese individuals to cardiovascular diseases [5].

A high proportion of body fat mass, in particular abdominal fat is one of the major risk factors for CVD [6], and as a result, obesity is an independent underlying predictor of CVD which is often related to elevated levels of inflammatory mediators [7, 8]. These inflammatory mediators are regarded as independent risk factors for future coronary events [8]. Proinflammatory cytokines are capable of triggering the synthesis of C-reactive protein (CRP) by hepatocytes [9]. There is substantial evidence supporting the role of CRP in the pathogenesis and worsening of vascular inflammation, vessel damage and clinical CVD complications [10].

Obesity has become a burgeoning epidemic in the public health [11] and is inevitably accompanied by the increased level of plasma cholesterol, triglyceride, and blood sugar as well as levels of insulin, which can elevate susceptibility to the cardiovascular diseases [12]. The aim of this study was to determine if these factors contribute to cardiovascular disease in women.

This study aimed to investigate the linkage between serum markers of obesity and risk of cardiovascular diseases, with particular reference to the adipokines galectin-3, plasminogen activator inhibitor-1 (PAI-1), IL-1β, CRP, monocyte chemoattractant protein-1 (MCP-1), and insulin.

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Three hundred and sixty women with body mass index (BMI) ≥ 25 were recruited from health centers of Tehran. Investigating obese individuals aged 18 to 50. Participants were excluded if they were taking medications or had history of type one diabetes mellitus. Smoking, alcohol consumption, pregnancy, lactation, and exercise were considered as additional exclusion criteria.

After an overnight (12 h) fast, volunteers attended to the clinical health centers and standard anthropometric parameters were recorded. Three readings were taken to calculate resting blood pressures at left brachial artery by an automated sphygmomanometer (Dinamap).


Indirect calorimetry (spirometer METALYZERR 3B-R3, Cortex Biophysik GmbH, Leipzig, Germany) was used to calculate resting metabolic rate (RMR). To do so, the amount of consumed O2 and produced CO2 was measured after/when subjects had rested for at least 20 min. Gas ventilation was calibrated prior to each test.

Laboratory methods

A blood sample was also taken to assess serum concentrations of glucose (FBS), lipids, and adipokines (CRP, IL-1β) using enzyme-linked immunosorbent assay kits (R&D Systems, Techne Corporation, Minneapolis, MN) according to the manufacturer’s instructions. All samples were analyzed in duplicates. The homeostasis model insulin resistance index (HOMA) was computed as the product of fasting glucose and insulin level divided by 22.5 with molar unit (mmol/L).

Statistical analysis

All statistical analysis was conducted by the SPSS version 22 (SPSS Inc., Chicago, IL). Data are presented as arithmetic means plus their 95% confidence interval (CI) and standard deviations unless otherwise stated.

Factor (principal component) analysis was performed to determine which plasma concentration of adipokines associated with most of observed variations. Two patterns were identified as shown in Additional file 1: Table S1. The significance of differences between low and high value of each pattern and CVD risk factors were computed by analysis of variance (ANOVA) (Additional file 2: Table S2). In addition, to keep uncorrelated factors and greater interpretability, the patterns were rotated and normalized using Varimax transformation method and Kaiser Method, respectively. Pearson’s correlation coefficient indicates the association between each adipokine pattern score and CVD risk factors (Additional file 3: Table S3). Multiple linear regression analysis was followed to calculate the incidence and strength of associations (Tables 1 and 2). Two-sided p values < 0.05 were considered as statistically significant. Confounders including age, physical activity, energy intake, and BMI were used to adjust for linear regression analysis.

Table 1 Association between demographics, medical and biomedical characteristics with patterns 1 of Adipokines
Table 2 Association between demographics, medical and biomedical characteristics with patterns 2 of adipokines


Subject characteristics

Table 3 depicts main clinical and biochemical characteristics of the subjects. Mean age ranged from 18 to 50 years and BMI ranged between 25 and 40.70 kg/m2.

Table 3 Characteristics of the study participants

Correlation analysis

Single correlation of each adipokines with clinical and biochemical risk factors of CVD are detailed in Additional file 3: Table S3. The adipokines galectin-3 appeared related to BMI (r = − 0.109, p = 0.038), diastolic blood pressure (DBP) (r = − 0.123, p = 0.023), body fat mass (BFM) (r = − 0.174, p = 0.003), ODP (r = − 0.119, p = 0.044), waist circumference (WC) (r = − 0.140, p = 0.017), FMI (r = − 0.177, p = 0.003), as well as waist-hip ratio (WHR) (r = − 0.140, p = 0.017). Similar results were obtained between PAI-1 and BMI (r = − 0.111, p = 0.036), DBP (r = − 0.141, p = 0.009), BFM (r = − 0.177, p = 0.003), ODP (r = − 0.120, p = 0.041), WHR (r = − 0.155, p = 0.008), FMI (r = − 0.176, p = 0.003), plus WHR (r = − 0.166, p = 0.005). In case of CRP, the significant correlations were observed with BMI (r = 0.121, p = 0.022), DBP (r = 0.129, p = 0.018), HDL (r = − 0.152, p = 0.007), hs.CRP (r = 0.858, p = 0.0001), HOMA (r = 0.167, p = 0.004), and ODP (r = − 0.133, p = 0.024). Neither IL-1β nor MCP-1 were significantly associated with any of the anthropocentric data, blood and body composition parameters except for a positive association between IL-1β and age (r = 0.128, p = 0.015) and negative correlation between MCP-1 and FBS (r = − 0.147, p = 0.009).

On the other hand, insulin shown very broad correlations with age (r = − 0.146, p = 0.006), weight (r = 0.240, p = 0.0001), BMI (r = 0.232, p = 0.0001), RMR (r = 0.317, p = 0.0001), SBP (r = 0.112, p = 0.039), DBP (r = 0.217, p = 0.0001), TG (r = 0.290, p = 0.0001), HDL (r = − 0.145, p = 0.01), hs.CRP (r = 0.178, p = 0.001), HOMA (r = 0.880, p = 0.0001), FBS (r = 0.176, p = 0.002), BFM (r = 0.227, p = 0.0001), fat-free mass (FFM) (r = 0.292, p = 0.0001), soft lean mass (SLM) (r = 0.278, p = 0.0001), SMM (r = 0.307, p = 0.0001), ODP (r = 0.253, p = 0.0001), WC (r = 0.307, p = 0.0001), FMI (r = 0.175, p = 0.003), WHR (r = 0.240, p = 0.0001).

Two patterns were identified. The first pattern was characterized by high level of galectin-3 and, PAI-1 and low level of IL-1β. The second one was associated with CRP, insulin and MCP-1 (Additional file 1: Table S1). As shown in Table 2, association analysis of adipokines patterns demonstrated that pattern 2 were strongly correlated with the higher scores for RMR, DBP, HOMA, lipid profile, and body composition parameters, while negatively associated with age and HDL level (all p < 0.05). However, SBP, cholesterol, LDL, FBS, FFMI, and WHR appeared unrelated to PCA2 (all p > 0.05).

In contrast, neither biochemical parameters nor blood pressure of participants was significantly correlated to PCA1 pattern (all p > 0.05). The first pattern was, however, significantly associated with BFM, ODP, WC, FMI, and WHR (p < 0.05 for all).


This study aimed to investigate the association between adipocytokines and insulin patterns with the risk of cardiovascular diseases. In this study we identified two separate adipokines patterns, explaining 56% of the total variance in the data. Of these, pattern 1 characterized by the high level of galectin-3, and PAI-1 and low concentration of IL-1β. The second one included CRP, MCP-1, plus insulin. In the linear regression model derived from our data, the link between the second pattern and body composition parameters, and biochemical markers of CVD was yielded significant p-values except for SBP, LDL, and FBS.

Previous investigations on the link of adipokines and CVD risk factors have been mostly limited to single adipokines [13, 14]. But in physiology, a complex network of chemical messengers contributes to the CVD [15]. Thus, identification and evaluation of these factors in combination with each other could, at least partly, open a clear window toward prediction of the CVD. To do so, PCA was employed as a powerful statistical tool to recognize potential contributors to the observed risk factors [16]. Next, univariate regression performed to provide detailed information about quantitative associations between adipokines level and biological outcomes of the interest.

Considering the number of independent variables (adipokines plus insulin) included in this study, PCA was preferentially used for data reduction by taking a linear combination of the existing 6 orthogonal variables, allowing us to identify potentially significant patterns of adipokines plus insulin associated with CVD risk factors [17].

In consensus with the literature, our results showed that CRP, MCP-1, and insulin may be the key determinants of CVD predisposition, suggesting inflammation plays a key role in CVD development. Unraveling the molecular mechanism behind these associations may elucidate their potential for prediction of the cardiovascular events. In this respect, obesity has already been associated with low-grade inflammation in humans [18, 19]. The exact trigger is unknown yet [20], however, a number of systemic chemical messengers particularly resistin are released into the bloodstream [21]. Resistin (also called adipose tissue-specific secretory factor) is a hormone derived from adipocytes and macrophages that could significantly contribute to inflammation and CVD [22]. Resistin has been demonstrated to increase LDL levels and contribute to insulin resistance [23, 24]. It also upregulates expression of an inflammatory component called MCP-1 [25]. MCP-1 is produced by multiple cell types, including fibroblasts, monocytes, mesangial and also endothelial cells either constitutively or after induction by oxidative stress [26]. Resistin recruits monocytes and T cells to the sites of inflammation or damaged tissues [27]. Migrated monocytes differentiate into the foam cells in sub endothelial space where they initiate to produce fatty streak formations that result in atherosclerotic plaque formation [28]. Some other monocytes differentiate into tissue-resident macrophages with the ability to produce proinflammatory cytokines TNF-α, IL-1, and IL-6 that affect the liver, heart, bones, kidney, and many other tissues [29, 30]. Of these, the liver releases acute phase proteins like CRP in response to mild inflammation. CRP is believed to cause inflammation on coronary vessels, subsequently leading to myocardial ischemia [31]. On the other hand, long-term elevation of insulin level during obesity, prolongs obesity, creating a positive feedback loop and inflammation changes into the chronic form. Insufficient reperfusion further exacerbates the inflammation in injured myocardium and causes myocardial necrosis [32].


Our findings support the hypothesis of multiple determinants in the prediction of CVD risk factors in obese adult females. The utility of PCA helped to statistically analyze a comprehensive panel of adipokines and identifying potential candidates for more detailed studies in the future. Based on the results of the PCA, the panel of CRP, MCP-1, and insulin were shown responsible for the most significant variability in cardiovascular disease risk factors, however, further investigations are required to confirm whether our adipokines patterns are associated with the clinical and biological.


To the best of our knowledge, this was the first study to investigate the adipokines pattern and CVD, however there were a number of limitations. The study was limited to the number of participants and same-sex samples. We only recruited obese females, therefore our results may not be applicable to the general population. Furthermore, we had a small number of predominantly inflammatory adipokines and further studies should look at introducing more adipokines another important limitation is the cross-sectional design of the study that prevented us from inferring causality.

Availability of data and materials

Since the privacy of research participants may be compromised, we cannot make the information publicly available.



Cardiovascular diseases


Tumor necrosis factor-alpha




Interleukin-1- beta


C-reactive protein


Plasminogen activator inhibitor-1


Monocyte chemoattractant protein-1


Body mass index


Resting metabolic rate


Fasting blood sugar


Confidence interval


Analysis of variance


Systolic blood pressure


Diastolic blood pressure


Body fat mass


Obesity degree percentage


Waist circumference


Waist-hip ratio


Fat-free mass


Soft lean mass


  1. 1.

    Braunwald E. Heart disease. Philadelphia: W.B. Saunders; 1988.

    Google Scholar 

  2. 2.

    Cosselman KE, Navas-Acien A, Kaufman JD. Environmental factors in cardiovascular disease. Nat Rev Cardiol. 2015;12:627.

    CAS  Article  Google Scholar 

  3. 3.

    Poirier P, Eckel RH. Obesity and cardiovascular disease. Circulation. 2002;4:448–53.

    Google Scholar 

  4. 4.

    Mattu HS, Randeva HS. Role of adipokines in cardiovascular. J Endocrinol. 2013;216:T17–36.

    CAS  Article  Google Scholar 

  5. 5.

    Tesauro M, Canale MP, Rodia G, Di Daniele N, Lauro D, Scuteri A, Cardillo CJCR. Metabolic syndrome, chronic kidney, and cardiovascular diseases: role of adipokines. Cardiol Res Pract. 2011;2011:11.

    Article  Google Scholar 

  6. 6.

    Després J-P, Lemieux I, Prud’Homme DJB. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ. 2001;322:716–20.

    Article  Google Scholar 

  7. 7.

    Smith SC Jr. Multiple risk factors for cardiovascular disease and diabetes mellitus. Am J Med. 2007;120:S3–11.

    Article  Google Scholar 

  8. 8.

    Das UJN. Is obesity an inflammatory condition? Nutrition. 2001;17:953–66.

    CAS  Article  Google Scholar 

  9. 9.

    Rifai N, Ridker PM. Inflammatory markers and coronary heart disease. Curr Opin Lipidol. 2002;13:383–9.

    CAS  Article  Google Scholar 

  10. 10.

    Cozlea D, Farcas D, Nagy A, Keresztesi A, Tifrea R, Cozlea L, Carașca E. The impact of C reactive protein on global cardiovascular risk on patients with coronary artery disease. Curr Health Sci J. 2013;39:225.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Flegal KM, Carroll MD, Ogden CL, Curtin LRJJ. Prevalence and trends in obesity among US adults. JAMA. 2010;1999–2008(303):235–41.

    Article  Google Scholar 

  12. 12.

    Ginsberg HN, MacCallum PR. The obesity, metabolic syndrome, and type 2 diabetes mellitus pandemic: Part I Increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus. J Cardiometab Syndr. 2009;4:113–9.

    Article  Google Scholar 

  13. 13.

    Nakamura K, Fuster JJ, Walsh K. Adipokines: a link between obesity and cardiovascular disease. J Cardiol. 2014;63:250–9.

    Article  Google Scholar 

  14. 14.

    Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular function. J Clin Endocrinol Metab. 2004;89:2563–8.

    CAS  Article  Google Scholar 

  15. 15.

    Wattanapitayakul SK, Bauer JA. Oxidative pathways in cardiovascular disease: roles, mechanisms, and therapeutic implications. Pharmacol Ther. 2001;89:187–206.

    CAS  Article  Google Scholar 

  16. 16.

    Jain S, Sharma S, Mandal T, Saxena MJP. Source apportionment of PM10 in Delhi, India using PCA/APCS, UNMIX and PMF. Particuology. 2018;37:107–18.

    CAS  Article  Google Scholar 

  17. 17.

    Flehmig G, Scholz M, Klöting N, Fasshauer M, Tönjes A, Stumvoll M, Youn B-S, Blüher M. Identification of adipokine clusters related to parameters of fat mass, insulin sensitivity and inflammation. PLoS ONE. 2014;9:e99785.

    Article  Google Scholar 

  18. 18.

    Coppack SW. Pro-inflammatory cytokines and adipose tissue. Proc Nutr Soc. 2001;60:349–56.

    CAS  Article  Google Scholar 

  19. 19.

    Clément K, Langin D. Regulation of inflammation-related genes in human adipose tissue. J Intern Med. 2007;262:422–30.

    Article  Google Scholar 

  20. 20.

    Slocum C, Kramer C, Genco C. Immune dysregulation mediated by the oral microbiome: potential link to chronic inflammation and atherosclerosis. J Intern Med. 2016;280:114–28.

    CAS  Article  Google Scholar 

  21. 21.

    Kim C, Park H, Kawada T, Kim J, Lim D, Hubbard N, Kwon B, Erickson KL, Yu R. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. Int J Obes. 2006;30:1347.

    CAS  Article  Google Scholar 

  22. 22.

    Wang H, Chu WS, Hemphill C, Elbein SC. Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians. J Clin Endocrinol Metab. 2002;87:2520–4.

    CAS  Article  Google Scholar 

  23. 23.

    De Luis D, Sagrado MG, Conde R, Aller R, Izaola O. Resistin levels and inflammatory markers in patients with morbid obesity. Nutr Hosp. 2010;25:630–4.

    PubMed  Google Scholar 

  24. 24.

    Park HK, Kwak MK, Kim HJ, Ahima RS. Linking resistin, inflammation, and cardiometabolic diseases. Korean J Intern Med. 2017;32:239.

    CAS  Article  Google Scholar 

  25. 25.

    Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol. 2005;174:5789–95.

    CAS  Article  Google Scholar 

  26. 26.

    Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytokine Res. 2009;29:313–26.

    CAS  Article  Google Scholar 

  27. 27.

    Carr MW, Roth SJ, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci. 1994;91:3652–6.

    CAS  Article  Google Scholar 

  28. 28.

    Bobryshev YV. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006;37:208–22.

    CAS  Article  Google Scholar 

  29. 29.

    Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-α and IL-12 in macrophages by NF-κB-dependent pathway. Biochem Biophys Res Commun. 2005;334:1092–101.

    CAS  Article  Google Scholar 

  30. 30.

    Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, Lazar MA. An inflammatory cascade leading to hyperresistinemia in humans. PLoS Med. 2004;1:e45.

    Article  Google Scholar 

  31. 31.

    Heinrich J, Schulte H, Schönfeld R, Köhler E, Assmann G. Association of variables of coagulation, fibrinolysis and acute-phase with atherosclerosis in coronary and peripheral arteries and those arteries supplying the brain. Thromb Haemost. 1995;73:374–9.

    CAS  Article  Google Scholar 

  32. 32.

    Pietilä K, Harmoinen A, Hermens W, Simoons M, Van de Werf F, Verstraete M. Serum C-reactive protein and infarct size in myocardial infarct patients with a closed versus an open infarct-related coronary artery after thrombolytic therapy. Eur Heart J. 1993;14:915–9.

    Article  Google Scholar 

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The authors thank the directors of the school of Nutritional and Dietetics at Tehran University of medical sciences for allowing them to conduct a comparative cross-sectional study for the purpose of evaluating CVDs risk factors. This study was supported by grants (ID: 95-03-161-33142 and 96-01-161-34479) from Tehran University of Medical Sciences.



Author information




SP, and SFS designed research; NB conducted research; KM and HY analyzed data; HY wrote the paper; KM had primary responsibility for final content. MA helped us in the process of revises and LS and CR improve grammar. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Khadijeh Mirzaei.

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All participants signed a written informed consent and the study was approved by Tehran University of Medical Sciences ethics committee (IR.TUMS.VCR.REC.1395.1597).

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Not applicable.

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All of authors declared that they have no competing interests.

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Supplementary information

Additional file 1: Table S1.

Principal factor loading of adipokines.

Additional file 2: Table S2.

Demographic, medical and biomedical characteristics with adherence to two groups of Adipokines patterns.

Additional file 3: Table S3.

Correlation between demographics, medical and biomedical characteristics with all of Adipokines and insulin.

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Yarizadeh, H., Setayesh, L., Askarpoor, M. et al. Principal component analysis of adipocytokines and insulin associate with risk factors of cardiovascular diseases. BMC Res Notes 13, 212 (2020).

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  • Adipocytokines
  • Cardiovascular diseases
  • Obesity