The association of IL-1β, IL-1α, IL-6, and E-selectin with the diastolic dysfunction in patients with type 2 diabetes mellitus and preserved ejection fraction

Dejan M. Marinković; Tamara Dragović; Predrag Djurić; Jelena Rakočević; Dragana Malović; Saša Kiković; Ivan Stanojević; Bratislav Dejanović; Petar Ristić; Zoran Hajduković

doi:10.2298/VSP241003015M

Dejan M. Marinković Military Medical Academy, *Clinic for Endocrinology, Belgrade, Serbia
Tamara Dragović Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia ; University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Predrag Djurić Military Medical Academy, Clinic for Cardiology, Belgrade, Serbia; University of Defence, Faculty of Medicine of the Military Medical Academy
Jelena Rakočević University of Belgrade, Faculty of Medicine, Institute for Histology and Embryology “Aleksandar Đ. Kostić”, Belgrade, Serbia
Dragana Malović Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia
Saša Kiković Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia
Ivan Stanojević Military Medical Academy, Institute for Medical Research, Belgrade, Serbia University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Bratislav Dejanović Military Medical Academy, Institut for Medical Biochemistry, Belgrade, Serbia
Petar Ristić Military Medical Academy, Clinic for Endocrinology, Belgrade, Serbia; University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia
Zoran Hajduković University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia

DOI: https://doi.org/10.2298/VSP241003015M

Keywords: biomarkers;, cardiomyopathies;, cardiovascular diseases;, cytokines;, diabetes mellitus, type 2;, echocardiography;, heart failure

Abstract

Background/Aim. The importance of chronic inflammation, endothelial dysfunction, certain cytokines, and selectins in the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVDs) is increasingly evident and supported by evidence. However, the role of chronic inflammation in the development of diastolic dysfunction (DD) in the early stages of cardiomyopathy in T2DM patients is insufficiently studied. The aim of this study was to examine the possible association of interleukin (IL)-1β, IL-1α, IL-6, and E-selectin with DD in T2DM patients with still preserved ejection fraction (EF). Methods. The research included a total of 74 subjects divided into two groups: a group with proven T2DM, i.e., diabetes group (DG) (n = 45), and a healthy control group (HCG) (n = 29). Echocardiographic parameters of DD and serum levels of IL-1β, IL-1α, IL-6 and E-selectin were compared between the two groups, and the correlation of echocardiographic parameters of DD and serum biomarkers was examined in both groups. Results. Subjects with T2DM had significantly different values of DD parameters compared to HCG but also higher values of IL-6 (19 pg/mL vs. 12 pg/mL, p = 0.002), E-selectin (2,036 pg/mL vs. 1,522 pg/mL, p < 0.001), and IL-1α (46 pg/mL vs. 37 pg/mL, p = 0.003). The majority of subjects who met the echocardiographic criteria of DD were from DG. In subjects with proven DD, significantly higher values of IL-6 (20.5 pg/mL vs. 16 pg/mL, p = 0.003) and IL-1β (15.0 pg/mL vs. 11.4 pg/mL, p = 0.036) were verified compared to subjects without DD. Conclusion. The results of our study indicate the presence of a connection between chronic inflammation and echocardiographic parameters with the onset of DD in the phases of preserved cardiac EF in patients with T2DM.

References

Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC Guidelines on diabetes, pre-diabetes, and cardio-vascular diseases developed in collaboration with the EASD: the Task Force on diabetes,mpre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and de-veloped in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 2013; 34(39): 3035–87. Erratum in: Eur Heart J 2014; 35(27): 1824.

Zhang H, Dhalla NS. The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease. Int J Mol Sci 2024; 25(2): 1082.

American Diabetes Association. Standards of Medical Care in Diabetes-2020 Abridged for Primary Care Providers. Clin Diabetes 2020; 38(1): 10–38.

Joseph JJ, Deedwania P, Acharya T, Aguilar D, Bhatt DL, Chyun DA, et al. Comprehensive Management of Cardiovascular Risk Factors for Adults With Type 2 Diabetes: Scientific Statement From the American Heart Association. Circulation 2022; 145(9): e722–59.

Saxena M, Srivastava N, Banerjee M. Association of IL6, TNF-a and IL-10 gene polymorphisms with type 2 diabetes mellitus. Mol Biol Rep 2013; 40(11): 6271–9.

Grossmann V, Schmitt VH, Zeller T, Panova-Noeva M, Schulz A, Laubert-Reh D, et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care 2015; 38(7): 1356–64.

Nadeem A, Mumtaz S, Naveed AK, Aslam M, Siddiqui A, Lodhi GM, et al. Gene-gene, gene-environment, gene-nutrient inter-actions and single nucleotide polymorphisms of inflammatory cytokines. World J Diabetes 2015; 6(4): 642–7.

Wang М, Li Y, Li S, Lv J. Endothelial Dysfunction and Diabetic Cardiomyopathy. Front Endocrinol (Lausanne) 2022; 13: 851941.

Ghanem SE, Abdel-Samiee M, Torky MH, Gaafar A, Mohamed SM, Salah Eldin GMM, et al. Role of resistin, IL-6 and NH2-terminal portion proBNP in the pathogenesis of cardiac disease in type 2 diabetes mellitus. BMJ Open Diabetes Res Care 2020; 8(1): e001206.

Kaur N, Guan Y, Raja R, Ruiz-Velasco A, Liu W. Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response. Front Physiol 2021; 12: 694864.

Fathelbab M, Fahmy EM, Elshormilisy AA, Gaafar AE, Waly NE. A putative role for oxidative stress in pathophysiology of diabetic cardiomyopathy. Egypt J Obes Diabetes Endocrinol 2017; 3(3): 95–9.

Ofstad AP. Myocardial dysfunction and cardiovascular disease in type 2 diabetes. Scand J Clin Lab Invest 2016; 76(4): 271–81.

Fang ZY, Schull-Meade R, Downey M, Prins J, Marwick TH. Determinants of subclinical diabetic heart disease. Diabetologia 2005; 48(2): 394–402.

Ceriello A, Catrinoiu D, Chandramouli C, Cosentino F, Dombrowsky AC, Itzhak B, et al. Heart failure in type 2 diabetes: Current perspectives on screening, diagnosis and management. Cardiovasc Diabetol 2021; 20(1): 218.

Jia G, DeMarco VG, Sowers JR. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol 2016; 12(3): 144–53.

Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J Am Soc Echocardiogr 2009; 22(2): 107–33.

Jia G, Hill MA, Sowers JR. Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res 2018; 122(4): 624–38

Liu X, Yang ZG, Gao Y, Xie LJ, Jiang L, Hu BY, et al. Left ventricular subclinical myocardial dysfunction in uncomplicated type 2 diabetes mellitus is associated with impaired myocardial perfusion: a contrast-enhanced cardiovascular magnetic resonance study. Cardiovasc 2 Diabetol 2018; 17(1): 139.

Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre‑diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41(2): 255–323. Erratum in: Eur Heart J 2020; 41(45): 4317.

Kossaify A, Nasr M. Diastolic dysfunction and the new recommendations for echocardiographic assessment of left ventricular diastolic function: summary of guidelines and novelties in diagnosis and grading. J Diagn Med Sonogr 2019; 35(4): 317–25.

Marinković DM, Dragović T, Stanojević I, Djurić P, Dejanović B, Rakočević J, et al. Low-grade inflammation and inflammatory mediators in individuals with prediabetes. Vojnosanit Pregl 2024; 81(9): 547–54.

Brahimaj A, Ligthart S, Ghanbari M, Ikram MA, Hofman A, Franco OH, et al. Novel inflammatory markers for incident pre-diabetes and type 2 diabetes: the Rotterdam Study. Eur J Epidemiol 2017; 32(3): 217–26.

Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A, et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003; 52(7): 1799–805.

Piccini JP, Klein L, Gheorghiade M, Bonow RO. New insights into diastolic heart failure: role of diabetes mellitus. Am J Med 2004; 116 Suppl 5A: 64S–75S.

Füth R, Dinh W, Bansemir L, Ziegler G, Bufe A, Wolfertz J, et al. Newly detected glucose disturbance is associated with a high prevalence of diastolic dysfunction: double risk for the development of heart failure? Acta Diabetol 2009; 46(4): 335–8.

Karwi QG, Ho KL, Pherwani S, Ketema EB, Sun Q, Lopaschuk GD. Concurrent diabetes and heart failure: Interplay and novel therapeutic approaches. Cardiovasc Res 2022; 118(3): 686–715. Erratum in: Cardiovasc Res 2022; 118(7): 1850.

Abudureyimu M, Luo X, Wang X, Sowers JR, Wang W, Ge J, et al. Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus: From pathophysiology to therapeutics. J Mol Cell Biol 2022; 14(5): mjac028.

Riehle C, Bauersachs J. Key inflammatory mechanisms underlying heart failure. Herz 2019; 44(2): 96–106.

Chou CH, Hung CS, Liao CW, Wei LH, Chen CW, Shun CT, et al. IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis. Cardiovasc Res 2018; 114(5): 690–702.

Avagimyan A, Fogacci F, Pogosova N, Kakrurskiy L, Kogan E, Urazova O, et al. Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts. Curr Probl Cardiol 2024; 49(1 Pt A): 102052.

Vig H, Ravinandan AP, Vishwas HN, Tyagi S, Rathore S, Wal A, et al. An Insight into the Pathogenesis of Diabetic Cardiomyopathy Along with the Novel Potential Therapeutic Approaches. Curr Diabetes Rev 2024; 20(1): e020523216416.

Dandamudi S, Slusser J, Mahoney DW, Redfield MM, Rodeheffer RJ, Chen HH. The prevalence of diabetic cardiomyopathy: A population-based study in Olmsted County, Minnesota. J Card Fail 2014; 20(5): 304–9.

Paolillo S, Marsico F, Prastaro M, Renga F, Esposito L, De Martino F, et al. Diabetic cardiomyopathy: definition, diagnosis, and therapeutic implications. Heart Fail Clin 2019; 15(3): 341–7.

Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2016; 17(12): 1321–60.

Wang Z, Shen XH, Feng WM, Ye G, Qiu W, Li B. Analysis of Inflammatory Mediators in Prediabetes and Newly Diagnosed Type 2 Diabetes Patients. J Diabetes Res 2016; 2016: 7965317.

Tiftikcioglu BI, Duksal T, Bilgin S, Kose S, Zorlu Y. Association between the levels of IL-6, sE-selectin and Distal sensory nerve conduction studies in patients with prediabetes. Eur Neurol 2016; 75(3–4): 124–31.

Al-Shukaili A, Al-Ghafri S, Al-Marhoobi S, Al-Abri S, Al-Lawati J, Al-Maskari M. Analysis of inflammatory mediators in type 2 diabetes patients. Int J Endocrinol 2013; 2013: 976810.

Weaver JR, Odanga JJ, Breathwaite EK, Treadwell ML, Murchinson AC, Walters G, et al. An increase in inflammation and islet dysfunction is a feature of prediabetes. Diabetes Metab Res Rev 2021; 37(6): e3405.

Ridker PM, Rane M. Interleukin-6 Signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021; 128(11): 1728–46.

Tsigos C, Papanicolaou DA, Kyrou I, Defensor R, Mitsiadis CS, Chrousos GP. Dose-dependent effects of recombinant human interleukin-6 on glucose regulation. J Clin Endocrinol Metab 1997; 82(12): 4167–70.

Spranger J, Kroke A, Möhlig M, Hoffmann K, Bergmann MM, Ristow M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52(3): 812–7.

Sari MI, Tala ZZ, Wahyuni DD. Association between Glycated Hemoglobin with the Levels of Serum Proinflammatory Cytokines and Antioxidants in Patients with Type 2 Diabetes Mellitus in Universitas Sumatera Utara Hospital. Open Access Maced J Med Sci 2019; 7(5): 715–20.

Tuttolomondo A, La Placa S, Di Raimondo D, Bellia C, Caruso A, Lo Sasso B, et al. Adiponectin, resistin and IL-6 plasma levels in subjects with diabetic foot and possible correlations with clinical variables and cardiovascular co-morbidity. Cardiovasc Diabetol 2010; 9: 50.

Abd El-Hameed AM, Eskandrani AA, Salah Abdel-Reheim E, Abdel Moneim A, Addaleel W. The amelioration effect of antidiabetic agents on cytokine expression in patients with type 2 diabetes mellitus. Saudi Pharm J 2024; 32(5): 102029.

Dinarello CA. Overview of the IL-1 Family in innate inflammation and acquired immunity. Immunol Rev 2018; 281(1): 8–27.

Szekely Y, Arbel Y. A Review of Interleukin-1 in Heart Disease: Where do we stand today? Cardiol Ther 2018; 7(1): 25–44.

Sokolova M, Sahraoui A, Høyem M, Øgaard J, Lien E, Aukrust P, et al. NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. Am J Physiol Endocrinol Metab 2018; 315(5): E912–23.

King BC, Kulak K, Krus U, Rosberg R, Golec E, Wozniak K, et al. Complement component C3 is highly expressed in human pancreatic islets and prevents β cell death via ATG16L1 interaction and autophagy regulation. Cell Metab 2019; 29(1): 202–10.

Di Paolo NC, Shayakhmetov DM. Interleukin-1α and the inflammatory process. Nat Immunol 2016; 17(8): 906–13.

Alfadul H, Sabico S, Al-Daghri NM. The role of interleukin-1β in type 2 diabetes mellitus: A systematic review and meta-analysis. Front Endocrinol (Lausanne) 2022; 13: 901616.

Jin Z, Zhang Q, Liu K, Wang S, Yan Y, Zhang B, et al. The association between interleukin family and diabetes mellitus and its complications: An overview of systematic reviews and meta-analyses. Diabetes Res Clin Pract 2024; 210: 111615.

Matsumoto K, Miyake S, Yano M, Ueki Y, Tominaga Y. High serum concentrations of soluble E-selectin in patients with impaired glucose tolerance with hyperinsulinemia. Atherosclerosis 2000; 152(2): 415–20.

Blum A, Pastukh N, Socea D, Jabaly H. Levels of adhesion molecules in peripheral blood correlat with stages of diabetic retinopathy and may serve as bio markers for microvascular complications. Cytokine 2018; 106: 76–9.

Siddiqui K, George TP, Mujammami M, Isnani A, Alfadda AA. The association of cell adhesion molecules and selectins (VCAM-1, ICAM-1, E-selectin, L-selectin, and P-selectin) with microvascular complications in patients with type 2 diabetes: A follow-up study. Front Endocrinol (Lausanne) 2023; 14: 1072288.

Zheng H, Sun W, Zhang Q, Zhang Y, Ji L, Liu X, et al. Proinflammatory cytokines predict the incidence of diabetic peripheral neuropathy over 5 years in Chinese type 2 diabetes patients: A prospective cohort study. EclinicalMedicine 2020; 31: 100649.

Ekelund C, Dereke J, Nilsson C, Landin-Olsson M. Are soluble E-selectin, ICAM-1, and VCAM-1 potential predictors for the development of diabetic retinopathy in young adults, 15–34 years of age? A Swedish prospective cohort study. PLoS One 2024; 19(6): e0304173.

Boonman-de Winter LJ, Rutten FH, Cramer MJ, Landman MJ, Liem AH, Rutten GE, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia 2012; 55(8): 2154–62.

Vaur L, Gueret P, Lievre M, Chabaud S, Passa P. Development of congestive heart failure in type 2 diabetic patients with microalbuminuria or proteinuria: Observations from the DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study. Diabetes Care 2003; 26(3): 855–60. Erratum in: Diabetes Care 2003; 26(8): 2489.

Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28(20): 2539–50.

Yan AT, Yan RT, Cushman M, Redheuil A, Tracy RP, Arnett DK, et al. Relationship of interleukin-6 with regional and global left-ventricular function in asymptomatic individuals without clinical cardiovascular disease: Insights from the multi-ethnic study of atherosclerosis. Eur Heart J 2010; 31(7): 875–82.

Meléndez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension 2010; 56(2): 225–31.

Collier P, Watson CJ, Voon V, Phelan D, Jan A, Mak G, et al. Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail 2011; 13(10): 1087–95.

Fedacko J, Singh RB, Gupta A, Hristova K, Toda E, Kumar A, et al. Inflammatory mediators in chronic heart failure in North India. Acta Cardiol 2014; 69(4): 391–8.

Toczylowski K, Hirnle T, Harasiuk D, Zabielski P, Lewczuk A, Dmitruk I, et al. Plasma concentration and expression of adipokines in epicardial and subcutaneous adipose tissue are associated with impaired left ventricular filling pattern. J Transl Med 2019; 17(1): 310.

Perez AL, Grodin JL, Chaikijurajai T, Wu Y, Hernandez AF, Butler J, et al. Interleukin-6 and outcomes in acute heart failure: An ASCEND-HF substudy. J Card Fail 2021; 27(6): 670–6.

Fernandes-Silva MM, Guimarães GV, Rigaud VO, Lofrano-Alves MS,Castro RE, Cruz LGdB, et al. Inflammatory biomarkers and effect of exercise on functional capacity in patients with heart failure: Insights from a randomized clinical trial. Eur J Prev Cardiol 2017; 24(8): 808–17.

Askevold ET, Nymo S, Ueland T, Gravning J, Wergeland R, Kjekshus J, et al. Soluble glycoprotein 130 predicts fatal outcomes in chronic heart failure: analysis from the Con-trolled Rosuvastatin Multinational Trial in Heart Failure (CORONA). Circ Heart Fail 2018; 6(1): 91–8.

Zhuravlyova L, Sokolnikova N. 0149: the relationship between resistin, interleukin-6 level and diastolic dysfunction in patients with type 2 diabetes mellitus. Arch Cardiovasc Dis Suppl 2015; 7(1): 33.

Jia C, Chen H, Zhang J, Zhou K, Zhuge Y, Niu C, et al. Role of pyroptosis in cardiovascular diseases. Int Immunopharmacol 2019; 67: 311–8.

Peh ZH, Dihoum A, Hutton D, Arthur JSC, Rena G, Khan F, et al. Inflammation as a therapeutic target in heart failure with preserved ejection fraction. Front Cardiovasc Med 2023; 10: 1125687.

Toldo S, Mezzaroma E, Bressi E, Marchetti C, Carbone S, Sonnino C, et al. Interleukin-1β blockade improves left ventricular systolic/diastolic function and restores contractility reserve in severe ischemic cardiomyopathy in the mouse. J Cardiovasc Pharmacol 2014; 64(1): 1–6.

Van Tassell BW, Arena R, Biondi-Zoccai G, Canada JM, Oddi C, Abouzaki NA, et al. Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study). Am J Cardiol 2014; 113(2): 321–7.

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119–31.

Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019; 139(10): 1289–99.