Abstract
Purpose
Increased serum interleukin-6 (IL-6) levels are associated with an increased risk of cardiovascular disease, and cardiovascular autonomic dysfunction is associated with high mortality in type 2 diabetic patients. However, the relationship between IL-6 levels and cardiovascular autonomic dysfunction has not been fully elucidated. The aim of this study was to determine whether serum IL-6 levels are associated with cardiovascular autonomic dysfunction in type 2 diabetic patients.
Methods
Eighty type 2 diabetic patients who did not have organic heart disease were categorized into a high IL-6 group (>2.5 pg/ml, n = 40, age 59 ± 12 years) or a non-high IL-6 group (<2.5 pg/ml, n = 40, 61 ± 12 years). Cardiac autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations and 123I-metaiodobenzylguanidine (MIBG) scintigraphy.
Results
The body mass index values (BMI), fasting insulin levels and homeostasis model assessment index values were higher in the high IL-6 group than in the non-high IL-6 group (p < 0.01). Early and delayed 123I-MIBG myocardial uptake values were lower (p < 0.01), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the high IL-6 group than in the non-high IL-6 group. Furthermore, multiple regression analysis revealed that the IL-6 level was independently predicted by the BMI and the myocardial uptake of 123I-MIBG during the delayed phase.
Conclusions
The results indicate that elevated IL-6 levels are associated with depressed cardiovascular autonomic function and obesity in type 2 diabetic patients.
Similar content being viewed by others
References
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836–43.
Bennet AM, Prince JA, Fei GZ, Lyrenäs L, Huang Y, Wiman B, et al. Interleukin-6 serum levels and genotypes influence the risk for myocardial infarction. Atherosclerosis 2003;171:359–67.
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;52:1799–805.
Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 2003;52:2784–9.
Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 2002;51:3391–9.
Sandler S, Bendtzen K, Eizirik DL, Welsh M. Interleukin-6 affects insulin secretion and glucose metabolism of rat pancreatic islets in vitro. Endocrinology 1990;126:1288–94.
Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996;94:2850–5.
La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998;351:478–84.
Reichard P, Pihl M. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Diabetes 1994;43:313–7.
Takahashi N, Anan F, Nakagawa M, Yufu K, Shinohara T, Tsubone T, et al. Hypoadiponectinemia in type 2 diabetes mellitus in men is associated with sympathetic overactivity as evaluated by cardiac 123I-metaiodobenzylguanidine scintigraphy. Metabolism 2007;56:919–24.
Kuzuya T, Nakagawa S, Satoh J, Kanazawa Y, Iwamoto Y, Kobayashi M, et al. Report of the Committee on the classification and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract 2002;55:65–85.
Liao D, Sloan RP, Cascio WE, Folsom AR, Liese AD, Evans GW, et al. Multiple metabolic syndrome is associated with lower heart rate variability. Diabetes Care 1998;21:2116–22.
Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450–8.
Anan F, Masaki T, Yonemochi H, Takahashi N, Nakagawa M, Eshima N, et al. Abdominal visceral fat accumulation is associated with the results of (123)I-metaiodobenzylguanidine myocardial scintigraphy in type 2 diabetic patients. Eur J Nucl Med Mol Imaging 2007;34:1189–97.
Sato T, Nishinaga M, Kawamoto A, Ozawa T, Takatsuji H. Accuracy of a continuous blood pressure monitor based on arterial tonometry. Hypertension 1993;21:866–74.
Biasucci LM, Vitelli A, Liuzzo G, Altamura S, Caligiuri G, Monaco C, et al. Elevated levels of interleukin-6 in unstable angina. Circulation 1996;94:874–7.
Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y, et al. Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol 2006;98:14–8.
Maeda K, Tsutamoto T, Wada A, Mabuchi N, Hayashi M, Tsutsui T, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 2000;36:1587–93.
Bastard JP, Jardel C, Bruckert E, Blondy P, Capeau J, Laville M, et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab 2000;85:3338–42.
Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 2002;106:679–84.
Mantysaari M, Kuikka J, Mustonen J, Tahvanainen K, Vanninen E, Lansimies E, et al. Noninvasive detection of cardiac sympathetic nervous dysfunction in diabetic patients using [123I]metaiodobenzylguanidine. Diabetes 1992;41:1069–75.
Schnell O, Muhr D, Weiss M, Kirsch CM, Haslbeck M, Tatsch K, et al. Three-year follow-up on scintigraphically assessed cardiac sympathetic denervation in patients with long-term insulin-dependent (type I) diabetes mellitus. J Diabetes Its Complicat 1997;11:307–13.
Gerritsen J, TenVoorde BJ, Dekker JM, Kingma R, Kostense PJ, Bouter LM, et al. Measures of cardiovascular autonomic nervous function: agreement, reproducibility, and reference values in middle age and elderly subjects. Diabetologia 2003;46:330–8.
Schofer J, Spielmann R, Schuchert A, Weber K, Schluter M. Iodine-123 metaiodobenzylguanidine scintigraphy a noninvasive method to demonstrate myocardial adrenergic nerve system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1988;12:1252–8.
Imamura Y, Ando H, Mitsuoka W, Egashira S, Masaki H, Ashihara T, et al. Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause. J Am Coll Cardiol 1995;26:1594–9.
Nagamachi S, Fujita S, Nishii R, Futami S, Tamura S, Mizuta M, et al. Prognostic value of cardiac I-123 metaiodobenzylguanidine imaging in patients with non-insulin-dependent diabetes mellitus. J Nucl Cardiol 2006;13:34–42.
Sakata K, Shirotani M, Yoshida H, Kurata C. Cardiac sympathetic nervous system in early essential hypertension assessed by 123I-MIBG. J Nucl Med 1999;40:6–11.
Spallone V, Menzinger G. Diagnosis of cardiovascular autonomic neuropathy in diabetes. Diabetes 1997;46:67–76.
Watanabe K, Sekiya M, Tsuruoka T, Funada J, Kameoka H, Miyagawa M, et al. Relationship between insulin resistance and cardiac sympathetic nervous function in essential hypertension. J Hypertens 1999;17:1161–8.
Ziegler D, Weise F, Langen KJ, Piolot R, Boy C, Hubinger A, et al. Effect of glycaemic control on myocardial sympathetic innervation assessed by [123I]metaiodobenzylguanidine scintigraphy: a 4-year prospective study in IDDM patients. Diabetologia 1998;41:443–51.
Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH, et al. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation 1999;99:546–51.
Yin F, Wang YY, Du JH, Li C, Lu ZZ, Han C, et al. Noncanonical cAMP pathway and p38 MAPK mediate beta2-adrenergic receptor-induced IL-6 production in neonatal mouse cardiac fibroblasts. J Mol Cell Cardiol 2006;40:384–93.
Gavras HP. Issues in hypertension: drug tolerability and special populations. Am J Hypertens 2001;14:231–6.
Lender D, Arauz-Pacheco C, Breen L, Mora-Mora P, Ramirez LC, Raskin P. A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients. Am J Hypertens 1999;12:298–303.
Kontopoulos AG, Athyros VG, Didangelos TP, Papageorgiou AA, Avramidis MJ, Mayroudi MC, et al. Effect of chronic quinapril administration on heart rate variability in patients with diabetic autonomic neuropathy. Diabetes Care 1997;20:355–61.
Rodgers JE, Patterson JH. Angiotensin II-receptor blockers: clinical relevance and therapeutic role. Am J Health Syst Pharm 2001;58:671–83.
Lefrandt JD, Heitmann J, Sevre K, Castellano M, Hausberg M, Fallon M, et al. The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: the VAMPHYRE study. Am J Hypertens 2001;14:1083–9.
Yamashina S, Yamazaki J. Role of MIBG myocardial scintigraphy in the assessment of heart failure: the need to establish evidence. Eur J Nucl Med Mol Imaging 2004;31:1353–5.
Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, et al. Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction. J Am Coll Cardiol 2005;45:661–7.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shinohara, T., Takahashi, N., Yufu, K. et al. Role of interleukin-6 levels in cardiovascular autonomic dysfunction in type 2 diabetic patients. Eur J Nucl Med Mol Imaging 35, 1616–1623 (2008). https://doi.org/10.1007/s00259-008-0809-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00259-008-0809-y