Endurance Exercise Alters Cellular Immune Status and Resistin Concentrations in Men Suffering from Non-insulin-dependent Type 2 Diabetes

Abstract

It has been demonstrated that alterations of adipocytokines can alter immune status in type 2 diabetes. The present study investigated changes of adipocytokine plasma concentrations and cellular immune status in overweight men, suffering from non-insulin dependent type 2 diabetes (n=14, age 61.0±8.7 years, BMI 31.1±3.5 kg/cm²). Subjects underwent a 3 months endurance exercise intervention (twice per week for up to 45 min) cycling at a heart rate corresponding to a 2 mmol/l lactate threshold. Before and after the intervention testing for adipocytokines (leptin, adiponectin, resistin) and cellular immune status (including T memory-cells and regulative T-cells) was performed by RIA and FACS accordingly.

The exercise intervention improved anthropometric and metabolic parameters of all subjects. We observed a significant decline for resistin and for the CD19⁺ B-cells. The CD4⁺CD25⁺CD127^low Treg-cells decreased, however not statistically significant. All other parameters remained unchanged.

In conclusion, even though only training twice a week, the exercise affected parts of the cellular immune system as well as resistin levels in men suffering from non-insulin dependent type 2 diabetes.

Key words

type 2 diabetes - endurance exercise - immune status - resistin

• References

• 1 Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-887
• 2 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 356-359
• 3 Villegas R, Perry IJ, Creagh D et al. Prevalence of the metabolic syndrome in middle-aged men and women. Diabetes Care 2003; 26: 3198-3199
• 4 AlSaraj F, McDermott JH, Cawood T et al. Prevalence of the metabolic syndrome in patients with diabetes mellitus. Ir J Med Sci 2009; 178: 309-313 PubMed PMID: 19495843. [Epub 2009 Jun 4]
• 5 Simpson KA, Singh MA. Effects of exercise on adiponectin: a systematic review. Obesity (Silver Spring) 2008; 16: 241-256 PubMed PMID: 18239630
• 6 Barnes KM, Miner JL. Role of resistin in insulin sensitivity in rodents and humans. Curr Protein Pept Sci 2009; 10: 96-107
• 7 Cai C, Hahn BH, Matarese G et al. Leptin in non-autoimmune inflammation. Inflamm Allergy Drug Targets 2009; 8: 285-291
• 8 Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 2000; 68: 437-446
• 9 La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol 2004; 4: 371-379
• 10 Okano K, Araki M, Yamamoto M et al. Exploration of hematological and immunological changes associated with the severity of type 2 diabetes mellitus in Japan. Nurs Health Sci 2008; 10: 65-69 PubMed: 18257834
• 11 Pradhan AD, Manson JE, Rifai N et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286: 327-334
• 12 Müller S, Martin S, Koenig W et al. Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia 2002; 45: 805-812 [Epub 2002 May 8]
• 13 Barzilay JI, Abraham L, Heckbert SR et al. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes 2001; 50: 2384-2389
• 14 Lindsay RS, Krakoff J, Hanson RL et al. Gamma globulin levels predict type 2 diabetes in the Pima Indian population. Diabetes 2001; 50: 1598-1603
• 15 Dunmore SJ, Brown JE. The role of adipokines in β-cell failure of type 2 diabetes. J Endocrinol 2013; 216: T37-T45 PubMed PMID: 22991412. Print 2013 Jan
• 16 Wannamethee SG, Lowe GD, Rumley A et al. Adipokines and risk of type 2 diabetes in older men. Diabetes Care 2007; 30: 1200-1205 [Epub 2007 Feb 23]
• 17 Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005; 26: 439-451
• 18 Steppan CM, Bailey ST, Bhat S et al. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307-312
• 19 Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem Biophys Res Commun 2001; 285: 561-564
• 20 Al-Salam S, Rashed H, Adeghate E. Diabetes mellitus is associated with an increased expression of resistin in human pancreatic islet cells. Islets 2011; 3: 246-249 [Epub 2011 Sep 1]
• 21 Minn AH, Patterson NB, Pack S et al. Resistin is expressed in pancreatic islets. Biochem Biophys Res Commun 2003; 310: 641-645
• 22 Lee JA, Kim JW, Kim DY. Effects of yoga exercise on serum adiponectin and metabolic syndrome factors in obese postmenopausal women. Menopause 2012; 19: 296-301 PubMed PMID: 22089179
• 23 Phillips MD, Patrizi RM, Cheek DJ et al. Resistance training reduces subclinical inflammation in obese, postmenopausal women. Med Sci Sports Exerc 2012; 44: 2099-2110 PubMed PMID: 22874536
• 24 Moran CN, Barwell ND, Malkova D et al. Effects of diabetes family history and exercise training on the expression of adiponectin and leptin and their receptors. Metabolism 2011; 60: 206-214 PubMed PMID: 20153489. [Epub 2010 Feb 12]
• 25 Campbell KL, Foster-Schubert KE, Makar KW et al. Gene Expression Changes in Adipose Tissue with Diet- and/or Exercise-Induced Weight Loss. Cancer Prev Res (Phila) 2013; 6: 217-231 PubMed PMID: 23341572. [Epub 2013 Jan 22]
• 26 Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E et al. Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity. Diabetes 2010; 59: 572-579 PubMed: 20028948. [Epub 2009 Dec 22]
• 27 Zois CE, Tokmakidis SP, Volaklis KA et al. Lipoprotein profile, glycemic control and physical fitness after strength and aerobic training in post-menopausal women with type 2 diabetes. Eur J Appl Physiol 2009; 106: 901-907 PubMed: 19458961. [Epub 2009 May 21]
• 28 Woods JA, Davis JM, Smith JA et al. Exercise and cellular innate immune function. Med Sci Sports Exerc 1999; 31: 57-66
• 29 Nieman DC, Pedersen BK. Exercise and immune function. Recent developments. Sports Med 1999; 27: 73-80
• 30 Trøseid M, Lappegård KT, Claudi T et al. Exercise reduces plasma levels of the chemokines MCP-1 and IL-8 in subjects with the metabolic syndrome. Eur Heart J 2004; 25: 349-355
• 31 Nieman DC, Buckley KS, Henson DA et al. Immune function in marathon runners versus sedentary controls. Med Sci Sports Exerc 1995; 27: 986-992
• 32 Beshgetoor D, Arrues S, McGuire K. Effect of competitive training on T-cell mediated immune function in Master’s female athletes. Int J Sports Med 2004; 25: 553-558
• 33 Raso V, Benard G, DA Silva Duarte AJ et al. Effect of resistance training on immunological parameters of healthy elderly women. Med Sci Sports Exerc 2007; 39: 2152-2159
• 34 Sibal L, Neely RD, Jones A et al. Friedewald equation underestimates low-density lipoprotein cholesterol at low concentrations in young people with and without Type 1 diabetes. Diabet Med 2010; 27: 37-45 PubMed PMID: 20121887
• 35 Stern SE, Williams K, Ferrannini E et al. Identification of individuals with insulin resistance using routine clinical measurements. Diabetes 2005; 54: 333-339
• 36 Human Leptin RIA Kit, Cat. # HL-81K [Internet]. 2012 Jun [cited 2012 Oct 8]. Available from: http://www.sceti.co.jp/medical/PdfFiles/LINCO/Human_Leptin_RIA_kit250.pdf
• 37 Schöndorf T, Maiworm A, Emmison N et al. Biological background and role of adiponectin as marker for insulin resistance and cardiovascular risk. Clin Lab 2005; 51: 489-494
• 38 Hammar N, Farahmand B, Gran M et al. Incidence of urinary tract infection in patients with type 2 diabetes. Experience from adverse event reporting in clinical trials. Pharmacoepidemiol Drug Saf 2010; 19: 1287-1292 PubMed: 20967764. [Epub 2010 Oct 21]
• 39 Patterson JE, Andriole VT. Bacterial urinary tract infections in diabetes. Infect Dis Clin North Am 1997; 11: 735-750
• 40 Muller LM, Gorter KJ, Hak E et al. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis 2005; 41: 281-288 [Epub 2005 Jun 16]
• 41 Calvet HM, Yoshikawa TT. Infections in diabetes. Infect Dis Clin North Am 2001; 15: 407-421 viii
• 42 Delamaire M, Maugendre D, Moreno M et al. Impaired leucocyte functions in diabetic patients. Diabet Med 1997; 14: 29-34
• 43 Michishita R, Shono N, Inoue T et al. Effect of exercise therapy on monocyte and neutrophil counts in overweight women. Am J Med Sci 2010; 339: 152-156 PubMed PMID: 20145432
• 44 Schmidt MI, Duncan BB, Sharrett AR et al. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 1999; 353: 1649-1652
• 45 Chung FM, Tsai JC, Chang DM et al. Peripheral total and differential leukocyte count in diabetic nephropathy: the relationship of plasma leptin to leukocytosis. Diabetes Care 2005; 28: 1710-1717
• 46 Unal M, Erdem S, Deniz G. The effects of chronic aerobic and anaerobic exercises n lymphocyte subgroups. Acta Physiol Hung 2005; 92: 163-171
• 47 Woods JA, Ceddia MA, Wolters BW et al. Effects of 6 months of moderate aerobic exercise training on immune function in the elderly. Mech Ageing Dev 1999; 109: 1-19
• 48 Saygin O, Karacabey K, Ozmerdivenli R et al. Effect of chronic exercise on immunoglobin, complement and leukocyte types in volleyball players and athletes. Neuro Endocrinol Lett 2006; 27: 271-276
• 49 Albert MA, Glynn RJ, Ridker PM. Effect of physical activity on serum C-reactive protein. Am J Cardiol 2004; 93: 221-225
• 50 Wannamethee SG, Lowe GD, Whincup PH et al. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002; 105: 1785-1790
• 51 Tisi PV, Hulse M, Chulakadabba A et al. Exercise training for intermittent claudication: does it adversely affect biochemical markers of the exercise-induced inflammatory response?. Eur J Vasc Endovasc Surg 1997; 14: 344-350
• 52 Mackinnon LT. Chronic exercise training effects on immune function. Med Sci Sports Exerc 2000; 32 (7 Suppl) S369-S376
• 53 Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL et al. Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000; 49: 32-38
• 54 Nieman DC, Nehlsen-Cannarella SL, Henson DA et al. Immune response to exercise training and/or energy restriction in obese women. Med Sci Sports Exerc 1998; 30: 679-686
• 55 Shimizu K, Kimura F, Akimoto T et al. Effect of moderate exercise training on T-helper cell subpopulations in elderly people. Exerc Immunol Rev 2008; 14: 24-37
• 56 Gueldner SH, Poon LW, La Via M et al. Long-term exercise patterns and immune function in healthy older women. A report of preliminary findings. Mech Ageing Dev 1997; 93: 215-222
• 57 Faustman D, Eisenbarth G, Daley J et al. Abnormal T-lymphocyte subsets in type I diabetes. Diabetes 1989; 38: 1462-1468
• 58 Rodier M, Andary M, Richard JL et al. Peripheral blood T-cell subsets studied by monoclonal antibodies in type 1 (insulin-dependent) diabetes: effect of blood glucose control. Diabetologia 1984; 27 Suppl: 136-138
• 59 Keast D, Cameron K, Morton AR. Exercise and the immune response. Sports Med 1988; 5: 248-267
• 60 Yeh SH, Chuang H, Lin LW et al. Regular tai chi chuan exercise enhances functional mobility and CD4CD25 regulatory T cells. Br J Sports Med 2006; 40: 239-243
• 61 Fujinami A, Obayashi H, Ohta K et al. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin Chim Acta 2004; 339: 57-63
• 62 Lee JH, Chan JL, Yiannakouris N et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 2003; 88: 4848-4856
• 63 Gueugnon C, Mougin F, Simon-Rigaud ML et al. Effects of an in-patient treatment program based on regular exercise and a balanced diet on high molecular weight adiponectin, resistin levels, and insulin resistance in adolescents with severe obesity. Appl Physiol Nutr Metab 2012; 37: 672-679 PubMed PMID: 22574715. [Epub 2012 May 11]
• 64 Izadpanah A, Barnard RJ, Almeda AJ et al. A short-term diet and exercise intervention ameliorates inflammation and markers of metabolic health in overweight/obese children. Am J Physiol Endocrinol Metab 2012; 303: E542-E550 PubMed PMID: 22713506. [Epub 2012 Jun 19]
• 65 Al-Harithy RN, Al-Ghamdi S. Serum resistin, adiposity and insulin resistance in Saudi women with type 2 diabetes mellitus. Ann Saudi Med 2005; 25: 283-287
• 66 Silha JV, Krsek M, Skrha JV et al. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 2003; 149: 331-335
• 67 Yeh SH, Chuang H, Lin LW et al. Tai chi chuan exercise decreases A1C levels along with increase of regulatory T-cells and decrease of cytotoxic T-cell population in type 2 diabetic patients. Diabetes Care 2007; 30: 716-718
• 68 Zeng C, Shi X, Zhang B et al. The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: relationship with metabolic factors and complications. J Mol Med (Berl) 2012; 90: 175-186 PubMed PMID: 21964948. [Epub 2011 Oct 1]
• 69 Allan SE, Broady R, Gregori S et al. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev 2008; 223: 391-421 PubMed PMID: 18613849
• 70 Hardy MY, Vari F, Rossetti T et al. A flow cytometry based assay for the enumeration of regulatory T cells in whole blood. J Immunol Methods 2012;
• 71 Seddiki N, Santner-Nanan B, Martinson J et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006; 203: 1693-1700 [Epub 2006 Jul 3]
• 72 Van Baak MA. Beta-adrenoceptor blockade and exercise. An update. Sports Med 1988; 5: 209-225
• 73 Beloka S, Gujic M, Deboeck G et al. Beta-adrenergic blockade and metabo-chemoreflex contributions to exercise capacity. Med Sci Sports Exerc 2008; 40: 1932-1938 PubMed PMID: 18845967
• 74 Vanhees L, Defoor JG, Schepers D et al. Effect of bisoprolol and atenolol on endurance exercise capacity in healthy men. J Hypertens 2000; 18: 35-43
• 75 Dubach P, Myers J, Bonetti P et al. Effects of bisoprolol fumarate on left ventricular size, function, and exercise capacity in patients with heart failure: analysis with magnetic resonance myocardial tagging. Am Heart J 2002; 143: 676-683
• 76 Issa VS, Guimarães GV, Rezende MV et al. Effects of bisoprolol on cardiac function and exercise in patients with heart failure. Arq Bras Cardiol 2007; 88: 340-345
• 77 Malin SK, Stephens BR, Sharoff CG et al. Metformin’s effect on exercise and postexercise substrate oxidation. Int J Sport Nutr Exerc Metab 2010; 20: 63-71
• 78 Braun B, Eze P, Stephens BR et al. Impact of metformin on peak aerobic capacity. Appl Physiol Nutr Metab 2008; 33: 61-67 PubMed PMID: 18347654
• 79 Johnson ST, Robert C, Bell GJ et al. Acute effect of metformin on exercise capacity in active males. Diabetes Obes Metab 2008; 10: 747-754 [Epub 2007 Oct 26]
• 80 Wong AK, Symon R, AlZadjali MA et al. The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Heart Fail 2012; 14: 1303-1310 PubMed PMID: 22740509. [Epub 2012 Jun 27]
• 81 Adamska A, Nikołajuk A, Karczewska-Kupczewska M et al. Relationships between serum adiponectin and soluble TNF-α receptors and glucose and lipid oxidation in lean and obese subjects. Acta Diabetol 2012; 49: 17-24 PubMed PMID: 21234613, PubMed Central PMCID: 3266493. [Epub 2011 Jan 15]
• 82 Arita Y, Kihara S, Ouchi N et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83
• 83 MVZ Laborzentrum Ettlingen GmbH [Internet]. Ettlingen: Leistungsverzeichnis [updated 2012 Aug 20; cited 2012 Oct 4] Available from http://www.laborzentrum.org/l.htm#document_tags
• 84 Bisset LR, Lung TL, Kaelin M et al. Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland. Eur J Haematol 2004; 72: 203-212
• 85 Gabriel H, Schmitt B, Kindermann W. Age-related increase of CD45RO+lymphocytes in physically active adults. Eur J Immunol 1993; 23: 2704-2706
• 86 Romeu MA, Mestre M, González L et al. Lymphocyte immunophenotyping by flow cytometry in normal adults. Comparison of fresh whole blood lysis technique, Ficoll-Paque separation and cryopreservation. J Immunol Methods 1992; 154: 7-10