Advertisement

Effect of Aerobic and Resistant Exercise Intervention on Inflammaging of Type 2 Diabetes Mellitus in Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis

Published:February 17, 2022DOI:https://doi.org/10.1016/j.jamda.2022.01.055

      Abstract

      Objectives

      To examine the effect of aerobic and resistant exercise intervention on inflammaging in middle-aged and older adults with type 2 diabetes mellitus (T2DM) using inflammatory cytokines, such as interleukin (IL)-1 β, IL-6, tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) as biomarkers.

      Design

      Systematic review and meta-analysis.

      Setting and Participants

      Middle-aged and older adults with T2DM in the community.

      Methods

      Articles were searched from 8 electronic databases. Randomized control trials (RCTs) published in English, from inception to October 31, 2021, were included in this review. Two authors conducted data extraction and quality appraisal independently following guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was conducted using Review Manager. Heterogeneity was investigated using subgroup and sensitivity analysis.

      Results

      This review included 14 RCTs. The meta-analysis showed significant improvement in IL-6 [Z = 3.05; 95% confidence interval (CI): −3.60 to −0.79; P = .002], CRP (Z = 2.44; 95% CI: −0.55 to −0.06; P = .01) and TNF-α levels (Z = 2.96; 95% CI: −2.21 to −0.45; P = .003) post-exercise programs. Subgroup analysis revealed that combined aerobic and resistance exercises and long-term exercises have more significant improvement to the outcomes than usual care. Based on the Grades of Recommendation, Assessment, Development and Evaluation system, considerable risk of bias and low level of certainty were revealed in all biomarker outcomes.

      Conclusions and Implications

      Exercise intervention is effective in improving inflammatory, metabolic, and lipid markers in middle-aged and older adults with T2DM. By modifying the levels of these markers with exercise, inflammation and insulin resistance can be improved. Long-term, combined aerobic and resistance exercise interventions have more significant effect on biomarkers. The small sample size of this meta-analysis limited the generalizability of the results. Future studies can consider adopting a more optimized exercise regimen to achieve effective T2DM management in middle-aged and older adults. Similar studies should expand to other populations and larger sample sizes to explore replicability of these effects.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the American Medical Directors Association
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Zheng Y.
        • Ley S.H.
        • Hu F.B.
        Global aetiology and epidemiology of type 2 diabetes mellitus and its complications.
        Nat Rev Endocrinol. 2018; 14: 88
        • Seuring T.
        • Archangelidi O.
        • Suhrcke M.
        The economic costs of type 2 diabetes: a global systematic review.
        Pharmacoeconomics. 2015; 33: 811-831
        • Li H.
        • Duan D.
        • Xu J.
        • et al.
        Ambient air pollution and risk of type 2 diabetes in the Chinese.
        Environ Sci Pollut Res. 2019; 26: 16261-16273
        • Ozougwu J.
        • Obimba K.
        • Belonwu C.
        • et al.
        The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus.
        J Physiol Pathophysiol. 2013; 4: 46-57
        • Suastika K.
        • Dwipayana P.
        • Semadi M.S.
        • et al.
        Age is an important risk factor for type 2 diabetes mellitus and cardiovascular diseases.
        Glucose Tolerance: Intech Open. 2012; : 67-76
        • Sazlina S.-G.
        • Mastura I.
        • Cheong A.T.
        • et al.
        Predictors of poor glycaemic control in older patients with type 2 diabetes mellitus.
        Singapore Med J. 2015; 56: 284-290
        • Franceschi C.
        • Garagnani P.
        • Parini P.
        • et al.
        Inflammaging: a new immune–metabolic viewpoint for age-related diseases.
        Nat Rev Endocrinol. 2018; 14: 576-590
        • Furman D.
        • Campisi J.
        • Verdin E.
        • et al.
        Chronic inflammation in the etiology of disease across the life span.
        Nat Med. 2019; 25: 1822-1832
        • Kotas M.E.
        • Medzhitov R.
        Homeostasis, inflammation, and disease susceptibility.
        Cell. 2015; 160: 816-827
        • Barnig C.
        • Bezema T.
        • Calder P.C.
        • et al.
        Activation of resolution pathways to prevent and fight chronic inflammation: lessons from asthma and inflammatory bowel disease.
        Front Immunol. 2019; 10: 1699
        • Calder P.C.
        • Ahluwalia N.
        • Albers R.
        • et al.
        A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies.
        Br J Nutr. 2013; 109: S1-S34
        • Del Giudice M.
        • Gangestad S.W.
        Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters.
        Brain Behav Immun. 2018; 70: 61-75
        • Gulati K.
        • Guhathakurta S.
        • Joshi J.
        • et al.
        Cytokines and their role in health and disease: a brief overview.
        MOJ Immunology. 2016; 4: 001221
        • Netea M.G.
        • Balkwill F.
        • Chonchol M.
        • et al.
        A guiding map for inflammation.
        Nat Immunol. 2017; 18: 826-831
        • Minihane A.M.
        • Vinoy S.
        • Russell W.R.
        • et al.
        Low-grade inflammation, diet composition and health: current research evidence and its translation.
        Br J Nutr. 2015; 114: 999-1012
        • Lainampetch J.
        • Panprathip P.
        • Phosat C.
        • et al.
        Association of tumor necrosis factor alpha, interleukin 6, and C-reactive protein with the risk of developing type 2 diabetes: a retrospective cohort study of rural Thais.
        J Diabet Res. 2019; 2019: 9051929
        • Phosat C.
        • Panprathip P.
        • Chumpathat N.
        • et al.
        Elevated C-reactive protein, interleukin 6, tumor necrosis factor alpha and glycemic load associated with type 2 diabetes mellitus in rural Thais: a cross-sectional study.
        BMC Endocrine Disord. 2017; 17: 44
        • Oguntibeju O.O.
        Type 2 diabetes mellitus, oxidative stress and inflammation: examining the links.
        Int J Physiol Pathophysiol Pharmacol. 2019; 11: 45-63
        • American Diabetes Association
        Standards of medical care in diabetes--2010.
        Diabetes Care. 2010; 33: S11-S61
        • Borai A.
        • Livingstone C.
        • Abdelaal F.
        • et al.
        The relationship between glycosylated haemoglobin (HbA1c) and measures of insulin resistance across a range of glucose tolerance.
        Scand J Clin Lab Invest. 2011; 71: 168-172
        • Khan M.A.B.
        • Hashim M.J.
        • King J.K.
        • et al.
        Epidemiology of type 2 diabetes - global burden of disease and forecasted trends.
        J Epidemiol Glob Health. 2020; 10: 107-111
        • Tsalamandris S.
        • Antonopoulos A.S.
        • Oikonomou E.
        • et al.
        The role of inflammation in diabetes: current concepts and future perspectives.
        Eur Cardiol. 2019; 14: 50-59
        • Kirwan J.P.
        • Sacks J.
        • Nieuwoudt S.
        The essential role of exercise in the management of type 2 diabetes.
        Cleve Clin J Med. 2017; 84: S15-S21
        • Karstoft K.
        • Pedersen B.K.
        Exercise and type 2 diabetes: focus on metabolism and inflammation.
        Immunol Cell Biol. 2016; 94: 146-150
        • Forouhi N.G.
        • Wareham N.J.
        Epidemiology of diabetes.
        Medicine (Abingdon). 2014; 42: 698-702
        • Cheng L.J.
        • Wang W.
        • Lim S.T.
        • et al.
        Factors associated with glycaemic control in patients with diabetes mellitus: a systematic literature review.
        J Clin Nurs. 2019; 28: 1433-1450
        • Thent Z.C.
        • Das S.
        • Henry L.J.
        Role of exercise in the management of diabetes mellitus: the global scenario.
        PLoS One. 2013; 8: e80436
        • Rada I.
        • Deldicque L.
        • Francaux M.
        • et al.
        Toll like receptor expression induced by exercise in obesity and metabolic syndrome: a systematic review.
        Exerc Immunol Rev. 2018; 24: 60-71
        • Beavers K.M.
        • Brinkley T.E.
        • Nicklas B.J.
        Effect of exercise training on chronic inflammation.
        Clin Chim Acta. 2010; 411: 785-793
        • Gómez-Rubio P.
        • Trapero I.
        The effects of exercise on IL-6 levels and cognitive performance in patients with schizophrenia.
        Diseases. 2019; 7: 11
        • Hammonds T.L.
        • Gathright E.C.
        • Goldstein C.M.
        • et al.
        Effects of exercise on C-reactive protein in healthy patients and in patients with heart disease: a meta-analysis.
        Heart Lung. 2016; 45: 273-282
        • Lapid K.
        • Graff J.M.
        Form(ul)ation of adipocytes by lipids.
        Adipocyte. 2017; 6: 176-186
        • Mann S.
        • Beedie C.
        • Jimenez A.
        Differential effects of aerobic exercise, resistance training and combined exercise modalities on cholesterol and the lipid profile: review, synthesis and recommendations.
        Sports Med. 2014; 44: 211-221
        • Wu Y.
        • Ding Y.
        • Tanaka Y.
        • et al.
        Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention.
        Int J Med Sci. 2014; 11: 1185
        • Zheng G.
        • Qiu P.
        • Xia R.
        • et al.
        Effect of aerobic exercise on inflammatory markers in healthy middle-aged and older adults: a systematic review and meta-analysis of randomized controlled trials.
        Front Aging Neurosci. 2019; 11: 98
        • Meneses-Echávez J.F.
        • Correa-Bautista J.E.
        • González-Jiménez E.
        • et al.
        The effect of exercise training on mediators of inflammation in breast cancer survivors: a systematic review with meta-analysis.
        Cancer Epidemiol Biomarkers Prev. 2016; 25: 1009-1017
        • Neefkes-Zonneveld C.R.
        • Bakkum A.J.
        • Bishop N.C.
        • et al.
        Effect of long-term physical activity and acute exercise on markers of systemic inflammation in persons with chronic spinal cord injury: a systematic review.
        Arch Phys Med Rehabil. 2015; 96: 30-42
        • Melo L.C.
        • Dativo-Medeiros J.
        • Menezes-Silva C.E.
        • et al.
        Physical exercise on inflammatory markers in type 2 diabetes patients: a systematic review of randomized controlled trials.
        Oxid Med Cell Longev. 2017; 2017: 8523728
        • Hayashino Y.
        • Jackson J.L.
        • Hirata T.
        • et al.
        Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.
        Metabolism. 2014; 63: 431-440
        • Shamseer L.
        • Moher D.
        • Clarke M.
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation.
        BMJ. 2015; 349: g7647
        • Cooper C.
        • Booth A.
        • Varley-Campbell J.
        • et al.
        Defining the process to literature searching in systematic reviews: a literature review of guidance and supporting studies.
        BMC Med Res Methodol. 2018; 18: 85
        • Tufanaru C.
        • Munn Z.
        • Aromataris E.
        • et al.
        Chapter 3: Systematic Reviews of effectiveness.
        in: Aromataris E. Munn Z. JBI Manual for Evidence Synthesis. The Joanna Briggs Institute, 2020: 71-87 (Available from)
        • Higgins J.P.
        • Altman D.G.
        • Gøtzsche P.C.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Higgins J.P.
        • Thomas J.
        • Chandler J.
        • et al.
        Cochrane handbook for systematic reviews of interventions.
        John Wiley & Sons, 2019
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Softw. 2010; 36: 1-48
        • Abd El-Kader S.M.
        • Al-Jiffri O.H.
        • Al-Shreef F.M.
        Aerobic exercises alleviate symptoms of fatigue related to inflammatory cytokines in obese patients with type 2 diabetes.
        Afr Health Sci. 2015; 15: 1142-1148
        • Annibalini G.
        • Lucertini F.
        • Agostini D.
        • et al.
        Concurrent aerobic and resistance training has anti-inflammatory effects and increases both plasma and leukocyte levels of IGF-1 in late middle-aged type 2 diabetic patients.
        Oxid Med Cell Longev. 2017; 2017: 3937842
        • Balducci S.
        • Zanuso S.
        • Nicolucci A.
        • et al.
        Anti-inflammatory effect of exercise training in subjects with type 2 diabetes and the metabolic syndrome is dependent on exercise modalities and independent of weight loss.
        Nutr Metab Cardiovasc Dis. 2010; 20: 608-617
        • Balducci S.
        • Zanuso S.
        • Cardelli P.
        • et al.
        Supervised exercise training counterbalances the adverse effects of insulin therapy in overweight/obese subjects with type 2 diabetes.
        Diabetes Care. 2012; 35: 39-41
        • Brooks N.
        • Layne J.E.
        • Gordon P.L.
        • et al.
        Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes.
        Int J Med Sci. 2006; 4: 19-27
        • Gordon P.L.
        • Vannier E.
        • Hamada K.
        • et al.
        Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes.
        Int J Immunopathol Pharmacol. 2006; 19: 739-749
        • Choi K.M.
        • Han K.A.
        • Ahn H.J.
        • et al.
        Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial.
        J Clin Endocrinol Metab. 2012; 97: 3751-3758
        • Dadrass A.
        • Mohamadzadeh Salamat K.
        • Hamidi K.
        • et al.
        Anti-inflammatory effects of vitamin D and resistance training in men with type 2 diabetes mellitus and vitamin D deficiency: a randomized, double-blinded, placebo-controlled clinical trial.
        J Diabetes Metab Disord. 2019; 18: 323-331
        • Hsieh P.-L.
        • Tseng C.-H.
        • Tseng Y.J.
        • et al.
        Resistance training improves muscle function and cardiometabolic risks but not quality of life in older people with type 2 diabetes mellitus: a randomized controlled trial.
        J Geriatr Phys Ther. 2018; 41: 65-76
        • Jorge M.L.
        • de Oliveira V.N.
        • Resende N.M.
        • et al.
        The effects of aerobic, resistance, and combined exercise on metabolic control, inflammatory markers, adipocytokines, and muscle insulin signaling in patients with type 2 diabetes mellitus.
        Metabolism. 2011; 60: 1244-1252
        • Oberbach A.
        • Lehmann S.
        • Kirsch K.
        • et al.
        Long-term exercise training decreases interleukin-6 (IL-6) serum levels in subjects with impaired glucose tolerance: effect of the -174G/C variant in IL-6 gene.
        Eur J Endocrinol. 2008; 159: 129-136
        • Ranasinghe C.
        • Devage S.
        • Constantine G.R.
        • et al.
        Glycemic and cardiometabolic effects of exercise in South Asian Sri Lankans with type 2 diabetes mellitus: A randomized controlled trial Sri Lanka diabetes aerobic and resistance training study (SL-DARTS).
        Diabetes Metab Syndr. 2021; 15: 77-85
        • Sabouri M.
        • Hatami E.
        • Pournemati P.
        • et al.
        Inflammatory, antioxidant and glycemic status to different mode of high-intensity training in type 2 diabetes mellitus.
        Mol Biol Rep. 2021; 48: 5291-5304
        • Magalhães J.P.
        • Santos D.A.
        • Correia I.R.
        • et al.
        Impact of combined training with different exercise intensities on inflammatory and lipid markers in type 2 diabetes: a secondary analysis from a 1-year randomized controlled trial.
        Cardiovasc Diabetol. 2020; 19: 169
        • McHugh M.L.
        Interrater reliability: the kappa statistic.
        Biochem Med (Zagreb). 2012; 22: 276-282
        • Pedersen B.K.
        Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease.
        Eur J Clin Invest. 2017; 47: 600-611
        • Mirza S.
        • Hossain M.
        • Mathews C.
        • et al.
        Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study.
        Cytokine. 2012; 57: 136-142
        • Rodrigues K.F.
        • Pietrani N.T.
        • Bosco A.A.
        • et al.
        IL-6, TNF-α, and IL-10 levels/polymorphisms and their association with type 2 diabetes mellitus and obesity in Brazilian individuals.
        Arch Endocrinol Metab. 2017; 61: 438-446
      1. DIAsource ImmunoAssays SA. IL-6, ELISA, 96 TESTS, 2021. https://www.diasource-diagnostics.com/IVD-Products/ImmunoAssays/Immunology-Markers/Interleukine-6-IL-6/IL-6-ELISA-96-tests. Accessed December 4, 2021.

        • Huang Y.-C.
        • Chen C.-C.
        • Wang T.-Y.
        • et al.
        C-reactive protein gene variants and their serum levels in early adult-onset type 2 diabetes mellitus.
        In Vivo. 2019; 33: 1685-1690
        • Kuczmarski M.F.
        • Mason M.A.
        • Allegro D.
        • et al.
        Diet quality is inversely associated with C-reactive protein levels in urban, low-income African-American and white adults.
        J Acad Nutr Diet. 2013; 113: 1620-1631
        • Liu X.
        • Men P.
        • Wang B.
        • et al.
        Effect of dipeptidyl-peptidase-4 inhibitors on C-reactive protein in patients with type 2 diabetes: a systematic review and meta-analysis.
        Lipids Health Dis. 2019; 18: 144
        • Cerqueira É.
        • Marinho D.A.
        • Neiva H.P.
        • et al.
        Inflammatory effects of high and moderate intensity exercise—a systematic review.
        Front Physiol. 2020; 10: 1550
        • Townsend J.R.
        • Hoffman J.R.
        • Fragala M.S.
        • et al.
        TNF-α and TNFR1 responses to recovery therapies following acute resistance exercise.
        Front Physiol. 2015; 6: 48
        • Macêdo Santiago L.Â.
        • Neto L.G.L.
        • Borges Pereira G.
        • et al.
        Effects of resistance training on immunoinflammatory response, TNF-alpha gene expression, and body composition in elderly women.
        J Aging Res. 2018; 2018: 1467025
        • Bernecker C.
        • Scherr J.
        • Schinner S.
        • et al.
        Evidence for an exercise induced increase of TNF-α and IL-6 in marathon runners.
        Scand J Med Sci Sports. 2013; 23: 207-214
        • Paulsen G.
        • Mikkelsen U.R.
        • Raastad T.
        • et al.
        Leucocytes, cytokines and satellite cells: what role do they play in muscle damage and regeneration following eccentric exercise?.
        Exerc Immunol Rev. 2012; 18: 42-97
        • Yang Z.
        • Scott C.A.
        • Mao C.
        • et al.
        Resistance exercise versus aerobic exercise for type 2 diabetes: a systematic review and meta-analysis.
        Sports Med. 2014; 44: 487-499
        • Baumert P.
        • Lake M.J.
        • Stewart C.E.
        • et al.
        Genetic variation and exercise-induced muscle damage: implications for athletic performance, injury and ageing.
        Eur J Appl Physiol. 2016; 116: 1595-1625
        • Pan B.
        • Ge L.
        • Xun Y.-Q.
        • et al.
        Exercise training modalities in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis.
        Int J Behav Nutr Phys Act. 2018; 15: 72
        • Liu Y.
        • Ye W.
        • Chen Q.
        • et al.
        Resistance exercise intensity is correlated with attenuation of HbA1c and insulin in patients with type 2 diabetes: a systematic review and meta-analysis.
        Int J Environ Res Public Health. 2019; 16: 140
        • Colberg S.R.
        • Sigal R.J.
        • Fernhall B.
        • et al.
        Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement.
        Diabetes Care. 2010; 33: e147-e167
        • Fleg J.L.
        Aerobic exercise in the elderly: a key to successful aging.
        Discov Med. 2012; 13: 223-228
        • Shaw B.S.
        • Shaw I.
        • Brown G.A.
        Resistance exercise is medicine: strength training in health promotion and rehabilitation.
        Int J Ther Rehabil. 2015; 22: 385-389
        • Lima L.G.
        • Bonardi J.T.M.
        • Campos G.O.
        • et al.
        Combined aerobic and resistance training: are there additional benefits for older hypertensive adults?.
        Clinics (Sao Paulo). 2017; 72: 363-369
        • Metsios G.S.
        • Moe R.H.
        • Kitas G.D.
        Exercise and inflammation.
        Best Pract Res Clin Rheumatol. 2020; 34: 101504