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      The effects of exercise on vascular endothelial function in type 2 diabetes: a systematic review and meta-analysis

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          Abstract

          Background

          Vascular endothelial dysfunction induced by hyperglycemia and elevated insulin resistance is a potent risk factor for cardiovascular disease and likely contributes to multiple chronic disease complications associated with aging. The aim of this study was to systematically review and quantify the effects of exercise on endothelial function (EF) in type 2 diabetes (T2D).

          Methods

          Five electronic databases were searched (until June 2017) for studies that met the following criteria: (i) randomized controlled trials; (ii) T2D aged ≥ 18 years; (iii) measured EF by brachial artery flow-mediated dilation (FMD); (iv) structured and supervised exercise intervention for ≥ 8 weeks.

          Results

          Thirteen cohorts, selected from eight studies (306 patients, average age 59 years), met the inclusion criteria. Exercise training significantly increased FMD (mean ES = 0.41, 95% CI 0.21–0.62, P < 0.001). Low to moderate intensity subgroups and aerobic exercise (AE) subgroups significantly increased FMD more than moderate to high intensity subgroups and combined AE and resistance exercise subgroups respectively ( P < 0.01, P < 0.05). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments reported that quality of evidence for all outcomes was moderate except shear rate showing low. Egger’s test showed no significant publication bias for all outcomes.

          Conclusion

          Our results suggest that in patients with T2D, lower intensity exercise has physiological meaningful effects on EF, in support of the emerging concept that the lower efforts of exercise are not necessarily less cardioprotective than higher intensity training.

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          Most cited references44

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          Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study.

          Marked reductions in cardiovascular disease (CVD) morbidity and mortality have occurred in the United States over the last 50 years. We tested the hypothesis that the relative burden of CVD attributable to diabetes mellitus (DM) has increased over the past 5 decades. Participants aged 45 to 64 years from the Framingham Heart Study, who attended examinations in an "early" time period (1952 to 1974), were compared with those who attended examinations in a later time period (1975 to 1998). The risk of CVD events (n=133 among those with and 1093 among those without DM) attributable to DM in the 2 time periods was assessed with Cox proportional hazards models; population attributable risk of DM as a CVD risk factor was calculated for each time period. The age- and sex-adjusted hazard ratio for DM as a CVD risk factor was 3.0 (95% CI, 2.3 to 3.9) in the earlier time period and 2.5 (95% CI, 1.9 to 3.2) in the later time period. The population attributable risk for DM as a CVD risk factor increased from 5.4% (95% CI, 3.8% to 6.9%) in the earlier time period to 8.7% (95% CI, 5.9% to 11.4%) in the later time period (P for attributable risk ratio=0.04), although multivariable adjustment resulted in attenuation of these findings (P=0.12); most of these observations were found among men. The proportion of CVD attributable to DM has increased over the past 50 years in Framingham. These findings emphasize the need for increased efforts to prevent DM and to aggressively treat and control CVD risk factors among those with DM.
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            Endothelial dysfunction in diabetes mellitus

            Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.
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              Shear stress mediates endothelial adaptations to exercise training in humans.

              Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate (P<0.005) and flow-mediated dilation percentage (P<0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 (P<0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb (P<0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans.
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                Author and article information

                Contributors
                junghoonlee000@gmail.com
                ldcheal@naver.com
                mhwang@inu.ac.kr
                mhamilt5@central.uh.edu
                713-743-9350 , ypark10@uh.edu
                Journal
                Diabetol Metab Syndr
                Diabetol Metab Syndr
                Diabetology & Metabolic Syndrome
                BioMed Central (London )
                1758-5996
                6 March 2018
                6 March 2018
                2018
                : 10
                : 15
                Affiliations
                [1 ]ISNI 0000 0004 0387 0116, GRID grid.411131.7, Laboratory of Human Physiology, , Korea National Sport University, ; Seoul, Republic of Korea
                [2 ]ISNI 0000 0004 0532 7395, GRID grid.412977.e, Exercise & Cardiovascular Physiology Laboratory, Division of Health and Exercise Science, , Incheon National University, ; Incheon, Republic of Korea
                [3 ]ISNI 0000 0004 0532 7395, GRID grid.412977.e, Sport Science Institute, , Incheon National University, ; Incheon, Republic of Korea
                [4 ]ISNI 0000 0004 1569 9707, GRID grid.266436.3, Texas Obesity Research Center from the Division of Research, and Department of Health and Human Performance, , University of Houston, ; Houston, TX USA
                [5 ]ISNI 0000 0004 1569 9707, GRID grid.266436.3, Laboratory of Integrated Physiology, Department of Health and Human Performance, , University of Houston, ; 3875 Holman St, Houston, TX 77204-6015 USA
                Article
                316
                10.1186/s13098-018-0316-7
                5840787
                29541164
                0114d601-2c3a-45e1-a046-901a6aaa1dbc
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 November 2017
                : 26 February 2018
                Funding
                Funded by: University of Houston (US) - DOR
                Award ID: Small Grant Program
                Award Recipient :
                Funded by: University of Houston (US)-CLASS
                Award ID: Research Progress Grant
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Nutrition & Dietetics
                type 2 diabetes,exercise training,endothelial function,flow mediated dilation,no bioavailability,sedentary,low intensity exercise

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