Sports Med 2004; 34 (6): 371-418

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371 1. The Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 2. Epidemiology of the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373 3. Metabolic Syndrome Phenotypes: Expert Panel Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376 4. Pathophysiology and Subclinical Metabolic Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 5. Physical Activity, Exercise and Metabolic Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 6. Overview: Exercise in the Treatment of the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 7. The Effects of Exercise Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 7.1 The Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 7.2 Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 7.3 Abdominal Adipose Tissue Accumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 7.4 Impaired Glucose Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 7.5 Atherogenic Dyslipidaemia: Systematic Review and Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . 390 7.6 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409 Prevention of the metabolic syndrome and treatment of its main characteristics Abstract are now considered of utmost importance in order to combat the epidemic of type 2 diabetes mellitus and to reduce the increased risk of cardiovascular disease and all-cause mortality. Insulin resistance/hyperinsulinaemia are consistently linked with a clustering of multiple clinical and subclinical metabolic risk factors. It is now widely recognised that obesity (especially abdominal fat accumulation), hyperglycaemia, dyslipidaemia and hypertension are common metabolic traits that, concurrently, constitute the distinctive insulin resistance or metabolic syndrome. Cross-sectional and prospective data provide an emerging picture of associations of both physical activity habits and cardiorespiratory fitness with the metabolic syndrome. The metabolic syndrome, is a disorder that requires aggressive multi-factorial intervention. Recent treatment guidelines have emphasised the clinical utility of diagnosis and an important treatment role for ‘therapeutic lifestyle change’, incorporating moderate physical activity. Several previous 372 Carroll & Dudfield narrative reviews have considered exercise training as an effective treatment for insulin resistance and other components of the syndrome. However, the evidence cited has been less consistent for exercise training effects on several metabolic syndrome variables, unless combined with appropriate dietary modifications to achieve weight loss. Recently published randomised controlled trial data concerning the effects of exercise training on separate metabolic syndrome traits are evaluated within this review. Novel systematic review and meta-analysis evidence is presented indicating that supervised, long-term, moderate to moderately vigorous intensity exercise training, in the absence of therapeutic weight loss, improves the dyslipidaemic profile by raising high density lipoprotein-cholesterol and lowering triglycerides in overweight and obese adults with characteristics of the metabolic syndrome. Lifestyle interventions, including exercise and dietary-induced weight loss may improve insulin resistance and glucose tolerance in obesity states and are highly effective in preventing or delaying the onset of type 2 diabetes in individuals with impaired glucose regulation. Randomised controlled trial evidence also indicates that exercise training decreases blood pressure in overweight/obese individuals with high normal blood pressure and hypertension. These evidence-based findings continue to support recommendations that supervised or partially supervised exercise training is an important initial adjunctive step in the treatment of individuals with the metabolic syndrome. Exercise training should be considered an essential part of ‘therapeutic lifestyle change’ and may concurrently improve insulin resistance and the entire cluster of metabolic risk factors. The purpose of this paper is to review the recentresistance,[13,14] now designated the metabolic synly published literature concerning the effects of indrome.[15-18] Epidemiological studies are evaluated creased physical activity and exercise on metabolic that provide an emerging picture of the prevalence abnormalities. Over the last decade, investigators and outcomes of metabolic risk factor clustering. have given increased attention to the complex role Cross-sectional and prospective associations of both of multiple metabolic abnormalities in the developphysical activity habits and cardiorespiratory fitness ment of related chronic diseases such as type 2 with the metabolic syndrome will be considered. diabetes mellitus and cardiovascular disease Recent working definitions of the metabolic or insu(CVD).[1-6] Insulin resistance is now recognised as lin resistance syndrome provided by several expert an early metabolic abnormality that precedes the groups[18-20] and therapeutic lifestyle implications development of type 2 diabetes.[7,8] Epidemiological will be outlined. The second aim is to review the evidence that insulin resistance and compensatory effects of exercise training on the major components hyperinsulinaemia are also risk factors for multiple of the metabolic syndrome, namely insulin resisrisk factor clustering, atherosclerosis and coronary tance, abdominal fat accumulation, hyperglycaemia, heart disease (CHD)[9-11] have added to the evolving dyslipidaemia and hypertension. Within contempoconcept of a distinct insulin-resistance syndrome. rary reviews,[21-25] exercise training has been considThis syndrome may represent the common soil for ered effective in the treatment of insulin resistance the development of both diabetes and CHD.[5,12] The and related components of the syndrome. However, first aim of this review is to summarise the recent the evidence for exercise effects has been considliterature on the clustering of lipid and non-lipid risk ered less consistent for dyslipidaemia, impaired glufactors of metabolic origin, closely linked to insulin cose regulation and hypertension, unless exercise  2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6) Exercise and Metabolic Abnormalities 373 training is combined with appropriate dietary modifat distribution as important in mediating metabolic fications to achieve weight loss.[24-28] Within this risk. Notably, Kaplan[43] described the clustering of review, interpretative emphasis will be given to the metabolic abnormalities associated with hyperinsuaccumulated evidence from randomised controlled linaemia as the ‘deadly quartet’, with reference to trials (RCTs) of exercise training on the major charthe combination of upper body fat accumulation, acteristics of the syndrome. This evidence-based hyperglycaemia, hypertriglyceridaemia and hyperapproach is consistent with recent scientific conventension. Over the years, metabolic clustering has tion.[29-31] Moreover, clinical trials that have examalso been given numerous labels, the most recent ined exercise training alone rather than those specifdesignations including the multiple metabolic synically combined with hypocalorific dietary changes drome,[44] metabolic syndrome X,[17,34] cardiowill be highlighted. vascular metabolic or cardiometabolic syndrome[45,46] and the dysmetabolic syndrome.[47] However, the terms, ‘insulin resistance’[20] or ‘meta1. The Metabolic Syndrome bolic syndrome’[18,19] are now most widely accepted Evidence for the clustering of CVD risk factors is for this clinical entity. For the purposes of this longstanding.[15,17] As early as 1923, Kylin dereview, the latter terminology will be adopted. scribed the constellation of hyperglycaemia, hyperuricaemia and hypertension (cited by 2. Epidemiology of the Groop[32]). Thereafter, the history of metabolic clusMetabolic Syndrome tering, including the contributions of Camus (1966), Albrink et al. (1980), Hanefeld, Leonhardt (1981), Since the mid-1980s, there had been considerable Modan et al. (1985) and Wingard et al. (1983), have interest in the epidemiology of the metabolic risk been variably described within several recent refactor clustering. Liese et al.[44] have comprehenviews.[13,17,32-35] The work of Pyorala et al. (1979), sively reviewed the analytical epidemiological studand Welborn and Wearne (1979) are acknowlies within this area. Several early population-based edged[17] as early publications relating hyperinsustudies provided evidence for the existence of an linaemia and glucose intolerance to CVD risk. The identifiable pathological syndrome, including those entity of a metabolic syndrome, however, did not showing associations of separate CVD risk factors receive much consideration until Reaven (1988) inwith incident development of type 2 diabetes.[48,49] troduced ‘Syndrome X’ in his Banting Lecture to the Other investigations demonstrated that hyperinsuAmerican Diabetes Association.[13] Syndrome X relinaemia and central adiposity preceded the develferred to a group of connected disorders characteropment of hypertension, dyslipidaemia and metaised by impaired glucose tolerance (IGT), dysbolic clusters.[50-53] Numerous analyses have been lipidaemia, hypertension, associated with increased subsequently published using statistical approaches risk of both type 2 diabetes and CVD.[13] Insulin (notably factor or principal component analysis) to resistance, located primarily in skeletal muscle and defining distinct metabolic clusters within diverse limited to non-oxidative glucose disposal was cited populations.[15,44,54-60] This multivariate correlation as the primary underlying mechanism for the synapproach has provided a method for empirically drome. The combination of insulin resistance and describing the clustering characteristics of related compensatory hyperinsulinaemia were considered metabolic variables and potentially underlying feanecessary for the development of other lipid and tures of the syndrome. As reviewed by Meigs[61] and non-lipid abnormalities.[13,36,37] Insulin resistance Liese et al.,[44] these investigations have indicated was also acknowledged as the central feature of this that the separate components of the syndrome may syndrome by De Fronzo and Ferrannini et al.[14,38,39] result from multiple underlying physiological proConcurrently, other researchers[40,41] (following the cesses, with a prominent role for insulin resisseminal publications of Vague[42]), recognised body tance.[15,61,62] The clustering of metabolic disorders  2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6) 374 Carroll & Dudfield has been increasingly evaluated within the framePublication of evidence from lipid-lowering clinwork of genetic epidemiology, including both famiical trial settings (West of Scotland Coronary Prely and twin studies.[63-68] vention Study[83] [WOSCOPS]) and preliminary data from the Scandinavian Simvastatin Survival Epidemiological investigations have documented Study (4S study)[98] and the Air Force/Texas Corothat the metabolic syndrome occurs commonly nary Atherosclerosis Prevention Study (AFCAPS/ among middle-aged and elderly individuals, with a TexCAPS)[98] also indicate that patients with metahigher prevalence in men and among older individubolic syndrome are 1.5 and 2 times more likely to als.[18,19] Table I and table II show the prevalence of have an acute CHD or CVD event than those withmultiple risk factors within numerous recent epideout the metabolic syndrome, respectively. Within miological studies among middle-aged and elderly the WOSCOPS study,[83] the metabolic syndrome adults.[69-90] Although comparisons between studies continued to predict CHD events significantly (hazare problematic due to differences in definitions and diagnostic criteria,[72] the tables clearly show the ard ratio 1.30) in a multivariate model incorporating frequent and widespread nature of metabolic risk conventional risk factors. Analysis of participants in factor clustering. The investigators of the European the control arms of the two other large clinical Group for the Study of Insulin Resistance[20] have trials[98] showed that patients categorised with the cited the frequency of a defined insulin resistance metabolic syndrome had increased risk of CVD syndrome to be between 7–36% for middle-aged events regardless of Framingham risk category males and between 5–22% for females of the same (Framingham CVD risk score >20 versus ≤20% age across eight population studies. Ferrannini et 10-year risk). These findings confirm that the metaal.[11] have estimated that only 30% of adults are free bolic syndrome is an important risk factor in the from at least one of the major defining risk characdevelopment of CHD/CVD events in both hyperteristics of the metabolic syndrome. Moreover, cholesterolaemic patients with CHD (4S study), within one random population survey, over 90% of among males with moderately raised cholesterol all hypertensive patients had at least one metabolic levels (WOSCOPS study), and adults with average risk factor in addition to hypertension itself.[76] Mulcholesterol levels (AFCAPS/TexCAPS study) both tiple metabolic clustering has been documented without evidence of CHD. These data support preacross a wide variety of ethnic groups with a high vious observations suggesting that metabolic synprevalence among Native and Mexican Americans drome confers additional risk not entirely accounted and Asian Indians, among other minority for by widely recommended traditional CHD scorgroups.[18,80,90] ing paradigms. It is now widely accepted that the metabolic The clinical importance of the metabolic synsyndrome has an important mediating role in the drome is due mainly to the increased risk imparted increased risk of CVD and type 2 diabetes.[15,18,19] by the concurrent clustering of several ‘indepenRecently, several investigations have shown that dent’ CVD risk factors within the same individuclusters of metabolic variables (including those al.[24] Some prospective studies[79,83] have reported identified by factor analysis) are associated with an increased risk of CHD associated with the metaincident development of diabetes,[55,91] CVD[92-97] bolic syndrome after adjusting for conventional risk and all-cause mortality.[71] Individuals exhibiting factors, but not above that explained by the individumetabolic clustering related to insulin resistance al effects of the defining variables.[79,83] Others have have been shown to have a 4to 11-fold increased indicated that there may be substantial additional relative risk for type 2 diabetes and a 2to 4-fold CVD risk above and beyond the individual risk increased risk of both CHD and CVD compared with individuals without this phenotype.[15] factors[88] (see section 4).  2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6) E xrcise nd M etbolic A borm aities 75  2004 A d is D a ta In fo rm a tio n BV . A ll rig h ts re se ve d . Sp o ts M e d 204; 34 6) Table I. Prevalence of metabolic clustering within middle-aged and older males within several recent population investigations Population n Age (y) Metabolic risk factors evaluated Participants with metabolic Reference clustering (%)