What is the Relationship Between Exercise and Metabolic Abnormalities?

48 Pages·2004·0.4 MB·English

REVIEW ARTICLE Sports Med 2004; 34 (6): 371-418
0112-1642/04/0006-0371/$31.00/0
 2004 Adis Data Information BV. All rights reserved.
What is the Relationship Between
Exercise and
Metabolic Abnormalities?
A Review of the Metabolic Syndrome
Sean Carroll1 and Mike Dudfield2
1 School of Leisure and Sports Studies, Beckett Park Campus, Leeds Metropolitan University,
Leeds, UK
2 Leeds Sports Development Unit, Leeds Leisure Services, Leeds, UK
Contents
Abstract....................................................................................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
Abstract Prevention of the metabolic syndrome and treatment of its main characteristics
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 syn-
drome. 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 aggres-
sive 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 indicat-
ing 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 recent- resistance,[13,14] now designated the metabolic syn-
ly published literature concerning the effects of in- drome.[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 develop- physical 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 resis-
risk factor clustering, atherosclerosis and coronary tance, abdominal fat accumulation, hyperglycaemia,
heart disease (CHD)[9-11] have added to the evolving dyslipidaemia and hypertension. Within contempo-
concept of a distinct insulin-resistance syndrome. rary reviews,[21-25] exercise training has been consid-
This 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 consid-
literature on the clustering of lipid and non-lipid risk ered less consistent for dyslipidaemia, impaired glu-
factors 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 modi- fat 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 hyperinsu-
accumulated evidence from randomised controlled linaemia as the ‘deadly quartet’, with reference to
trials (RCTs) of exercise training on the major char- the combination of upper body fat accumulation,
acteristics of the syndrome. This evidence-based hyperglycaemia, hypertriglyceridaemia and hyper-
approach is consistent with recent scientific conven- tension. Over the years, metabolic clustering has
tion.[29-31] Moreover, clinical trials that have exam- also been given numerous labels, the most recent
ined exercise training alone rather than those specif- designations including the multiple metabolic syn-
ically combined with hypocalorific dietary changes drome,[44] metabolic syndrome X,[17,34] cardio-
will be highlighted. vascular metabolic or cardiometabolic syn-
drome[45,46] and the dysmetabolic syndrome.[47]
1. The Metabolic Syndrome However, the terms, ‘insulin resistance’[20] or ‘meta-
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 de- review, 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 clus- Metabolic 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 re- factor clustering. Liese et al.[44] have comprehen-
views.[13,17,32-35] The work of Pyorala et al. (1979), sively reviewed the analytical epidemiological stud-
and Welborn and Wearne (1979) are acknowl- ies within this area. Several early population-based
edged[17] as early publications relating hyperinsu- studies 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) in- with incident development of type 2 diabetes.[48,49]
troduced ‘Syndrome X’ in his Banting Lecture to the Other investigations demonstrated that hyperinsu-
American Diabetes Association.[13] Syndrome X re- linaemia and central adiposity preceded the devel-
ferred to a group of connected disorders character- opment of hypertension, dyslipidaemia and meta-
ised by impaired glucose tolerance (IGT), dys- bolic 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 syn- approach 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 fea-
necessary 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 pro-
Concurrently, other researchers[40,41] (following the cesses, with a prominent role for insulin resis-
seminal 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 frame- Publication of evidence from lipid-lowering clin-
work of genetic epidemiology, including both fami- ical trial settings (West of Scotland Coronary Pre-
ly and twin studies.[63-68] vention Study[83] [WOSCOPS]) and preliminary
data from the Scandinavian Simvastatin Survival
Epidemiological investigations have documented
that the metabolic syndrome occurs commonly Study (4S study)[98] and the Air Force/Texas Coro-
among middle-aged and elderly individuals, with a nary Atherosclerosis Prevention Study (AFCAPS/
higher prevalence in men and among older individu- TexCAPS)[98] also indicate that patients with meta-
als.[18,19] Table I and table II show the prevalence of bolic syndrome are 1.5 and 2 times more likely to
multiple risk factors within numerous recent epide- have an acute CHD or CVD event than those with-
miological studies among middle-aged and elderly out the metabolic syndrome, respectively. Within
adults.[69-90] Although comparisons between studies the WOSCOPS study,[83] the metabolic syndrome
are problematic due to differences in definitions and continued to predict CHD events significantly (haz-
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 meta-
al.[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 charac-
development of CHD/CVD events in both hyper-
teristics 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] Mul-
cholesterol levels (AFCAPS/TexCAPS study) both
tiple metabolic clustering has been documented
without evidence of CHD. These data support pre-
across a wide variety of ethnic groups with a high
vious observations suggesting that metabolic syn-
prevalence among Native and Mexican Americans
drome confers additional risk not entirely accounted
and Asian Indians, among other minority
for by widely recommended traditional CHD scor-
groups.[18,80,90]
ing paradigms.
It is now widely accepted that the metabolic
The clinical importance of the metabolic syn-
syndrome 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 ‘indepen-
Recently, several investigations have shown that
dent’ CVD risk factors within the same individu-
clusters of metabolic variables (including those
al.[24] Some prospective studies[79,83] have reported
identified by factor analysis) are associated with
incident development of diabetes,[55,91] CVD[92-97] an increased risk of CHD associated with the meta-
and all-cause mortality.[71] Individuals exhibiting bolic syndrome after adjusting for conventional risk
metabolic clustering related to insulin resistance factors, but not above that explained by the individu-
have been shown to have a 4- to 11-fold increased al effects of the defining variables.[79,83] Others have
relative risk for type 2 diabetes and a 2- to 4-fold indicated that there may be substantial additional
increased risk of both CHD and CVD compared CVD risk above and beyond the individual risk
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
2004 TPaobpluela It.i oPnrevalence of metabolic clustering within middle-anged and oldAegr em (ayl)es withinM seetvaebroalilc r ericsekn fta pcotoprusl aetvioanlu iantveedstigations Participants with metabolic Reference xerc
A is
d clustering (%) e
is D >2 ≥3 an
a d
ta Informa WKFiunhpliatpenihoda Ilsl cIIh aSetumdiyc, HLeoanrdt oDni,s UeaKse Risk Factor Study, 24297728 4329––6603 IIGGTT,, FSIB, PH,T HND, LH-DCL, -TCG, ,T WGHR 2N8R.6 175..48 6593 Metabo
tion B Naples, Italy 1252 35–64 IFG, HTN, DBP 28.6 7.0 70 lic A
V Risk factors & Life Expectancy Project, 9 studies, Italy 25561 20–69 IFG, HTN, HDL-C, TG 42.1 15.1 71 b
. All rig Framingham Offspring Study, Framingham, USA 2406 18–74 IFG, SBP, TC, HDL-C, TG, BMI 37.0 18.0 54 norm
hts rese GBoottnhiean, bSewrge,d Senw/eFdinelannd 391 5385–70 WWHHOO ddeeffiinniittiioonn::[[1188]] iinncc.. HIFOGM, FAI IR N65R.0 1155..08 7734 alities
rv NHANES III 1988–1994, multicentre, USA 1398 42–55 T2D, IFG/IGT, HTN, TC, HDL-C, TG 40.6 17.9 75
e
d
. Oulu, Finland WHO definition:[18] inc. FI (without obesity) 76
259 50.9 ± 6.1 Control 13.5 14.7
261 50.5 ± 5.9 Hypertensive on medication 26.8 28.7
Dallas, Texas, USA 15534 20–88 IFG, SBP, WC, TG 14.9 5.6 77
British Regional Heart Study. 18 selected British towns 5222 40–59 IFG, HTN, TC, HDL-C, TG 46.8 10.2 78
Hypertensive
Caerphilly and Speedwell studies, UK 4197 45–63 FI, FG, TG, BMI, DBP NR 20.0 > 4 79
metabolic risk
factors
EGIR multicentre, 8 participating European studies 1384 <40 EGIR definition[20] 13.0 20
3250 40–55 20.0
2996 >55 33.0
NHANES III 1988–1994, multicentre, USA 8814 >20 NCEP ATP III definition[19] 44.9 24.0 80
Kuppio Ischaemic Heart Disease Risk Factor Study, 1209 42–60 NCEP ATP III definition:[19] 81
Finland
with WC >102.0cm 8.8
with WC >94.0cm 14.0
WHO definition/EGIR[19] inc. FI and IFG 14.2
with WC >94.0cm 13.4
NHANES III 1988–1994, multicentre, USA 2857 40–74 Age-adjusted WHO definition:[18] inc. 27.6 82
Spo adults OGTT and fasting HOMA
rts M Age-adjusted NCEP ATP III definition[19] 25.1
e
d
2
0
04 Continued next page
; 3
4 (6) 375
376 Carroll & Dudfield
C=S2
nAge (y)Metabolic risk factors evaluatedParticipants with metabolicReferenceclustering (%)≥>23±[19]644755.2 5.5Adapted NCEP ATP III definition: inc.57.026.283BMI [19]A150330–79NCEP ATP III definition26.984 [18]470WHO definition: inc. FI30.3 [19]NCEP ATP III definition24.7 [18]WHO definition: inc. FI24.7 [18]45040–79WHO definition: inc. HOMA IR32.985 [19]NCEP ATP III definition16.5 ssure; EGIR = European Group for the study of Insulin Resistance; FG = fasting glucose; FI = fasting hyperinsulinaemia; HDL-Homeostasis Model Assessment, Fasting Insulin Resistance Index; HTN = hypertension; IFG = impaired fasting glucose; IGT R = not reported; NCEP ATP III = National Cholesterol Education Programme, Adult Treatment Panel III; NHANES III = Third UOGTT = oral glucose tolerance test; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; T2D = type O = World Health Organization; WHR = waist-to-hip circumference ratio. dbovbTfhbapiieCtHm(ToseSedsbnthoNihsanteeuioyoanrosthhamehddeec ouconerceslpdllCceuia3EWW tnuieiiyihmdne.lswciey ostcvclc fxdEilm.ts syie term ,c aSh naiweneciib hs gp PdMd ctt rsiees sosey (ey lhhhol nouoitgi)Ote itoit vyncxnsh aoiiei,taeNkad uamucm nnthstehcsripdnratbnbeeulrAlistaetegaur aaa tdrr pidla lo reteapslma rbtevoeaelyrPtasdb foei lonetldhoabdmnsui em.o ita uualoen ni[gtwcce uepii itd8edntn olntItencizit d eeni4 tlutahxa uaeaoiaesorint] taeln iastb alefsg pulaceif,lerTnchnttsatyc neso Hi,cioirdisr elhaC)l [ni.storitonidireoc 8 l,ntir ttseetaantmiG4 Sioohndiewuet ybie.t acn,rdn Ic 8iWmy ndot rm reeiIt Npou(i5lyhstisoittmt-o)ltse nWh]nauh,aynerseeh ubi,rmHei yccodaa ndelnlet ,es lilaivttuoii y HitneebnadstOeh ehntpenpst reeemn axitl ys dleteoeeitiO hsriytr slhdns ,tpd(nr aind aittoe eh[mP icnfeemehpi a)1eaaantc6g sinlfnnel s7si anesdrrlse ectdde6a f-tdeop giEe.otent l2cmeeyo[rsse –usstweei80te nNpeede pndtas rffyyt9]8spdcnaPitl nodf/ioiube]at aspCn 2hf niiinehiohtsil nco,ad(e ifsihid nr%yli csanEicAnacyaelsiel tecenaeriegpvlgiaaidna t liPgmoony cvomTgn i on etsendlidtonan mt ci enla hr PfgAotii ois pyntnisrsio o fba rccayhh f)enincihtn iidaen Tg elerit tmhdcynePy os oce cao i eIntngPtoa( eetudpCprniIaresgthvnisettoncrfotrIh illrieannrcyieIe-eHro aea ias sotgacertbIiduitnt cnrr burehtna ImllasrrDtoflirar eyw/ddW drlpeah eedal:orimmugeeans e ri t me ebiriwpwf rmecohseps voIitne edlefeihyrshipinItmmoersveiritttiaiotiihI oanditasaleltekswiaari)lnhndyheeeacss------r---/..,.
Table I. Contd Population West of Scotland Prevention Study, Scotland, UK(moderately hypercholesterolaemic men) Framingham Offspring Study, Massachusetts, US San Antonio Heart Study, Texas, USA Bruneck, Italy BMI = body mass index; DBP = diastolic blood pre= high density lipoprotein-cholesterol; HOMA IR = impaired glucose tolerance; inc. = incorporating; NNational Health & Nutrition Examination Survey; diabetes mellitus; WC = waist circumference; WH usadsliaiwcCdonnaissraergHiiwssmssolfttnuusooihemDen pillccr sfiiiwil etiinnittaehaar.ci i[i)dttoeqa8tss,iir 4h n onoukee]ami .ntna snn rllvprssseyWeott eoir t iwtwawmalrniaHesvbv sese uoeOoieisrortsrnneo leyfe is o acct. anui hgiuni nnnaolToessdidststy nnsh euau eng euddblNl irsdlis ilnwuaneCsy,rw lcpno ilsEriotsioysmneehttPiss hsndrtoeeiw ioi situv sdvinir(etotitteiiabg toiasdnyfvtnyekklihu eitrn e te ai rusyiarnoua ltes -nsmidfnsivtao dnihecdecnenb gxaerjhtagsen ,uaa ta iflb t swntr beritthoangedhesueeclqct diotir stfr cuie sWef.ena t eeerhas cai nTrHyssetuelftehhesnsolnOtoddyeeee-rt
 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6)
 E
2004 A TPaobpluela ItIi.o Pnrevalence of metabolic clustering within middle-anged and oldAegre f e(ym)ales witMhine tasebvoelicra rl isrekc feanctt oprosp euvlaatliuoant eindvestigations Participants with metabolic Reference xercis
dis Da c>l2ustering (%) ≥3 e and
ta Inform Amtuhletircoesnctlreer,o UsiSs ARisk in Communities Study, 5237 53.3 ± 5.6 IFG, HTN, HDL-C, TG 11.9 1.6 52 Metab
a Rancho Bernado, South California, USA 303 50–84 IFG/IGT, T2D, HTN, HDL-C, TG 7.9 86 o
tion B Risk Factors and Life Expectancy Project, multicentre, 18495 20–69 IFG, HTN, HDL-C, TG 37.2 15.3 71 lic A
V. All rig IFtaralymingham Offspring Study, Framingham, USA 2569 18–74 IFG, SBP, TC, HDL-C, TG, BMI 38.0 19.0 54 bnorm
hts reserv NDHalAlaNs,E TSe IxIIa, sm, UulSticAentre, USA 13681918 5240.–18 8± 19.8 IIFFGG/, IGSBT,P T, 2WDC, ,H TTGN, TC, HDL-C, TG, FI 336..54 105..68 7566 alities
e
d. Botnia, Sweden/Finland 1133 35–70 WHO definition:[18] inc. HOMA IR 10.0 74
Oulu, Finland WHO definition:[18] inc. FI (without obesity) 77
267 51.8 ± 6.0 Control 5.6 5.2
258 51.8 ± 5.9 Hypertensive on medication 16.7 26.4
EGIR, multicentre, 8 participating European studies 1412 <40 EGIR definition[20] 3.0 20
3773 40–55 7.0
3772 >55 17.0
NHANES III 1988–1994, multicentre, USA 1887 >20 NCEP ATP III definition[19] 40.7 22.8 80
NHANES III 1988–1994, multicentre, USA 2857 40–74 Age-adjusted WHO definition:[18] inc. 32.1 82
adults OGTT and fasting HOMA
Age-adjusted NCEP ATP III definition[19] 32.9
Framingham Offspring Study, Massachusetts, USA 1721 30–79 NCEP ATP III definition[19] 21.4 84
San Antonio Heart Study, Texas, USA 611 WHO definition:[18] inc. FI 19.7
NCEP ATP III definition[19] 21.3
WHO definition:[18] inc. FI 17.2
Bruneck, Italy 450 40–79 WHO definition:[18] inc. HOMA IR 35.9 85
NCEP ATP III definition[19] 19.1
Spo Women’s Health Study 14719 NCEP ATP III definition[19] 45.7 24.4 87
rts M BMI = body mass index; EGIR = European Group for the study of Insulin Resistance; FI = fasting hyperinsulinaemia; HDL-C = high density lipoprotein-cholesterol; HOMA IR =
e
d Homeostasis Model Assessment, Fasting Insulin Resistance Index; HTN = hypertension; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; inc. = incorporating;
2
0 NCEP ATP III = National Cholesterol Education Programme, Adult Treatment Panel III; NHANES III = Third US National Health & Nutrition Examination Survey; OGTT = oral
0
4; 3 glucose tolerance test; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; T2D = type 2 diabetes mellitus; WC = waist circumference; WHO = World Health
4 (6) Organization. 377
 3
20 Table III. Comparison of recent expert panel[18-20] guideline criteria for the diagnosis of the metabolic or insulin resistance syndromea 78
0
4
A Metabolic risk factor WHO (1998) diagnostic level[18]b NCEP ATP III (2000) diagnostic level[19]c EGIR (2002) diagnostic level[20]d
d
is D Obesity (abdominal obesity) BMI ≥30.0 kg/m2 and/or waist to hip Waist circumference: >102.0cm (M), Waist circumference: >94.0cm (M);
a
ta circumference ratio >0.9 (M), >0.85 (F) >88.0cm (F) >80.0cm (F)
In
fo
rm Insulin resistance/glucose intolerance Type 2 diabetes, impaired glucose Impaired fasting glucose ≥6.1 mmol/L Hyperinsulinaemia – fasting insulin
a
tio tolerance or insulin resistance above the upper quartile for non-
n
B (Lowest 25% percentile for insulin diabetic individuals
V
. A sensitivity by euglycaemic clamp or Impaired fasting plasma glucose ≥6.1
ll rig highest quartile fasting insulin or mmol/L (≥5.6 mmol/L venous or
h
ts re HOMA) capillary whole blood)
se
rve Dyslipidaemia
d
.
HDL-C <0.9 mmol/L (M) <1.04 mmol/L (M) <1.00 mmol/L (M and F) and/or
<1.0 mmol/L (F) <1.30 mmol/L (F) treatment for dyslipidaemia
triglycerides ≥1.69 mmol/L ≥ 1.69 mmol/L ≥2.0 mmol/L
Blood pressure ≥140/90mm Hg ≥ 130/85mm Hg and/or treatment for ≥140/90mm Hg and/or treatment for
hypertension hypertension
Microalbuminuria Overnight urinary albumin excretion Not utilised for diagnosis Not utilised for diagnosis
rate ≥20.0 µg/min
a The American Association of Clinical Endocrinologists (AACE) have proposed an additional set of clinical criteria for the ‘insulin resistance syndrome’.[3] These criteria
have been likened to a hybrid of those of the ATP III and WHO metabolic syndrome.[2] The term ‘insulin resistance syndrome’ does not include categorical diabetes. The
precise diagnostic criteria are not well specified and left to clinical judgement. In patients without impaired FG, a 2-hour postglucose challenge is recommended.
b To meet WHO (1998) criteria, an individual with impaired glucose tolerance must meet two or more other metabolic criteria to be diagnosed with the metabolic syndrome.
An individual with normal glucose tolerance must meet two metabolic criteria in addition to being diagnosed insulin resistant.
c Under the NCEP ATP III (2000) criteria, an individual must meet at least three of the metabolic risk factor criteria to be diagnosed with the metabolic syndrome. Some
males can develop risk factors when the waist circumference is only marginally increased (94–102cm).
Sports Med 200 BdMIhE =yG pbIeRor din(y2s 0um0lian2sa) sep mrinoidvaie dmxe;u aEsntG mIaRlet ee=rt n Etawutiorvo eop red amenfoin rGietir ooonuf poth ff eot hro ett hhmeer e stctauobdmoylp icoo fns eIynnnstdsur loitnom Rbee ef sodirsi atnagonnnco-eds;ei aFdb ew=t iiftceh m inthdaeilve iisnd;su HuallDisn,L- rt-ehCse i =sin tahsniugclhien -dsreeynsnsidsirttoya mnlicpeeo. psryontderino-mcheo. lAesnt einrodli;v iHduOaMl Aw it=h Hfaosmtinegostasis Model Carroll & D
4; 34 (6) Assessment; M = males; NCEP ATP III = National Cholesterol Education Programme, Adult Treatment Panel III; WHO = World Health Organization. udfield
Exercise and Metabolic Abnormalities 379
4. Pathophysiology and Subclinical ine malnutrition) leading to a ‘thrifty phenotype’
Metabolic Abnormalities which manifests itself under adverse circumstances
in adult life remains an intriguing hypothesis.[146]
Elucidation of the complex pathophysiological Low birth weight and early life events, adult socio-
mechanisms underlying metabolic syndrome re- economic and lifestyle influences may independent-
mains a ‘work-in-progress’[17] and is beyond the ly and in combination contribute to insulin resis-
scope of this review. Insulin resistance, upper body tance and increased metabolic syndrome risk.[147] In
fat accumulation (particularly intra-abdominally), 462 nondiabetic middle-aged Caucasian men,[148]
impaired postprandial lipid metabolism and in- those with low birth size were at least 2-fold more
creased intracellular lipid content of skeletal muscle likely to have the metabolic syndrome (WHO defi-
appear relevant to this heterogeneous condition nition) following adjustment for childhood or adult
which probably develops through a generalised im- socioeconomic status or adult body mass index
balance in the metabolism of both carbohydrates and (BMI). Thinness at birth was even more clearly
lipids.[13,16,33,43,62,88,99-103] associated with the metabolic syndrome in men en-
It is considered that the clustering of the main gaging in <25 min/wk of vigorous leisure time phys-
characteristics of the metabolic syndrome allows the ical activity and in men with a maximum oxygen
clinician to assume that other sub-clinical risk fac- consumption (V˙O2max) of <28.6 mL/kg/min. In con-
tors, not routinely measured, are also present.[16,18] trast, among active and fit men, the association was
Indeed, several authors[104] have emphasised that the absent. Thus it was considered that regular strenu-
syndrome often constitutes an interplay of multiple ous physical activity and maintenance of cardiore-
subtle biochemical abnormalities, often none suffi- spiratory fitness may lessen the lifelong metabolic
ciently aberrant to be considered a risk factor by abnormalities associated with thinness at birth.
itself. Since the original description of Syndrome
X,[13] numerous other subsidiary features have been 5. Physical Activity, Exercise and
added.[19,105-108] Table IV includes many of the mis- Metabolic Risk
cellaneous sub-clinical abnormalities that have been
associated with the metabolic syndrome. The fea- In prospective cohort studies, higher levels of
tures of the syndrome appear highly related and physical activity and cardiorespiratory fitness have
involve several physiological systems.[19,38,61,104,109] quite consistently protected against the development
Clinicians should recognise that the co-occurrences of diabetes and CVD[148,171-176] and combined end-
of these metabolic abnormalities are almost certain- points.[177] Physical activity has been inversely asso-
ly related to insulin resistance/hyperinsu- ciated with the risk of these conditions, specifically
linaemia.[16,18,110] Furthermore, there is substantial CVD, in a dose-response fashion.[178,179] Physical
evidence that they are all CVD risks warranting activity may protect against these conditions in part
aggressive therapeutic intervention.[16,111] through components of the metabolic syn-
Heritability has been shown to be important in drome.[180-183] Byberg et al.[182] have shown that
the development of insulin resistance[32,145] and the adjustment for insulin, proinsulin and split proinsu-
mutual clustering of metabolic variables.[32,101,145] lin conferred the largest attenuation of the increased
Genetic predisposition (related to several candidate risk of CVD mortality associated with sedentary
genes[32]) in combination with the effect of environ- behaviour among middle-aged males. These meta-
mental factors is likely to influence the development bolic variables were also those that over time show-
of insulin resistance and/or the clinical expression of ed the largest improvement associated with in-
the metabolic syndrome. Table V outlines several creased physical activity.[175,182]
commonly cited environmental risk factors for insu- Numerous epidemiological studies have now re-
lin resistance and/or the metabolic syndrome. The ported significant associations between physical ac-
role of an unfavourable fetal environment (intrauter- tivity and cardiorespiratory fitness measures with
 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6)
380 Carroll & Dudfield
Table IV. Potential subclinical metabolic abnormalities associated with the metabolic syndrome[16,17,108,109]
Insulin resistance Cardiovascular system disorders[112-117]
↓ Insulin-mediated glucose disposal in tissues (muscle, liver, fat) ↑ Sympathetic adrenergic activity (increased heart rate and cardiac
output, decreased heart rate variability)
Fasting and post-challenge hyperinsulinaemia Left ventricular hypertrophy or ↑ wall thickness and concentric
remodelling
↓ Insulin receptor number and proteins of the insulin signalling Vascular smooth muscle hypertrophy
cascade
Altered GLUT-4 expression (major insulin-stimulated glucose Inelastic blood vessels
transporter)
Impaired glycogen synthesis Absent nocturnal decreases in heart rate and blood pressure
Dyslipidaemia Salt sensitive hypertension
↑ Non-esterified free fatty acids (resistance to insulin suppression Pro-thrombotic disorders[118-121]
of postprandial adipose tissue lipolysis)
↑ Postprandial lipaemia (including chylomicrons and remnants) ↑ Plasminogen activator inhibitor-1
↑ VLDL synthesis and secretion, and apolipoprotein B secretion Hyperfibrinogenaemia
↑ Small dense LDL-C (↓ LDL particle size) ↑ Plasma/blood viscosity
Altered pituitary-adrenal function[99,122] ↑ Factor VII:C
Hypercortisolaemia, ↑ glucocortocoids Endothelial dysfunction/low-grade inflammation[123-131]
↑ Glucocortocoid receptor function Impaired skeletal muscle vasodilation (impaired endothelial derived
nitric oxide production)
↓ Growth hormone ↑ Plasma concentration of vascular adhesion molecules
Sex hormone interactions[132] ↑ Highly sensitive C-reactive protein and interleukin 6
↑ Androgens (F) Alterations in the tumour necrosis factor-α system
↓ Androgens (M) Altered liver function[103,133]
↓ DHEA ↑ Glucose production
Polycystic ovary syndrome ↓ Insulin removal
Altered renal function[134] ↑γ-Glutamyl transpeptidase
Sodium retention ↑ Hepatic lipase activity
↑ Renin-angiotensin-aldosterone Altered skeletal muscle[100-102,135-140]
↓ Uric acid clearance ↑ Intramuscular triglycerides
Microalbuminuria Altered plasma membrane phospholipids
Altered adipose tissue physiology[141-144] ↑ Type II a fibres
↑ Visceral fat accumulation ↓ Muscle capillary density
Disordered fat storage and mobilisation Altered glycolytic and oxidative enzyme capacities
Hyperleptinaemia (leptin resistance)
↓ Adiponectin
DHEA = dehydroepiandrosterone; F = females; GLUT-4 = glucose transporter; LDL-C = low density lipoprotein-cholesterol; M = males;
VLDL = very low density lipoprotein; ↓ indicates decrease; ↑ indicates increase.
insulin resistance and most other separate compon- of metabolic risk factors within both cross-sectional
ents of the metabolic syndrome among both young, and prospective settings[77,180,189-193] (table VI).
middle-aged and older adults.[24,69,147,184-188] How- Strong inverse associations between physical ac-
ever, the potential importance of physical activity tivity, cardiorespiratory fitness and the clustering of
and cardiorespiratory fitness in the development of metabolic variables have been shown in several
multiple metabolic abnormalities has been less ex- cross-sectional investigations across different ethnic
tensively investigated compared with other lifestyle and socioeconomic groups, mainly representing
factors.[44] Only recently can epidemiological data middle-aged Caucasian men and women. Within the
be evaluated for associations between physical ac- population-based Kuoppio study,[180] men who en-
tivity and cardiovascular fitness and the clustering gaged in at least moderate-intensity (≥4.5 metabolic
 2004 Adis Data Information BV. All rights reserved. Sports Med 2004; 34 (6)