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A review about the effect of leisure-timephysical activity (LTPA) on componentsof the metabolic syndrome Marco Valenti1 Paola De Nicola21 Chair of Biostatistics and Epidemiology, Faculty of Human Movement and Sport Science, L’Aquila University, Italy.
2 PhD course in Movement and Sport Sciences, Faculty of Human Movement and Sport Science, L’Aquila University, Italy.
Valenti M, De Nicola P. A review about the effect of leisure-time physical activity (LTPA) on
components of the metabolic syndrome
Ital J Sport Sci 2004; 11: 56-86
Dyslipidemia and possibly lipid peroxidation play important roles in the development of macro-and microvascular disease in type 1 diabetes mellitus. Little is known, however, of the role ofaerobic exercise in dyslipidemia and resting and exercise-induced lipid peroxidation in type 1diabetes. Despite the well-known effect of leisure-time physical activity (LTPA) on components ofthe metabolic syndrome, little is known of the association of LTPA and cardiorespiratory fitness(maximal oxygen consumption, VO2max) with development of the metabolic syndrome itself. Arandomized controlled trial assessing the effect of a 12-16 week aerobic exercise program onVO2max and the lipid profile was carried out in otherwise healthy young men with type 1diabetes. The effect of acute physical exercise on oxidative stress and antioxidant defenses and therelation to VO2max in men with type 1 diabetes was also evaluated. Literature supports promotionof moderate and vigorous leisure-time physical activity in otherwise healthy type 1 diabetic men toimprove dyslipidemia and cardiorespiratory fitness and possibly decrease lipid peroxidation, andin middle-aged non-diabetic men, to decrease the risk for development of the metabolic syndromeand thereby chronic and progressive diseases such as diabetes and atherosclerosis. Key words: Diabetes, insulin-dependent; diabetes, non-insulin-dependent; metabolic syndro-me X; exercise; physical fitness; oxidative stress; lipid peroxidation; antioxidants; glutathione;obesity; hyperinsulinemia; apolipoproteins, lipoproteins; triglycerides; hypertension; randomi-zed controlled trials; prospective studies; risk factors; male. Introduction
2 diabetes mellitus and cardiovascular disease (CVD) Type 1 and type 2 diabetes mellitus are major (Reaven, 1988; Kaplan, 1989; DeFronzo and worldwide health problems predisposing to markedly Ferrannini, 1991; Kaplan, 1996; Liese et al., 1998; increased cardiovascular mortality and serious Lempiäinen et al., 1999; Pyörälä et al., 2000).
morbidity and mortality related to development of Roughly one third of middle-aged Americans may nephropathy, neuropathy and retinopathy (Zimmet et have the metabolic syndrome as defined by the al., 1997). The metabolic syndrome, a concurrence of National Cholesterol Education Program (NCEP) disturbed glucose and insulin metabolism, (Ford et al., 2002). Using a different definition, 17% overweight and abdominal fat distribution, mild of men and 7% of women were estimated to have the dyslipidemia and hypertension, is from a clinical and metabolic syndrome based on a community study in public health standpoint most important because of Pieksämäki, Finland (Vanhala et al., 1997).
its association with subsequent development of type Physical exercise is a cornerstone of therapy for type ITALIAN JOURNAL of SPORT SCIENCES
1 and type 2 diabetes mellitus (DM). Observational species such as superoxide (Nath et al., 1984; studies suggest that physical activity and physical Ceriello et al., 1991; Wolff et al., 1991; Dandona et fitness may decrease the risk for CVD in both non- al., 1996) or hydrogen peroxide (Wierusz-Wysocka diabetic persons (Paffenbarger et al., 1986; Ekelund et al., 1995; Ruiz Munoz et al., 1997), or decreasing et al., 1988; Blair et al., 1989; Sandvik et al., 1993; antioxidant defenses (Asayama et al., 1993; Tsai et Lakka et al., 1994a; Laukkanen et al., 2001) and al., 1994; Ceriello et al., 1997; Santini et al., 1997).
those with type 1 (Moy et al., 1993) and type 2 These mechanisms include glucose autoxidation diabetes (Wei et al., 2000). This protective effect may (Hunt et al., 1990; Wolff et al., 1991) and formation be mediated in part through components of the of advanced glycation endproducts (AGE) (Lyons, metabolic syndrome. In non-diabetic persons, 1993; Schleicher et al., 1997), activation of the intervention studies, physical exercise has in variable polyol pathway (Cameron and Cotter, 1993; degrees and at least in the short term decreased Grunewald et al., 1993; De Mattia et al., 1994; weight and visceral fat accumulation (Ivy, 1997; Rice Kashiwagi et al., 1994; Cameron et al., 1996; et al., 1999; Ross et al., 2000), increased high- Kashiwagi et al., 1996) and altered cell and density lipoprotein (HDL) cholesterol and decreased glutathione redox status (Grunewald et al., 1993; De triglyceride levels (Tran et al., 1983; Haskell, 1984), Mattia et al., 1994; Kashiwagi et al., 1994; decreased blood pressure (Arroll and Beaglehole, Kashiwagi et al., 1996) and ascorbate metabolism 1992) and improved insulin sensitivity (Ivy, 1997; (Sinclair et al., 1991), antioxidant enzyme Rice et al., 1999; Ross et al., 2000). Physical exercise inactivation (Arai et al., 1987; Blakytny and Harding, may also decrease serum low-density lipoprotein 1992; Kawamura et al., 1992), perturbations in nitric (LDL) cholesterol levels (Stefanick et al., 1998).
oxide and prostaglandin metabolism (Tesfamariam, Results from mainly small and uncontrolled studies 1994) and insulin resistance (Rifici et al., 1994; testing the effects of regular aerobic exercise on the Niskanen et al., 1995a; Vijayalingam et al., 1996).
lipid profile in type 1 DM individuals have, however, No consensus has been reached as to the relative been variable (Wallberg-Henriksson et al., 1982; importance of these mechanisms. Despite strong Yki-Jarvinen et al., 1984; Wallberg-Henriksson et al., evidence indicating a pathogenic role of oxidative stress in the development of atherosclerosis and Oxidative stress has been increasingly implicated in microvascular complications in DM, controversy the accelerated atherosclerosis and microvascular exists about whether the increased oxidative stress is complications of diabetes mellitus (Cameron and merely associative rather than causal, or even Cotter, 1993; Lyons, 1993; Tesfamariam, 1994; whether oxidative stress is increased at all in DM.
Cameron et al., 1996). Oxidative stress can result in In prospective cohort studies, higher levels of physical activity have quite consistently protected (Halliwell, 1994), including oxidative modification against development of both CVD and type 2 of LDL cholesterol, believed to be central in the diabetes mellitus (Berlin and Colditz, 1990; pathogenesis of atherosclerois, and endothelial Helmrich et al., 1994; Lakka et al., 1994a; Lynch et dysfunction (Haberland et al., 1988; Lyons, 1993; al., 1996; Laukkanen et al., 2001), both of which are commonly associated with the metabolic syndrome.
Many recent studies suggest that even moderate Although the pathogenesis of the metabolic exercise increases free radical production beyond the syndrome remains unclear, the metabolic syndrome capacity of antioxidant defenses, resulting in is in its early stages characterized by mild and oxidative stress (Wallberg-Henriksson et al., 1982; varying degrees of abnormalities of insulin, glucose Yki-Jarvinen et al., 1984; Wallberg-Henriksson et al., and lipid metabolism, hypertension and overweight, 1986; Stefanick et al., 1998). On the other hand, which if unchecked may progress over years to overt regular exercise may strengthen antioxidant defenses diseases such as diabetes and atherosclerosis in its and decrease resting and acute exercise-induced various manifestations (Liese et al., 1998). Because oxidative stress (Vasankari et al., 1998; Bailey et al., of the current epidemic of overweight and sedentary 2001; Miyazaki et al., 2001). Little is known about lifestyle worldwide, the metabolic syndrome poses a exercise-induced oxidative stress in diabetes mellitus.
serious and growing problem for clinicians and The mechanisms underlying the apparent increased oxidative stress in diabetes are not entirely clear.
Although physical exercise favorably affects Accumulating evidence points to many, often individual components of the metabolic syndrome, interrelated mechanisms (Cameron and Cotter, 1993; little evidence exists showing that physical activity Lyons, 1993; Tesfamariam, 1994; Cameron et al., prevents the metabolic syndrome itself. Such 1996), increasing production of reactive oxygen information is necessary for healthcare providers and VOL. 11 - NUMERO 1-2 2004
public health policy makers seeking to prevent the and sedentariness in both Western and developing consequences of the metabolic syndrome already at countries, the prevalence of type 2 DM is growing at an exponential rate (Zimmet and Lefebvre, 1996; Previously, clinical and epidemiological research on the metabolic syndrome was hampered by the lack of characterized by insulin resistance coupled with an standard definitions. To address this problem, the inability of the pancreas to sufficiently compensate World Health Organization (WHO) (Alberti and by increasing insulin secretion, with onset generally in middle or old age. Onset is insidious, and published definitions of the metabolic syndrome. ketoacidosis is rare. The prevalence of type 2 DMamong adults varies from less than 5% to over 40%depending on the population in question (Zimmet et REVIEW OF THE LITERATURE
al., 1997). The pathogenesis of type 2 diabetes is still Classification of diabetes mellitus
unclear, although multiple genetic and environmental Diabetes mellitus is a major worldwide health factors clearly interplay to produce the disease.
problem predisposing to markedly increased Although the pathophysiology is still unclear, cardiovascular mortality and serious morbidity and variable defects of metabolism in skeletal muscle, mortality related to development of nephropathy, fat, liver and pancreas contribute to increased insulin neuropathy and retinopathy (Zimmet et al., 1997).
resistance and abnormal insulin secretion. In the Diabetes mellitus is characterized by derangements in Botnia study, roughly 85% of type 2 diabetic patients carbohydrate and lipid metabolism, and is diagnosed had the metabolic syndrome as defined by the WHO by the presence of hyperglycemia. Diabetes has been traditionally divided mainly into type 1 and type 2 The current WHO criteria for type 2 diabetes mellitus use a fasting plasma glucose level of ≥ 7.0 Type 1 DM make up about 15% of the cases of DM or a two-hour post-load level of 11.1 mmol·l-1 in a in Finland, is marked by deficient or absent insulin 75-g oral glucose tolerance test as cutoffs for type 2 secretion by the pancreas and tends to occur before diabetes (Alberti and Zimmet, 1998). These criteria middle age (Eriksson et al., 1992). The presence of are similar to the American Diabetes Association islet cell antibodies (ICA) or glutamic acid criteria (Expert Committee on the Diagnosis and decarboxylase antibodies (GADA), markers of Classification of Diabetes Mellitus 1997). The autoimmune ß-cell destruction, are usually detected American criteria differ especially from previous at onset. Especially in younger patients, development criteria in that an oral glucose tolerance test is of symptomatic hyperglycemia is rapid, and recommended only when the fasting glucose level is ketoacidosis common. Features of the metabolic below 7.0 mmol·l-1 but the suspicion of diabetes is syndrome are not usually present. Like the general population, however, many type 1 diabetic patients Maturity-onset diabetes of the young (MODY) is a develop insulin resistance and features of the genetically, metabolically, and clinically metabolic syndrome, which may have adverse heterogeneous type of type 2 diabetes mellitus that consequences with respect to microvascular appears to account for less than 5% of diabetes complications and CVD (Stuhldreher et al., 1992; (Velho and Froguel, 1998; Fajans et al., 2001).
Koivisto et al., 1996; Idzior-Walus et al., 2001; Gestational diabetes mellitus is carbohydrate Orchard et al., 2002). Insulin resistance may intolerance with onset or first recognition during alternatively develop as a consequence of pregnancy (Jovanovic and Pettitt, 2001). Women hyperglycemia (glucose toxicity) (Yki-Jarvinen, with gestational diabetes also are at greater risk for 1992). A subgroup of adult-onset diabetes with ICA developing type 2 diabetes themselves (Kahn and or GADA and slow-onset insulin deficiency are now Williamson, 2000). There are numerous other classified according to the most recent WHO uncommon forms of diabetes that are not included in classification as a subgroup of type 1 DM (Alberti the above classifications. Insulin-deficient diabetes and Zimmet, 1998; Tuomi et al., 1999; Shaw et al., can result from destruction of islet cells through 2000). In Finland, up to 10% of all diabetic patients acute, recurrent, or chronic pancreatitis (Malka et al., have this form of diabetes, also called latent 2000). Rare mitochondrial mutations have been autoimmune diabetes in adults (LADA) (Niskanen et described in which diabetes is a manifestation (Reardon et al., 1992). Uncommon lipodystrophy Type 2 diabetes is the most common form of diabetes, about 85% in Finland (Eriksson et al., hyperinsulinemia and subsequent diabetes (Bhayana 1992). Due to dietary habits and increasing obesity ITALIAN JOURNAL of SPORT SCIENCES
The lipid profile in type 1 diabetes
Many studies have also shown that endurance The lipid profile is quantitatively normal in type 1 training decreases LDL cholesterol and less diabetic patients in good glycemic control and frequently triglyceride levels (Stefanick et al., 1998).
without microvascular complications, with only The role of weight loss or body composition changes subtle adverse changes in e.g. VLDL and LDL size in these lipid changes is still controversial and HDL and LDL cholesterol triglyceride content (Thompson, 1990a; Williams et al., 1990), although (Verges, 1999; Perez et al., 2000). Despite a many studies have shown favorable effects of regular relatively normal lipid profile on average, it should exercise on the lipid profile independent of weight be noted that similarly high proportions of type 1 loss (Thompson et al., 1997). Antiatherogenic effects diabetic patients as non-diabetic individuals have of physical exercise on apolipoproteins B (apo B) elevated LDL lipoprotein concentrations (Verges, and A-I (apo A-I) in non-diabetic individuals have 1999; Perez et al., 2000). In patients in poor been less consistently observed, but appear to have glycemic control or who have nephropathy, elevated been related mainly to weight loss (Schwartz, 1987; LDL cholesterol, apolipoprotein B and triglyceride 1988; Despres et al., 1991; Williams et al., 1992; levels are more often present (Verges, 1999; Perez et al., 2000; Chaturvedi et al., 2001). Adverse levels of Results from mainly small and uncontrolled studies HDL cholesterol and triglycerides are also associated testing the effects of regular aerobic exercise on the with manifestations of the metabolic syndrome in lipid profile in type 1 DM individuals have been type 1 diabetes (Idzior-Walus et al., 2001).
variable. In a small controlled but not randomizedstudy Yki-Jarvinen et al. (Yki-Jarvinen et al., 1984)also found increases in the HDL/total cholesterol Lipoproteins, apolipoproteins
ratio, without significant changes in HDL- or total and lipids as risk factors in type
cholesterol, body mass index (BMI) or glycemic 1 diabetes
control after six weeks of ergometer cycling exercise Decreased HDL and high LDL cholesterol and for 60 min 4 days a week. The relative change did not triglyceride levels are established cardiovascular risk differ significantly between the training and control factors in non-diabetic (Kannel et al., 1971) and type groups, however. In an uncontrolled study 2 (non-insulin-dependent) DM individuals (Uusitupa investigating the effect of three months of regular et al., 1993). The role of the HDL subfractions HDL exercise in 20 type 1 DM men and women 22-48 years old, LDL decreased by 14% and HDL increased (Salonen et al., 1991), but not all (Stampfer et al., by 10%, with concomitant weight loss and decreased percent body fat (Lehmann et al., 1997).
be more important in reducing cardiovascular risk Corresponding changes in apo B and apo A-I were because of its role in reverse cholesterol transport also found. A 16-week program of 60 min mixed and (Eisenberg, 1984). Low apoliprotein (apo) A-I and aerobic exercise three times a week decreased total high apo B levels are also associated with increased cholesterol without effects on HDL, triglycerides, risk for cardiovascular death (Stampfer et al., 1991).
body weight or glycemic control in nine 25-46 year Much less, however, is known of the role of old men with type 1 DM in an uncontrolled study lipoprotein and apolipoprotein levels in the (Wallberg-Henriksson et al., 1982). Twenty minutes of pathogenesis of the accelerated atherosclerosis daily bicycle exercise had no effect on major lipid (Krolewski et al., 1987) in type 1 DM. Even so, profile indices after five months in 25-45 year old results from cross-sectional studies suggest that lipoprotein and apolipoprotein levels are also improvement in maximal oxygen consumption important cardiovascular risk factors in type 1 DM (VO2max) was noted (Wallberg-Henriksson et al., (Maser et al., 1991; Winocour et al., 1992; Koivisto 1986). Reasons for conflicting results may be differences in the number, age and gender of thesubjects, the type of training protocol, glycemic statusand baseline lipid status or seasonal variation in lipids.
Aerobic exercise and the lipid
profile in type 1 diabetes mellitus

Regular exercise in non-diabetic subjects is best Oxidative stress and antioxidant
known to increase HDL cholesterol and the defenses
HDL/total cholesterol ratio (e.g., (Williams, 1996; Oxidative stress has been defined as the imbalance of 1997); reviewed in (Stefanick and Wood, 1994; U.S.
pro-oxidant and antioxidant forces in favor of the Department of Health and Human Services, 1996)).
former (Steinberg et al., 1989; 2002). Oxidative VOL. 11 - NUMERO 1-2 2004
stress can result in widespread lipid, protein and result of increased oxidative stress (Tesfamariam, DNA damage (Halliwell, 1994), including oxidative 1994; Soriano et al., 2001). Nitric oxide, itself an modification of LDL cholesterol, believed to be ROS, may react with superoxide to form the highly central in the pathogenesis of atherosclerois, and toxic peroxynitrite radical (Soriano et al., 2001).
endothelial dysfunction (Haberland et al., 1988; Increased prostaglandin synthesis and alterations in Steinberg et al., 1989; Lyons, 1993; Tesfamariam, the balance of opposing prostaglandins may also 1994; Witztum, 1994). Oxidized LDL cholesterol is contribute to endothelial dysfunction and platelet found in high concentrations in atherosclerotic activation (Tesfamariam, 1994). High insulin and lesions, and at least in vitro, uptake of LDL by insulin-like growth factor-1 concentrations may mononuclear cells and macrophages does not occur increase superoxide production in mononuclear cells without oxidation of the LDL (Haberland et al., (Rifici et al., 1994). Insulin resistance has also been 1988; Steinberg et al., 1989; Yla-Herttuala et al., linked to lipid peroxidation and impaired antioxidant 1989; Lyons, 1993; Tesfamariam, 1994; Witztum, defenses (Rifici et al., 1994; Niskanen et al., 1995a; 1994). The apparent increased oxidative stress in Vijayalingam et al., 1996). No consensus has been diabetes mellitus has been implicated in the reached as to the relative importance of these accelerated atherosclerosis and microvascular complications of diabetes (Cameron and Cotter,1993; Lyons, 1993; Tesfamariam, 1994; Cameron etal., 1996).
A l t e r a t i o n s i n g l u t a t h i o n e
The mechanisms underlying the increased oxidative metabolism in type 1 diabetes
stress in diabetes are not entirely clear. Accumulating Tissue glutathione plays a central role in antioxidant evidence points to many, often interrelated defenses (Meister, 1995; Sen et al., 2000). Reduced mechanisms (Cameron and Cotter, 1993; Lyons, glutathione (GSH) detoxifies reactive oxygen species 1993; Tesfamariam, 1994; Cameron et al., 1996), such as hydrogen peroxide and lipid peroxides increasing production of reactive oxygen species directly or in a glutathione peroxidase (GPX) - (ROS) such as superoxide (Nath et al., 1984; Ceriello catalyzed mechanism. Glutathione also regenerates et al., 1991; Wolff et al., 1991; Dandona et al., 1996) the major aqueous and lipid phase antioxidants or hydrogen peroxide (Wierusz-Wysocka et al., 1995; ascorbate and a-tocopherol. Glutathione reductase Ruiz Munoz et al., 1997), or decreasing antioxidant (GRD) catalyzes the NADPH-dependent reduction of defenses (Figure 1, Asayama et al., 1993; Tsai et al., oxidized glutathione, serving to maintain 1994; Ceriello et al., 1997; Santini et al., 1997)).
intracellular glutathione stores and a favorable redox Glucose autoxidation and formation of advanced status. Glutathione-S-transferase (GST) catalyzes the glycation endproducts (AGE) not only generate reaction between the -SH group and potential ROS, but also may activate nuclear factor κB and alkylating agents, rendering them more water soluble adhesion molecules and induce lipid peroxidation and suitable for transport out of the cell. GST can (Lyons, 1993; Schleicher et al., 1997; Arnalich et al., also use peroxides as a substrate (Mannervik and 2001). Activation of the polyol pathway may decrease the NADPH/NADP+ ratio, resulting in Platelet GSH content were ten-fold lower in type 1 reductive stress and possibly adversely affecting DM patients with glycated Hb greater than 7%, but NADPH-dependent antioxidant enzyme activity no further decrease was found when glycated Hb was (Cameron and Cotter, 1993; Grunewald et al., 1993; greater than 11% (Muruganandam et al., 1992). Di De Mattia et al., 1994; Kashiwagi et al., 1994; Simplicio et al. (1995) found normal GSH levels, Cameron et al., 1996; Kashiwagi et al., 1996).
increased GRD activity and decreased thiol Increased reductive and oxidative stress may also transferase activity in platelets of 46 type 1 DM alter cell and glutathione redox status (Grunewald et patients. Platelets from the DM patients also had a al., 1993; De Mattia et al., 1994; Kashiwagi et al., lower level of threshold for aggregation induced by 1994; Kashiwagi et al., 1996) and ascorbate arachidonic acid. Children with type 1 DM also had metabolism (Sinclair et al., 1991; Maxwell et al., lower erythrocyte GSH than control subjects (Jain 1997; Cunningham, 1998; Seghieri et al., 1998), and McVie, 1994). Hemoglobin A1c (HbA1c) was although plasma vitamin E levels are not decreased inversely correlated with red cell GSH content.
(Vessby et al., 2002). Glycation may also inactivate Thornalley et al. (Thornalley et al., 1996) found an antioxidant enzymes like glutathione reductase and inverse correlation between erythrocyte GSH levels superoxide dismutase (Arai et al., 1987; Blakytny and the presence of DM complications in type 1 and Harding, 1992; Kawamura et al., 1992).
patients. Normal blood GSH levels were found in 43 Endothelial dysfunction and injury may occur as a patients with type 1 DM compared to 21 non-diabetic ITALIAN JOURNAL of SPORT SCIENCES
toxic species such as peroxynitrite, in addition to Most studies have found decreased blood or red cell having direct toxic effects (Tesfamariam, 1994).
glutathione levels in type 2 DM patients (Thomas et Alternatively, superoxide can be dismutated to much al., 1985; Murakami et al., 1989; De Mattia et al., more reactive hydrogen peroxide, which through the 1994; Yoshida et al., 1995; Ciuchi et al., 1997). Less Fenton reaction can then lead to highly toxic firm conclusions can be drawn in type 1 DM hydroxyl radical formation (Wolff et al., 1991). patients. Further information is also needed about Red cell Cu,Zn/SOD activity has also been found to whether levels are decreased in patients without be decreased in type 1 DM patients (Kawamura et al., 1992; Skrha et al., 1996). Red cell glycosylated complications have even lower levels, although some Cu,Zn-SOD levels were elevated in type 1 DM studies do suggest this. The pathophysiological patients (Kawamura et al., 1992). Glycation appears significance of decreased glutathione levels in to decrease Cu,Zn-SOD activity, which could predispose to oxidative damage (Kawamura et al.,1992). Decreased red cell Cu,Zn-SOD activity hasbeen found in type 1 DM patients with retinopathy Glutathione-dependent enzymes
in type 1 diabetes
microvascular complications (Jennings et al., 1991; Blood GRD activity was lower in 11 children with Skrha et al., 1994), although no difference was found type 1 DM compared to 49 healthy children between patients without retinopathy and healthy (Stahlberg and Hietanen, 1991). On the other hand, individuals (Jennings et al., 1991). Yaquoob et al.
normal red cell GRD activity has been found (Walter (1994) reported increased red cell superoxide et al., 1991; Muruganandam et al., 1992) In type 1 dismutase and serum malondialdehyde (MDA) in DM red cell selenium content and GPX activity were decreased (Osterode et al., 1996). Walter et al. (1991) microalbuminuria compared to healthy subjects.
found no difference in whole blood GPX activity in There was no difference, however, between DM 57 type 1 and type 2 DM patients compared to 28 patients with normo- or microalbuminuria, in non-diabetic control patients, a finding supported by agreement with another study (Leonard et al., 1995).
Leonard et al. (Leonard et al., 1995). Normal red cell In contrast, red cell Cu,Zn-SOD activity has been GST enzyme kinetics have also been found in type 1 found to be similar in Type 1 DM patients and DM patients (Muruganandam et al., 1992). healthy individuals, irrespective of microvascular Changes in glutathione-dependent enzymes in complications (Walter et al., 1991). EC-SOD can diabetic patients are inconsistent. Differences in also be glycated, although glycation does not affect results cannot be completely explained by study enzyme activity (Adachi et al., 1994). EC-SOD activity was found to be similar in 23 children withtype 1 DM of varying duration and healthy children(Marklund and Hagglof, 1984).
I m p a i r m e n t o f s u p e r o x i d e
The wide variability among studies does not allow dismutase and catalase activity
conclusions to be drawn as to whether SOD isoform in type 1 diabetes
activity is abnormal in diabetic patients. Again, Superoxide dismutase and catalase are major differences in methodology or study design do not antioxidant enzymes (Michiels et al., 1994). SOD completely explain the conflicting findings among exists in three different isoforms. Cu,Zn-SOD is studies. Less information is available about catalase mostly in the cytosol and dismutates superoxide to activity in type 1 DM. Normal red blood cell catalase hydrogen peroxide. Extracellular (EC) SOD is found activity has been reported (Seghieri et al., 2001).
in the plasma and extracellular space. Mn-SOD islocated in mitochondria. Catalase is a hydrogenperoxide decomposing enzyme mainly localized to L i p i d p e r o x i d a t i o n i n t y p e 1
peroxisomes or microperoxisomes. Decreased diabetes
Cu,Zn-SOD activity coupled with the increased Use of thiobarbituric acid reactive substances superoxide or H2O2 production that may occur in DM (TBARS) as an index of lipid peroxidation was (Ceriello et al., 1991; Wolff et al., 1991) could pioneered by Yagi (1976), whose group also showed predispose to increased oxidative stress, especially if increased plasma TBARS levels in diabetes (Sato et not compensated with increased catalase or Se-GPX al., 1979). Walter et al. (Walter et al., 1991) found activity. Superoxide may react with other reactive increased plasma peroxide concentrations in 57 Type oxygen species such as nitric oxide to form highly 1 and Type 2 DM patients compared to 28 non- VOL. 11 - NUMERO 1-2 2004
diabetic control patients. Higher plasma MDA levels DM patients as in control subjects, and were also were found in 67 middle aged diabetic patients (20 similar in smokers (Leonard et al., 1995). Zoppini et type 1, 47 type 2) than in 40 healthy subjects al. (Zoppini et al., 1996) also found similar plasma (Noberasco et al., 1991). MDA levels showed a TBARS levels in 56 type 1 DM patients as in 32 age- significant correlation with glycosylated Hb. Women and sex-matched control subjects, but TBARS were with well controlled type 1 DM had higher levels of higher in type 1 DM smokers. No differences in lipid peroxidation during pregnancy than healthy plasma MDA and 8-iso-prostaglandin F2 αlevels were found between 38 type 1 diabetic patients and Plasma TBARS levels were higher in 117 type 1 and 41 control subjects, despite a lower total antioxidant 2 DM patients than in 53 control subjects, independently of metabolic control (Gallou et al., Whether lipid peroxidation is increased in DM even 1993). There were no differences between type 1 and before development of micro- and macrovascular disease is unclear. Many published studies have hydroperoxide levels were elevated in hospitalized found increased lipid peroxidation in type 1 DM ketotic type 1 DM patients (Faure et al., 1993). One patients, but conflicting results have also been found.
week after achieving glycemic control with insulin Inconsistent evidence also suggests that increased treatment, MDA levels approached reference values.
lipid peroxidation and impaired antioxidant defenses Plasma TBARS were elevated in women but not men may be more pronounced in women with type 1 DM.
in a study investigating lipid peroxidation in 56 The differing findings cannot be explained simply young adult type 1 DM and 56 matched non-diabetic based on study design or methodology. A causal role control subjects (Evans and Orchard, 1994). TBARS for lipid peroxidation in the development of diabetic levels were elevated in 158 DM patients compared to macro- and microvascular complications is far from control subjects (Griesmacher et al., 1995). TBARS levels were increased in 18 type 1 DM patients withno or mild retinopathy compared to previouslyestablished reference values (Faure et al., 1995). The Lipid peroxidation and type 1
initial plasma H2O2 and MDA levels in 15 patients diabetic complications
with Type 1 and 15 with Type 2 diabetes before and Jennings et al. (1987) reported increased serum after 2 weeks of intensive treatment were higher than conjugated diene levels in 26 diabetic patients with in control subjects (Wierusz-Wysocka et al., 1995).
microangiopathy compared to 36 diabetic patients After 2 weeks of treatment, the values for both without microangiopathy. Lipid peroxides were also parameters were lower; although still higher than in significantly elevated in 15 type 1 patients with the control group. Lipid hydroperoxides and retinopathy compared to type 1 DM patients without conjugated dienes were elevated and total antioxidan microvascular complications (Jennings et al., 1991).
capacity decreased in 72 patients with well- Plasma TBARS levels correlated with albumin controlled type 1 DM and without complications, excretion in 64 type 1 and type 2 DM patients (Knobl independently of metabolic control or diabetes et al., 1993). Twenty-one normotensive type 1 duration (Santini et al., 1997). In a later study by the diabetic patients without microalbuminuria but with same goup, these basic findings were repeated in 37 evidence of endothelial injury (elevated levels of patients with uncomplicated type 1 diabetes and 29 non-diabetic men and women. Compared with the thrombomodulin content and angiotensin converting diabetic men, diabetic women had even higher levels enzyme activity) had elevated levels of serum MDA of lipid hydroperoxides and lower antioxidant compared to patients without evidence of endothelial injury (Yaqoob et al., 1993). Type 1 and 2 DM On the other hand, serum levels of a conjugated patients in poor metabolic control or with angiopathy diene isomer of linoleic acid was lower in type 1DM had higher levels of TBARS than those in good patients than control subjects (Collier et al., 1988).
control or without angiopathy, independently of lipid No difference in serum conjugated diene levels levels (Griesmacher et al., 1995). In type 1 DM between otherwise healthy diabetic patients and patients with microangiopathy, the oxidized healthy control subjects were noted, although LDL/normal LDL antibody ratio was paradoxically conjugated diene levels were increased in 26 diabetic lower than in patients without complications, most patients with microangiopathy compared to 36 likely due to oxidized LDL specific immune diabetic patients without microangiopathy and 36 complexes found exclusively in antibody-negative control subjects (Jennings et al., 1991). Plasma TBARS levels were similar in 17-40 year old type 1 In contrast, levels of serum MDA were similar ITALIAN JOURNAL of SPORT SCIENCES
and inversely correlated to HbA1c. Recently diagnosed type 1 DM patients (n=25) with poor microalbuminuria (Yaqoob et al., 1994). TBARS glycemic control showed higher electronegative LDL levels were similar in 16 patients with micro-or (suggesting a higher degree of oxidaton), similar macroalbuminuria compared to 69 normoalbuminuric LDL subfraction phenotype and lower susceptibility patients in young type 1 DM patients (Leonard et al., to oxidation compared to 25 matched healthy control subjects (Sanchez Quesada et al., 1996). After three There seems to be no clear consensus as to whether months of intensive insulin therapy, HbA1c and LDL patients who have developed diabetic complications electronegativity decreased, but no changes in LDL have increased lipid peroxidation compared to susceptibility to oxidation or LDL subfraction patients without complications, although more studies have reported higher levels of lipid peroxidation in In contrast, there was no difference between 20 type DM patients with complications than in patients 1 diabetic patients in moderate glycemic control and without complications. Further studies are needed to non-diabetic subjects in the susceptibility of LDL clarify this issue and also whether such increased cholesterol to either copper – dependent or non- oxidative stress is pathologically important or merely transition metal-dependent oxidation (O-Brien et al., a marker of micro- or macrovascular damage.
1995). Furthermore, there was no difference betweenthe groups for LDL vitamin E content, LDL fattyacid composition in cholesterol esters or Susceptibility of LDL cholesterol
triglycerides, but LDL glycation was elevated in the to oxidation in type 1 diabetes
type 1 DM subjects. There was no differencebetween 34 type 1 DM patients without clinical signs Susceptibility of LDL to oxidation was strongly of vascular disease and 22 healthy control patients in correlated with degree of LDL glycosylation. LDL the oxidizability of LDL and very-low-density and red blood cell (RBC) membranes in 11normolipidemic type 1 and 18 type 2 DM patients lipoprotein (VLDL) (Jain et al., 1998). There was no were more susceptible to oxidation than in normal difference in the susceptibility to in vitro oxidation of subjects (Rabini et al., 1994). The susceptibility of LDL isolated from 15 type 1 DM patients in good LDL to copper-catalyzed oxidation was greatest in 22 familial hypertriglyceridemic patients while macrovascular disease or proteinuria compared with intermediate values were found in 24 type 1, 16 type control subjects (Jenkins et al., 1996). The particle 2 and 14 abdominally obese patients compared to size, lipid composition, fatty acid content, gluteal-femoral obese subjects and controls antioxidant content, and glycation were similar for (Cominacini et al., 1994). The different susceptibility LDL isolated from both groups. LDL size was to oxidation found in the different groups of patients smaller in 31 type 1 diabetic patients than in 45 was only partially explained by plasma triglyceride control subjects, but susceptibility of LDL values. Plasma TRAP (total peroxyl radical trapping cholesterol to oxidation was similar (Skyrme-Jones potential) was less and susceptibility of LDL to oxidation as measured by the lag phase of conjugated Most studies have found increased susceptibility of diene formation after initiation of LDL oxidation by LDL cholesterol to oxidation in DM patients, the addition of copper was greater in poorly although some studies have had conflicting results.
controlled type 1 diabetic subjects than in normal Studies carried out to date do not allow firm control subjects (Tsai et al., 1994). This could not be conclusions to be drawn about whether LDL is more attributed to the presence of oxidation-susceptible, susceptible to oxidation in DM patients without small, dense LDL particles in the diabetic subjects, complications than in healthy subjects, or about what whose lipoprotein particle distribution did not differ effect complications and glycemic control have on from the control subjects. LDL from both type 1 the susceptibility of LDL to oxidation.
(n=20) and type 2 (n=20) diabetic patients exhibiteda shorter lag phase duration for conjugated dieneformation, regardless of the presence of vascular A u t o a n t i b o d i e s t o o x i d i z e d
complications (Beaudeux et al., 1995). LDL cholesterol in type 1 diabetes
exhibited a shorter lagtime and a lower α-tocopherol Levels of anti-oxidized LDL antibodies and anti- / LDL ratio for 10 type 1 and 53 type 2 diabetic MDA-modified LDL antibodies were similar in 16 patients than for sex and age-matched control type 1 diabetes mellitus patients free of subjects (Leonhardt et al., 1996). The lagtime was macrovascular complications and 16 control subjects positively correlated to the LDL a-tocopherol/LDL (Mironova et al., 1997). In 101 type 1 DM normo- VOL. 11 - NUMERO 1-2 2004
and macroalbuminuric patients with a long duration normoxic exercise after four weeks of aerobic of diabetes and 54 healthy subjects, antibodies training in a trial in which the normoxic training against MDA-modified LDL did not differ among group served as the control group (Bailey et al., normoalbuminuric DM, albuminuric DM and control 2001). Twelve weeks of high-intensity endurance subjects (Korpinen et al., 1997). In contrast, training increased erythrocyte SOD and GPX antibodies to oxidized LDL cholesterol were 1.5-fold antioxidant enzyme activities and decreased higher in 38 type 1 diabetic patients free of neutrophil superoxide production in response to macrovascular disease than in 33 normal subjects exhausting exercise in an uncontrolled study (Makimattila et al., 1999). Antibodies to oxidized (Miyazaki et al., 2001). A reduction in exercise- LDL were correlated with age in normal subjects, but induced lipid peroxidation in erythrocyte membrane not with age, duration of disease, LDL-cholesterol, was also observed. Reduced glutathione levels HbA1c or degree of microvascular complications in increased in five age-matched control subjects with high-intensity aerobic training, whereas only oxidized Relatively few studies have examined the association glutathione levels increased in 17 patients with of type 1 DM with autoantibodies to oxidized LDL, COPD (Rabinovich et al., 2001). Immediately after but no clear consensus suggesting increased oxidized acute treadmill exercise, 46 claudicants developed LDL antibodies in type 1 diabetes has been found.
significant neutrophil activation and degranulation The fact that type 1 diabetes has an autoimmune with free radical damage, an effect that decreased basis could explain some of the variation in results.
after three months of exercise training. No effect wasseen in 22 control subjects (Turton et al., 2002).
No randomized controlled trials of aerobic training Oxidative stress and antioxidant
on indices of oxidative stress or antioxidant defenses defenses in physical exercise
have yet been published. Nonetheless, some evidencesuggests that exercise training may favorably affect Many recent studies have shown that even moderate indices of oxidative stress and antioxidant protection exercise may increase free radical production beyond in some diseases and in healthy persons, although the capacity of antioxidant defenses, resulting in contradictory findings exist (Bergholm et al., 1999).
oxidative stress (Davies et al., 1982; Alessio, 1993;Sen et al., 1994b; Ji, 1995; Sen, 1995; Liu et al.,1999). In animals, exercise training may strengthen The metabolic syndrome
antioxidant defenses and may reduce resting andacute exercise-induced oxidative stress (Alessio and The concurrence of disturbed glucose and insulin Goldfarb, 1988; Sen et al., 1992; Sen, 1995; Kim et al., 1996a; Kim et al., 1996b). Several theses and distribution, mild dyslipidemia and hypertension, has reviews on the topic have been published by given rise to the concept of the metabolic syndrome, members of our research team (Sen, 1994; Sen, also known as Syndrome X, the Deadly Quartet, and 1995; Atalay, 1998; Khanna, 1998; Sen et al., 2000).
the insulin resistance syndrome (Reaven, 1988; Therefore review of oxidative stress and antioxidant Kaplan, 1989; DeFronzo and Ferrannini, 1991; defenses in physical exercise here will be limited Kaplan, 1996; Liese et al., 1998). Although the briefly to exercise intervention studies and oxidative metabolic syndrome has been in the scientific limelight only since being re-introduced as Relatively few studies on the effect of exercise Syndrome X in 1988 (Reaven, 1988; Liese et al., training on indices of oxidative stress or antioxidant 1998), clustering of hypertension, hyperglycemia and defenses in humans have been published. A 10-month gout was described already in 1923 (Kylin, 1923).
exercise program that increased VO2max by 19% also Insulin resistance has been considered to be the decreased LDL oxidation and other lipid risk factors underlying abnormality of this syndrome. The in an uncontrolled study in 34 sedentary men and 70 pathogenesis of this syndrome has multiple origins, women (Vasankari et al., 1998). On the other hand, but obesity and sedentary lifestyle coupled with diet three months of relatively intense running training in and still largely unknown genetic factors clearly nine fit men decreased circulating antioxidants (uric interact to produce it (Reaven, 1988; Kaplan, 1989; acid, SH-groups, α-tocopherol, beta-carotene, retinol) DeFronzo and Ferrannini, 1991; Bouchard, 1995; except ascorbate, without affecting the lag time for Kaplan, 1996; Liese et al., 1998). The metabolic the susceptibility of plasma LDL to oxidation in vitro syndrome is from a clinical and public health (Bergholm et al., 1999). Normoxic and especially standpoint most important because of subsequent intermittent hypoxic training attenuated the increases high morbidity and mortality from diseases such as in lipid hydroperoxides and MDA induced by acute type 2 diabetes and CVD (Reaven, 1988; Kaplan, ITALIAN JOURNAL of SPORT SCIENCES
1989; DeFronzo and Ferrannini, 1991; Kaplan, 1996; DeNino et al., 2001; Smith et al., 2001; Cnop et al., Liese et al., 1998; Lempiäinen et al., 1999; Pyörälä et al., 2000). Patients with type 1 diabetes are also not More recently, the concept of ectopic fat deposition immune from the metabolic syndrome and its has been developed (Ginsberg, 2000; Kahn and Flier, consequences, including CVD and microvascular 2000; Kelley and Mandarino, 2000; Shulman, 2000).
disease (Stuhldreher et al., 1992; Koivisto et al., 1996; Idzior-Walus et al., 2001; Orchard et al., subcutaneous and visceral fat, the degree of lipid 2002). Overweight and physical inactivity also storage in skeletal muscle and liver has also been appear to bring about the metabolic syndrome in type shown to be powerful determinants of insulin sensitivity. Peripheral adipocytes have limited As the epidemic of obesity and sedentary lifestyle reserves for storing fat. Those reserves in turn continues worldwide, the metabolic syndrome and its depend in part on genetic and environmental factors.
consequences, especially diabetes, can be expected to As the ability of the peripheral adipocyte to store fat become increasingly common at younger ages. In the is exceeded, the fat cells become insulin resistant, US type 2 diabetes is indeed becoming alarmingly reulting in increased lipolysis and release of fatty common in particularly Hispanic, black and acids into the blood stream, and decreased uptake of American Indian children (Ludwig and Ebbeling, fatty acids. This in turn results in not only abdominal 2001). Although the metabolic syndrome has been subcutaneous and visceral fat deposition, but also less closely associated with coronary heart disease storage of lipids in liver and skeletal muscle. than with type 2 diabetes, the obesity epidemic and Triglyceride accumulation in the liver results in its associated metabolic syndrome may explain the decreased hepatic insulin sensitivity and increased plateauing in the decline in the incidence of VLDL production, which results in increased transfer myocardial infarction over the past ten years in the of cholesterol esters from HDL and LDL cholesterol United States (Rosamond et al., 1998).
to VLDL cholesterol in exchange for triglyceride(Eisenberg, 1984; Ginsberg, 2000; Kahn and Flier,2000). This in turn impairs reverse cholesterol Pathophysiology of the
transport and results in a decrease HDL levels, a shift metabolic syndrome
in balance to HDL3 cholesterol, and a shift from large The pathogensis of the metabolic syndrome is poorly buoyant LDL particles to small dense LDL particles.
understood, and will be discussed here only briefly.
Increased hepatic insulin resistance also results in An abdominal distribution of fat appears to be inappropriate gluconeogenesis postprandially. particularly deleterious (Figure 2, Larsson et al., Skeletal muscle is a major determinant of whole- 1984; Folsom et al., 1993; Rexrode et al., 1998; body glucose disposal (Kahn and Flier, 2000; Kelley Folsom et al., 2000). Abdominal fat can also be and Mandarino, 2000). More recent evidence divided into subcutaneous and visceral compartments suggests that intramuscular lipid deposits play a that can be assessed with computed tomography or major role in decreasing glucose uptake in skeletal magnetic resonance imaging. Mainly experimental muscle (Ginsberg, 2000; Kahn and Flier, 2000; evidence suggests that abdominal obesity may Kelley and Mandarino, 2000; Shulman, 2000).
mediate its deleterious effects on carbohydrate and Intramuscular lipids appear to decrease glycogen lipid metabolism through the increased lipolytic syntheis and impair glucose transport by activating activity of especially omental fat, which drains protein kinase Cθ, which results in a cascade that directly into the portal-venous system (Bjorntorp, phosphorylates insulin substrates 1 and 2, impairing 1991). This in turn results in higher non-esterified the insulin reseptor ’s ability to activate fatty acid concentrations, with consequent insulin phosphatidylisositol kinase 3 and ultimately resistance in the liver and skeletal muscle, and impairing glucose transport into the cell.
dyslipidemia. According to this “portal hypothesis”, Paradoxically, the ability to utilize fatty acids as an because of the higher lipolytic activity of visceral energy source in the resting state is impaired in than subcutaneous abdominal fat, visceral fat should insulin resistance, whereas in insulin-stimulated be more closely associated with insulin resistance states, glucose oxidation is impaired (Kelley and and its associated metabolic derangements (Bjorntorp, 1991). The pathophysiological As the metabolic syndrome becomes more severe, significance of these subdivisions are unclear, interplay between genetic susceptibility, insulin however (Despres et al., 1989; Abate et al., 1995; resistance and diet may lead to progressive ß-cell Goodpaster et al., 1997; Brochu et al., 2000; Kelley failure and impaired insulin secretory capacity et al., 2000; Ross et al., 2000; Sardinha et al., 2000; (Nijpels, 1998; Cavaghan et al., 2000; Hu et al., VOL. 11 - NUMERO 1-2 2004
2001; Kahn et al., 2001; Trayhurn and Beattie, 2001).
World Health Organization, 2000; Uusitupa, 2001), As ß-cell secretory capacity declines, impaired diet (Hu et al. 2001; Uusitupa 2001; Bray et al., glucose tolerance (IGT) develops. IGT is common in 2002), low childhood and adult socioeconomic status older persons, up to 25% of individuals of European (Brunner et al., 1997; Davey Smith and Hart, 1997; descent. Roughly 5-10% of persons with IGT convert Lawlor et al., 2002) and low birthweight and rapid to frank diabetes yearly, again with weight gain, diet, childhood growth (Forsen et al., 2000; Eriksson et al., genetic susceptibility and insulin resistance contributing to the progressive ß-cell failure. Themanifestations of cardiovascular risk factors such asdyslipidemia, hypertension, endothelial dysfunction, D e f i n i t i o n s o f t h e m e t a b o l i c
inflammation, hypercoagulability and impaired syndrome
fibrinolysis, obesity and abnormal insulin and glucose metabolism predispose persons with the experimental research that has been published on the metabolic syndrome to development of another metabolic syndrome, definitions of the metabolic important end-stage consequence of the metabolic syndrome and the various cut-offs for its components syndrome, cardiovascular disease (Reaven, 1988; have varied widely (Liese et al., 1998). The World Kaplan, 1989; DeFronzo and Ferrannini, 1991; Health Organization (WHO) consultation for the Kaplan, 1996; Liese et al., 1998; Lempiäinen et al., classification of diabetes and its complications (Alberti and Zimmet 1998) and the National Disturbances in the adrenal-pituitary axis (Bjorntorp Cholesterol Education Program (NCEP) Expert and Rosmond, 2000), inflammation (Pradhan and Panel have recently published definitions of the Ridker, 2002) and abnormal sex steroid metabolism (Livingstone and Collison, 2002) have all been The WHO published a working definition of the proposed to contribute to or exacerbate the metabolic syndrome meant to facilitate research on development of the metabolic syndrome, but the metabolic syndrome and aid comparability evidence for these abnormalities as the primary between studies, rather than serve as a strict mechanism for the pathogenisis of the metabolic definition (Alberti and Zimmet, 1998). The metabolic syndrome is insufficient. Adipose tissue also syndrome was defined (without assumptions of produces hormones, cytokines and other peptides causality) for men as: insulin resistance in the top such as angiotensinogen, adipsin, acylation- 25% of the population as measured by the euglycemic stimulating protein, adiponectin, retinol-binding hyperinsulinemic clamp or presence of impaired protein, leptin, resistin, tumor neorosis factor α, glucose tolerance (IGT) or type 2 diabetes and the interleukin 6, plasminogen activator inhibitor-1 thatmay play a role in insulin resistance, inflammation presence of at least two of the following: abdominal and the development of diabetes and CVD (Fruhbeck obesity (waist-hip ratio >0.90 or BMI ≥30 kg·m-2), et al., 2001; Trayhurn and Beattie, 2001; Pradhan and dyslipidemia (serum triglycerides ≥1.70 mmol·l-1 or HDL cholesterol <0.9 mmol·l-1), hypertension The pathophysiology behind the association of (≥160/90), or microalbuminuria. These core obesity and insulin resistance with hypertension is components were considered most suitable for a also poorly understood. Contributing mechanisms general definition (Liese et al., 1998), although many include resistance to insulin-mediated vasodilation other disturbances, e.g. disorders of coagulation and and endothelial dysfunction (McFarlane et al., 2001; endothelial function, hyperuricemia and elevated Steinberg and Baron, 2002), hyperinsulinemia- leptin levels, have been associated with the metabolic mediated increased sodium and water absorption (Esler et al., 2001; McFarlane et al., 2001; Montani This working definition has not been without et al., 2002) and activation of the sympathetic criticism. Inclusion of microalbuminuria as a core nervous system (Esler et al., 2001; McFarlane et al., component is controversial, and microalbuminuria in non-diabetic individuals is uncommon (Hodge et al., Environmental and genetic (Groop and Orho- 1996; Zavaroni et al., 1996; Jager et al., 1998; Balkau Melander, 2001; Ukkola and Bouchard, 2001) factors and Charles, 1999). The most appropriate measure of contribute to both the development of overweight and abdominal obesity is also in dispute. Although waist- the propensity for insulin resistance and ectopic fat hip ratio may carry information relevant to disease deposition and other manifestations of the metabolic endpoints independently of waist girth or BMI syndrome (Figure 2). Environmental factors include (Folsom et al., 2000), waist circumference correlates sedentary lifestyle and poor physical fitness (U.S.
better with visceral fat deposits as measured by Department of Health and Human Services, 1996; computerized tomography (Seidell et al., 1988).
Defining adiposity as waist girth ≥94 cm has been independently of other cardiovascular risk factors proposed by the European Group for the Study of (Casassus et al., 1992; Yarnell et al., 1994; Lakka et Insulin Resistance (EGIR) (Balkau and Charles, 1999). Furthermore, the euglycemic hyperinsulinemic The gold standard for measuring whole-body insulin clamp is not practical for epidemiological research.
resistance is the euglycemic hyperinsulinemic clamp The EGIR recommended use of fasting insulin levels (Ferrannini and Mari, 1998). The procedure is time- to estimate insulin resistance and IFG as a substitute and labor-intensive, however, and not practical for for IGT in epidemiological studies (Balkau and especially epidemiological studies or routine clinical Charles, 1999). The EGIR also proposed lower cut- use. As a substitute, use of fasting insulin levels has offs for hypertension (≥140/90) (Balkau and Charles been recommended (Balkau and Charles, 1999).
1999) that are in accordance with current WHO-ISH Indeed, fasting insulin levels have a correlation of at (International Society of Hypertension) and Sixth least 0.6 in non-diabetic individuals (Laakso, 1993).
Joint National Committee recommendations (Balkau Although no internationally agreed cut-offs are available, the top quarter of insulin resistance as The NCEP Expert Panel has also recently published a measured by the clamp (Alberti and Zimmet, 1998) definition of the metabolic syndrome for clinical use or as estimated by fasting insulin levels (Balkau and (NCEP, 2001). The metabolic syndrome was defined as three or more of the following: fasting plasma homeostasis model assessment (HOMA) (Matthews glucose levels ≥6.1 mmol·l-1, serum triglycerides ≥1.7 et al., 1985) is a common method of estimating mmol·l-1, serum HDL <1.0 mmol·l-1, blood pressure insulin resistance based on fasting insulin and ≥130/85 mmHg, waist girth >102 cm. Use of waist glucose levels. The recently validated quantitative circumference >94 cm was suggested for some men insulin sensitivity check index (QUICKI) is also who may be genetically susceptible to insulin based on fasting insulin and glucose concentrations resistance (NCEP, 2001). Over 30% of middle-aged and is closely (inversely) correlated with HOMA, persons in the US have been reported to have the differing mainly in being normally distributed (Katz metabolic syndrome as defined by the NCEP (Ford et et al., 2000). The correlation of insulin sensitivity as estimated by QUICKI and the euglycemic clamp was0.75, better than the minimal model intravenousglucose tolerance test (Katz et al., 2000). Some Components of the metabolic
controversy still exists, however, about whether these syndrome
measures predict insulin resistance better than fasting H y p e r i n s u l i n e m i a a n d i n s u l i n
insulin levels (Yeni-Komshian et al., 2000).
Hyperinsulinemia and insulin resistance have intercorrelated variables into a smaller set of consistently predicted type 2 diabetes, even when underlying uncorrelated factors that can be used to adjusted for other components of the metabolic syndrome (Charles et al., 1991; Martin et al., 1992; phenomena, and is particularly well suited for Lillioja et al., 1993; Haffner et al., 1995).
analysis with components of or related to the Hyperinsulinemia has also predicted hypertension metabolic syndrome (Edwards et al., 1994; Meigs, independently of obesity (Skarfors et al., 1991; 2000; Pyörälä et al., 2000). Although previous Lissner et al., 1992; Salonen et al., 1998), although in studies sometimes have generated separate lipid some studies only in subgroups, such as non-diabetic (Lempiäinen et al., 1999; Chen et al., 2000; Pyörälä non-Hispanic whites (Shetterly et al., 1994) and lean et al., 2000) or blood pressure factors (Meigs et al., normoglycemic individuals (Haffner et al., 1992).
1997; Chen et al., 1999; Lempiäinen et al., 1999; Hyperinsulinemia has also predicted dyslipidemia Chen et al., 2000; Hodge et al., 2001; Lindblad et al., independently of obesity in some (Haffner et al., 2001), with differences at least in part related to the 1992; Salonen et al., 1998), but not all (Mykkanen et variables entered into the analyses, the factor al., 1994a) studies. These findings suggest that explaining the greatest variance has consistently had insulin resistance may precede development of heavy loadings by measures of adiposity and fat hypertension and dyslipidemia in the early stages of distribution, insulin and glucose (Edwards et al., the metabolic syndrome. Hyperinsulinemia has also 1994; Meigs et al., 1997; Gray et al., 1998; Chen et predicted CVD incidence or mortality (Casassus et al., 1999; Lempiäinen et al., 1999; Chen et al., 2000; al., 1992; Yarnell et al., 1994; Despres et al., 1996; Pyörälä et al., 2000; Snehalatha et al., 2000; Hodge Lakka et al., 1996; Perry et al., 1996; Lakka et al., et al., 2001; Lindblad et al., 2001), all components of 2000; Pyorala et al., 2000), although often not VOL. 11 - NUMERO 1-2 2004
distribution. Waist girth and even BMI correlate In epidemiological studies employing factor analysis, better than the waist-hip ratio with CT or MRI fasting glucose and two-hour post-load glucose measures of abdominal obesity (Seidell et al., 1987).
levels have also consistently associated with the It has been suggested that the use of waist factor explaining the greatest variance and having circumference should be preferred over waist-hip heavy loadings by measures of adiposity and fat ratio (National Institutes of Health. National Heart, distribution and insulin (Edwards et al., 1994; Meigs 1998; World Health Organization, 2000), although et al., 1997; Gray et al., 1998; Chen et al., 1999; the waist-hip ratio may offer additional information Lempiäinen et al., 1999; Chen et al., 2000; Pyörälä et affecting health outcomes not related to abdominal al., 2000; Snehalatha et al., 2000; Hodge et al., 2001; fat distribution (Han et al., 1998). It should be noted, Lindblad et al., 2001). Both fasting and two-hour however, that as obesity increases, abdominal obesity post-load glucose levels can therefore be considered also generally increases. Even BMI alone correlates a core component of the metabolic syndrome. nearly as well as waist circumference with abdominal Type 1 and type 2 diabetes mellitus have a well- fat as measured by computed tomography (Seidell et characterized 2-4-fold increased risk for CVD that is al., 1987). Cut-offs of 94 cm and 102 cm for waist independent of known cardiovascular risk factors circumference have been suggested as action levels (Krolewski et al., 1987; Marks and Raskin, 2000; for intervention in men. These cut-offs are based on a large cross-sectional population-based study in the cardiovascular mortality (Gabir et al., 2000a; Netherlands, in which those cut-offs corresponded to Eschwege et al., 2001; Rajala et al., 2001). There is a BMIs of≥25 and 30 kg·m-2, and were associated with graded increase in the cardiovascular risk of fasting increased prevalence of chronic diseases and and two-hour post-load glucose levels even in the cardiovascular risk factors (Lean et al., 1998). normal range (Coutinho et al., 1999). Both IFG and Visceral abdominal fat has been reported to be IGT are strong predictors of future diabetes associated with insulin resistance independently of (Edelstein et al., 1997; Gabir et al., 2000b; de Vegt et total body fat or subcutaneous abdominal fat (Despres et al., 1989; Brochu et al., 2000; Ross et al.,2000; DeNino et al., 2001; Cnop et al., 2002; Ross etal., 2002), but many other studies have found that Overweight and an abdominal
subcutaneous abdominal adipose tissue is as strong fat distribution
or stronger correlate of insulin resistance (Abate et The most widely used measure of adiposity is the al., 1995; Goodpaster et al., 1997; Kelley et al., BMI (kg·m-2), which is independent of height.
2000; Sardinha et al., 2000; Smith et al., 2001).
Despite its crudeness, BMI provides a good index of Subcutaneous fat tissue can be further divided into overall adiposity at the population level (World deep and superficial compartments, and visceral fat Health Organization, 2000). Somewhat more tissue can be divided into retroperitoneal and accurate calculations of percent body fat may be intraperitoneal compartments (Kelley et al., 2000; obtained from skinfold measures and bioelectrical Smith et al., 2001; Janssen et al., 2002), although the impedance, but these measures require sex- and age- pathophysiological significance of these subdivisions dependent norms that may vary from population to population (Heymsfield et al., 1997; Ellis, 2000). The Adiposity and an abdominal fat distribution have most accurate and widely used measurements of also consistently loaded onto the factor explaining adiposity are currently obtained through underwater the greatest variance and having heavy loadings by weighing and dual-energy X-ray absorptiometry measures of insulin and glucose metabolism in (Heymsfield et al. 1997; Ellis 2000), although these epidemiological studies employing factor analysis methods are not practical for most epidemiological (Edwards et al., 1994; Meigs et al., 1997; Gray et al., studies. The WHO and the National Institute of 1998; Chen et al., 1999; Lempiäinen et al., 1999; Health have defined overweight as BMI≥25 kg·m-2, Chen et al., 2000; Pyörälä et al., 2000; Snehalatha et and obesity as BMI≥30 kg·m-2(National Institutes of al., 2000; Hodge et al., 2001; Lindblad et al., 2001).
Health. National Heart, 1998; World Health Although insulin resistance has been considered to be the underlying abnormality of the metabolic An abdominal distribution of fat appears to be syndrome, overweight and obesity are clearly the particularly deleterious (Larsson et al., 1984; Folsom main triggering factors (Liese et al., 1998). et al., 1993; Rexrode et al., 1998; Folsom et al., An abdominal distribution of fat as measured by 2000). Waist and the waist-hip ratio are the most waist girth or waist-hip ratio has predicted common anthropometric measures of abdominal fat cardiovascular endpoints even after adjustment for ITALIAN JOURNAL of SPORT SCIENCES
BMI (Larsson et al., 1984; Folsom et al., 1993; decrease in coronary morbidity and mortality is less Rexrode et al., 1998; Folsom et al., 2000).
than what would be predicted by epidemiological Interestingly, the independent contribution of waist studies, however. This has been speculated to be due circumference or waist-hip ratio over BMI to the in part to adverse effects of (high-dose) diuretics and development of diabetes is not as clear (Ohlson et al., (non-selective) beta-blockers on insulin resistance, 1985; Chan et al., 1994; Wei et al., 1997).
dyslipidemia and other factors related to themetabolic syndrome, or alternatively, that only partof the mortality associated with hypertension is due Dyslipidemia
to blood pressure itself (Thompson, 1990b; Black, Low fasting serum HDL cholesterol levels and 1996; Brook, 2000; Reyes, 2002). Hypertension is hypertriglyceridemia are consistently associated with also an independent risk factor for type 2 diabetes the other components of the metabolic syndrome (Ohlson et al., 1988; Haffner et al., 1990; Mykkanen (Reaven, 1988; Kaplan, 1989; DeFronzo and Ferrannini, 1991; Mykkanen et al., 1994a; Kaplan,1996; Mykkanen et al., 1997; Liese et al., 1998).
Other lipid subfractions such as apolipoprotein A1 Physical activity
and B levels, small dense LDL cholestrerol and HDL and cardiorespiratory fitness
subfractions are associated with the metabolic In intervention studies in non-diabetic persons, syndrome as well (Mykkanen et al., 1994a; aerobic physical exercise has in variable degrees and Mykkanen et al., 1997; Liese et al., 1998). at least in the short term decreased weight and Dyslipidemia has predicted the incidence of type 2 visceral fat accumulation (Ivy, 1997; Rice et al., diabetes mellitus in several studies (Ohlson et al., 1999; Ross et al., 2000), improved insulin sensitivity 1988; Haffner et al., 1990; McPhillips et al., 1990; (Ivy, 1997; Rice et al., 1999; Ross et al., 2000) Perry et al., 1995). Low HDL cholesterol levels are a increased HDL cholesterol and decreased triglyceride well-established risk factor for CVD (Boden, 2000).
levels (Tran et al., 1983; Haskell, 1984), and The independent role of triglycerides as a decreased blood pressure (Arroll and Beaglehole, cardiovascular risk factor is more controversial, 1992) in addition to increasing cardiorespiratory although a meta-analysis suggests that triglycerides fitness. These changes have often occurred are an independent risk factor (Hokanson and Austin, independently of weight loss, although it is not completely clear how much of these favorable effects Lipoprotein Cholesterol Intervention Trial showed a are independent of weight loss and changes in body decrease in cardiovascular events in men with low HDL cholesterol levels but normal LDL cholesterol The mechanisms by which exercise may increase levels who treated with gemfibrozil. Because insulin sensitivity independently of weight loss are gemfibrozil is an HDL-elevating and triglyceride- only partly understood. Exercise appears to acutely lowering drug, this study offers additional support increase glucose uptake in part through the for the importance of triglyceride and HDL levels as mechanistic action of contraction, perhaps partially cardiovascular risk factors (Rubins et al., 1999).
mediated by increased translocation of glucosetransporter ptotein (GLUT) 4 to the plasmamembrane (Henriksen, 2002). Tyrosine Blood pressure
phosphorylation of the insulin receptor and insulin Hyperinsulinemia was associated with the incidence receptor substrate-1 is also increased (Henriksen, of hypertension and dyslipidemia in the Kuopio 2002), which may explain in part increased insulin- Ischaemic Heart Disease Risk Factor Study (KIHD) stimulated glucose transport in skeletal muscle. The cohort of middle-aged men (Salonen et al., 1998).
acute effects of exercise mostly disappear within 24 Obesity and abdominal fat distribution also have a hours. More chronically, regular exercise appears to well-described association with hypertension (Cassano et al., 1990; Jousilahti et al., 1995; Curhan translocation (Henriksen, 2002), insulin receptor et al., 1996; Haffner et al., 1996; Kannel, 1996; autophosphorylation (Youngren et al., 2001), insulin- Srinivasan et al., 1996; Harris et al., 2000; Juhaeri et stimulated glucose transport in skeletal muscle (Henriksen, 2002), whole body glucose disposal and Hypertension is a classic cardiovascular risk factor, glucose tolerance (Dengel et al., 1998; Pratley et al., as has been demonstrated by both longitudinal cohort 2000). Other factors contributing to the mechanisms studies and blood pressure medication trials (Psaty et by which regular exercise may increase insulin al., 1997; Kannel, 2000). The magnitude of the sensitivity include effects on the interplay between VOL. 11 - NUMERO 1-2 2004
skeletal muscle fiber type, oxidative capacity and intramuscular lipid content (Goodpaster et al., 2001) epidemiological data are not completely consistent, and blood flow and endothelial function (Stewart, vigorous physical activity and high cardiorespiratory 2002). Mechanisms by which physical exercise may fitness seem to offer greater benefit against most produce favorable changes more specifically in cardiovascular and metabolic risk factors than lipoprotein and lipid metabolism even in the absence moderate physical activity or fitness. The shape of of weight loss include decreasing hepatic triglyceride the dose-response relationship for the intensity of lipase activity and increasing skeletal muscle physical activity or cardiorespiratory fitness with lipoprotein lipase activity (Svedenhag et al., 1983; respect to cardiovascualar mortality has also been Thompson et al., 1997). Hepatic lipase activity seems debated. Some have argued that the relationship is to be inversely related to insulin sensitivity (Perret et curvilinear (Blair and Brodney, 1999), with the most al., 2002), whereas skeletal muscle lipoprotein lipase benefit gained in the low-fit or sedentary groups, activity may be positively related to insulin whereas others have argued that at least for physical activity the relationship is linear (Williams, 2001), or No trials or observational studies regarding physical even that a minimum threshold level in intensity fitness or aerobic exercise and the development of around 6 METs is necessary for physical activity to the metabolic syndrome using standard definitions be cardioprotective (Shephard, 2001). Low-intensity have been published. In a cross-sectional study, leisure-time physical activity (LTPA) has consistently Whaley and coworkers (Whaley et al., 1999) found a been less strongly associated with most chronic strong inverse dose-response relationship between disease endpoints than moderate or vigorous exercise total time on a maximal treadmill exercise test and (Berlin and Colditz, 1990; Lynch et al., 1996), but the number of metabolic abnormalities in a large may have other important functions, e.g. in weight cohort of men and women attending the Cooper control after weight loss in the obese (Bjorntorp Clinic. Carroll et al. (Carroll et al., 2000) observed an inverse dose-response relationship between indirectly Based on the intervention and epidemiological predicted VO2max (in ml·kg-1 per minute), and the evidence, the Center for Disease Control (CDC) and likelihood of the clustering of metabolic factors in the American College of Sports Medicine (ACSM) 711 working men who presented for preventive have jointly published recommendations that adults assessment at a private hospital. In the study by engage in at least 30 min of moderate physical Carroll and coworkers (Carroll et al., 2000), the age- activity on most, and preferably all, days of the adjusted association between physical activity and week. It is nonetheless acknowledged that further the likelihood of the clustering of metabolic factors benefit may be gained by engaging in regular increased with the intensity of physical activity. Recently, lifestyle interventions including regularphysical activity have been shown to more than halfthe incidence of diabetes in persons with IGT Other factors related to the
(Tuomilehto et al., 2001; Knowler et al., 2002).
metabolic syndrome
Whether this would also apply to persons with the Many other factors have also been found to be metabolic syndrome in general, or whether exercise associated with the metabolic syndrome (Liese et al., alone would have a therapeutic effect has not been 1998), including other lipid, lipoprotein and tested. Observational studies suggest that physical apolipoprotein abnormalities such as increased small activity and cardiorespiratory fitness may decrease dense LDL lipoprotein (Festa et al., 1999), elevated the risk for CVD both in non-diabetic persons apolipoprotein B and decreased apolipoprotein A-2 (Paffenbarger et al., 1986; Ekelund et al., 1988; Blair concentrations, hemostatic factors including et al., 1989; Sandvik et al., 1993; Lakka et al., 1994a; fibrinogen (Sakkinen et al., 2000; Temelkova- Laukkanen et al., 2001) and those with type 1 (Moy Kurktschiev et al., 2002), inflammatory factors et al., 1993) and type 2 diabetes (Wei et al., 2000).
including C-reactive protein (CRP) (Frohlich et al., Longitudinal cohort studies also show a decreased 2000; Chambers et al., 2001; Hak et al., 2001; incidence of diabetes mellitus in persons who are fit Temelkova-Kurktschiev et al., 2002), hyperuricemia or who engage in moderate or vigorous levels of (Costa et al., 2002), hyperleptinemia (Jansson et al., physical activity compared to sedentary or unfit 2002), endothelial dysfunction (Balletshofer et al., individuals (Helmrich et al., 1991; Manson et al., 2000), sleep apnea (Vgontzas et al., 2000) and alterations in sex homones including decreased The relative benefit of vigorous physical activity testosterone levels in men, increased androgen levels compared with moderate-intensity physical activity in women and decreased sex hormone binding ITALIAN JOURNAL of SPORT SCIENCES
globulins in both sexes (Pugeat et al., 2000; Stellato leisure-time physical activity of various intensities et al., 2000; Jansson et al., 2002). Microalbuminuria and cardiorespiratory fitness with development of the has also been proposed to be related to the metabolic metabolic syndrome as defined by the WHO and the syndrome (Hodge et al., 1996; Mykkanen et al., NCEP over four years in middle-aged non-diabetic men without the metabolic syndrome at baseline. For the purpose of a general definition, however,abdominal obesity, disturbances in insulin andglucose metabolism, dyslipidemia and hypertensionas core components have been considered mostappropriate (Alberti and Zimmet, 1998).
Microalbuminuria was originally proposed by the References
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Zavaroni et al., 1996; Jager et al., 1998; Balkau and and Hirano K. (1994) Quantitative and qualitative changes Charles, 1999). The NCEP considered similar core of extracellular-superoxide dismutase in patients with components in their clinically oriented definition of various diseases. Clinica Chimica Acta 229, 123-131. the metabolic syndrome, but did not include a Adams JD, Jr., Lauterburg BH and Mitchell JR (1983) measure of insulin resistance or hyperinsulinemia, Plasma glutathione and glutathione disulfide in the rat: nor did they include microalbuminuria.
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Aebi H (1984) Catalase in vitro. Methods in Enzymology Conclusions
Based upon the discussed literature, rationale exists Alberti KG and Zimmet PZ (1998) Definition, diagnosis to purpose a series of studies, in order to assess the and classification of diabetes mellitus and its effect of aerobic exercise training on lipid and complications. Part 1: diagnosis and classification of lipoprotein levels and resting and exercise induced diabetes mellitus. Provisional report of a WHOconsultation. Diabetic Medicine 15, 539-553. oxidative stress in type 1 diabetes and to assess theassociation of leisure-time physical activity and Alessio H and Goldfarb AH (1988) Lipid peroxidation andscavenger enzymes during exercise: adaptive response to cardiorespiratory fitness with development of the training. Journal of Applied Physiology 64, 1333-1336.
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International School of Liquid Crystals 10th Workshop COMPUTATIONAL METHODS FOR POLYMERS AND LIQUID CRYSTALLINE POLYMERS A NATO Advanced Research Workshop Erice (TP), Centre E. Majorana, July 16 - 22, 2003 Directors of the Workshop: P. Pasini, S. Žumer INVITED TALKS G. Allegra G. Allegra J. H.R. Clarke and W. den Otter J. H.R. Clarke, A. Sunaidi

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PIEDMONT COMMUNITY SERVICES Assessment / Social History Identifying Information Presenting Problem, Onset and History of ProblemInformation pertaining to this assessment was gathered from the mother, client, and chart. Client is referred to IIH from case management due to demonstrating disrespectful behaviors towards peers and adults. The mother reports that client is exhibiting aggr

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