metabolically healthy obese ( mho ) term refers to obese individuals who are relatively insulin sensitive and normotensive and have favourable glucose and lipid profile inspite of high levels of obesity [ 1 , 2 ] .
evidence suggests that mho individuals as based on bmi criteria may account for as much as 2030% of obese population [ 3 , 4 ] .
mho subset of individuals is relatively protected from obesity related cardio - metabolic disturbances that increase cardiovascular disease ( cvd ) risk in metabolically abnormal obese .
however , data concerning the exact risk of cvd in mho as compared to healthy normal weight individuals is limited , and most data are confined to women at narrow age range .
carotid artery intima media thickness ( cimt ) is a non - invasive surrogate marker of subclinical atherosclerosis and an indicator of cvd risk [ 6 , 7 ] .
in addition , imt is associated with age , male gender , obesity , and traditional risk factors [ 811 ] . beside traditional cvd risk factors ,
obesity is associated with changes in insulin like growth factor-1 ( igf-1 ) [ 12 , 13 ] which may be linked to atherosclerosis .
previous studies concerning the association between igf-1 and atherosclerosis have led to conflicting results ; some authors found positive association between igf-1 and imt in men   and in both men and women , while others found inverse association between igf-1 and carotid imt in healthy women .
another study in middle aged subjects showed that imt and igf-1 are positively associated in women and inversely in men .
greater subclinical cvd burden in metabolically benign obese individuals compared to metabolically healthy lean women was recently reported .
further studying of subclinical cvd profile in mho men and women and investigation of its correlates may help in proper management of mho individuals .
the aim of the present study was to assess carotid intima media thickness ( cimt ) as a marker of subclinical atherosclerosis in metabolically healthy obese ( mho ) subjects as compared to healthy nonobese subjects .
also we evaluated the relation of cimt with age , sex , and igf-1 in mho subjects .
the study comprised 75 mho subjects ( 37 men and 38 women , mean age 48.85  11.59 years ) and 80 age , and sex , matched healthy nonobese ( bmi 2024.9  kg / m ) control subjects ( table 1 ) .
healthy obese adults were included in the study , and they were recruited from obesity clinic of specialized medical hospital , mansoura university , egypt . all subjects signed an informed consent to be included in our study .
exclusion criteria included smoking , alcohol consumption , cardiovascular , inflammatory or metabolic diseases , known or suspected pituitary , thyroid , adrenal or gonadal dysfunction , pregnancy , abnormal liver function tests , and medications ( antihypertensive , lipid lowering , hypoglycaemic agents , growth hormone , anabolic steroids , glucocorticoids , hormone replacement , and hormonal contraception ) .
anthropometric measurements including height , weight , body mass index ( bmi ) , and waist circumference ( wc ) were obtained using standardized techniques ; height was measured to the nearest 0.5  cm , body weight was measured to the nearest 1.0  kg using mechanical weight scale ( in the fasting state in the morning while wearing light clothes and no shoes ) .
bmi was calculated as weight / height ( kg / m ) , and wc was measured at the highest point of the iliac crest at the end of normal expiration .
blood pressure ( bp ) was measured in the sitting position , with a mercury sphygmomanometer after a 10-minute rest .
the systolic and diastolic blood pressure were read to the nearest 2 mmhg and recorded at the appearance ( phase i ) and disappearance ( phase v ) of korotkoff 's sounds respectively .
metabolically healthy state , defined as having 0 to 1 out of six cardiometabolic abnormalities including ( 1 ) bp 130/85 , ( 2 ) fasting triglyceride level 150  mg / dl , ( 3 ) hdl - c < 40  mg / dl in men and < 50  mg / dl in women , ( 4 ) fasting glucose 100  mg / dl ( atp - iii cut - off values ) , ( 5 ) homa - ir > 2.7 , ( 6 ) high sensitive c - reactive protein ( hs - crp ) > 3  mg / l ( cutoff values for homa - ir and hs - crp were obtained from karelis and rabasa - lhoret ) .
fasting blood sample ( 10  ml ) was drawn from cubital vein of each participant in the sitting position between 8.00 and 10.00 a.m. , after 12 hours of fasting .
each blood sample was divided into two tubes , one of them containing edta for preparation of plasma and the other for preparation of serum .
plasma glucose and serum lipids were assayed immediately , and the remaining of the samples were kept in aliquots at 70c till the time of the rest of assays . fasting plasma glucose ( fpg ) was estimated using commercially available kit supplied by human ( germany ) .
fasting serum insulin was assayed by a solid - phase , enzyme - labeled chemiluminescent immunometric assay using immulite analyzer supplied by siemens ( usa ) .
homeostasis model assessment of insulin resistance ( homa - ir ) index was calculated according to the formula : homa - ir = fasting insulin ( u / ml )  fasting glucose ( mmol / l)/22.5 .
total cholesterol ( tc ) , triglyceride ( tg ) , and high density lipoprotein cholesterol ( hdl - c ) were assayed by commercially available kits , cobas ( integra-400 ) supplied by roche diagnostic , germany .
low density lipoprotein cholesterol ( ldl - c ) was calculated according to friedewald et al . .
high sensitivity crp ( hs - crp ) was estimated using an immunoenzymometric assay supplied by monobind inc .
serum igf-1 was estimated by immunoenzymometric assay supplied by roy bio ( usa ) with intraassay cv < 10% , inter - assay < 12% , and no cross - reactivity with other cytokines .
carotid imt was measured by b mode ultrasound using high frequency transducers 47 and 512  mhz ; all subjects were examined with atl 5000 , usa , and philips 11xe , the netherlands .
subjects lie supine with slight head tilt to the contralateral of the examined side , with elevation of the shoulder to stretch the neck in subjects with short neck .
common carotid artery ( cca ) was scanned bilaterally ( in the longitudinal and transverse views ) 1  cm before carotid bulb over a length of 1  cm at the far wall of both ccas .
imt thickness was measured at plaque free segments only as the distance between the leading edge of the lumen - intima interface and media - adventitia interface .
two measurements were taken from each side and averaged ; then , the mean carotid imt was calculated as the average of measurements obtained from both ccas ( figure 1 ) .
student 's t - test was conducted to compare the mean of continuous variables in two groups .
baseline characteristics of the mho subjects and nonobese healthy controls are shown in table 1 .
mho subjects had significantly higher sbp , fasting insulin , homa - ir , tg , ldl - c , crp , and cimt ( 0.78  0.15 versus 0.67  0.10 ) and significantly lower hdl - c and igf-1 ( 203.7  40.3 versus 229.4  57.5 ) than those of healthy nonobese subjects .
mho participants were divided into 2 groups according to sex . compared to mho women ,
no significant difference was observed between mho men and women regarding fasting insulin , homa - ir , tg , hs - crp , and igf-1 ( table 2 ) .
cimt was significantly higher in mho men than in mho women ( 0.82  0.16 versus 0.74  0.14 ) ( table 2 ) .
mho women were divided into 2 age subgroups with respect to menopausal state : from 30 to 50 year ( premenopausal ) and above 50 years ( after menopause ) , and they were compared to their age range matched subgroups of mho men ; cimt was significantly higher in mho men age subgroup ranged from 30 to 50 years than that in their age ranging matched pre - menopausal mho women .
however , the difference in cimt between mho men and women age subgroups above 50 years was insignificant ( figure 2 ) .
the correlation between cimt and other parameters in mho subjects is shown in table 3 .
cimt was positively correlated with age , bmi , wc , sbp , homa - ir , tg , and ldl - c and negatively correlated with igf-1 .
regression analysis was done to identify predictors of cimt in mho ( table 4 ) .
age , sex , sbp , bmi , wc , homa - ir , tg , ldl - c , and igf-1 were entered in the regression model .
only middle age , male gender , wc , and igf-1 remained independently and significantly associated with cimt in mho subjects .
the exact effect of metabolic healthy obesity on subclinical cardiovascular disease particularly in relation to age , sex , and different risk factors is not clearly defined . in the current study , we assessed cimt and its relation to age , sex and igf-1 in mho .
the main finding was elevated cimt and reduced igf-1 in mho subjects ; furthermore , imt in mho subjects was independently associated with male gender , middle age , and igf-1 .
our results are in agreement with previous findings of higher cimt in metabolically benign overweight / obese women compared to normal weight women . in addition rnlv et al .  
confirmed that the risk of cvd and mortality is elevated in mho individuals compared to metabolically healthy and lean individuals .
in contrast , park et al .   found similar cimt in healthy obese and healthy normal weight individuals . despite relatively favourable cardiometabolic profile in mho
as compared to metabolically abnormal one [ 1 , 2 ] , mho individuals appear to have greater subclinical cvd than normal healthy individuals .
these data go in line with our findings of less favourable metabolic profile in mho as indicated by significantly higher fasting insulin , homa - ir , tg , and ldl - c , and significantly lower hdl - c .
obesity itself may contribute independently to carotid structure and function abnormalities and early atherosclerotic changes in obese are only partially explained by traditional cv risk factors .
obesity may modulate cca diameter and may induce adaptive changes in carotid wall thickness independent of metabolic and atherosclerotic factors .
in addition to the increase in bp , obesity is associated with an elevation in total blood volume , basic cardiac output , and heart rate , which can induce new intima proliferation through changes in arterial wall stress .
in addition , we found significant correlations between cimt and bmi , wc , sbp , tg , ldl - c , and homa - ir in mho subjects .
however , among all previous cardio - metabolic variables , only wc was a significant predictor of cimt .
lakka el al .   demonstrated that abdominal obesity can be associated with progressive increase in cimt independently of general obesity and other risk factors . in healthy individuals ,
wc as a measure of abdominal obesity correlates better than bmi with subclinical atherosclerosis evaluated by cimt .
de michele et al .   also found a significant association between whr and carotid wall thickening independent of fasting insulin concentration .
we suggest that the presence of visceral obesity is more important than insulin resistance in healthy obese and the effect of insulin resistance may be confounded by wc , and some measured ( igf-1 ) or unmeasured factors .
our findings suggest that abdominal obesity in mho individuals may exert an independent effect on atherosclerosis and it may mediate the effect of obesity on early atherosclerosis so , reduction of wc should be a target not only in metabolically abnormal obese subjects but also in mho subjects .
less favourable inflammatory profile indicated by significantly higher hs - crp levels was detected in mho subjects .
we found insignificant relation between hs - crp and cimt . in agreement , sinning et al .   found no independent association between cimt and crp .
it is suggested that crp is more predictive for cardiovascular prognosis in subjects of established carotid atherosclerosis .
in addition , age was the most significant predictor of cimt among mho subjects ; this is consistent with previous studies reporting an association between imt and age in both genders [ 8 , 9 ] .
aging induces intrinsic changes in the arterial wall including progressive increase in intimal thickness , and this constant increase in imt over age is an effect present in both male and female . in accordance with a previously reported gender difference in imt , we found that mho men had significantly higher cimt than mho women , and the male gender remained independently associated with cimt ; this can be explained in part by a small increase in ldl - c and decrease in hdl - c in our mho men as compared to mho women .
furthermore , the difference in cimt between mho men and women in the current study seems to be influenced by menopausal status because it was more significant between middle age , than older age , subgroups .
tan et al .   reported that traditional risk factors explain only a small amount of gender variance in imt , supporting the hypothesis that other sex hormone - related , behavioural , or genetic factors may play a role in the gender differences .
igf-1 is a nontraditional factor which has been linked to atherosclerosis and obesity [ 12 , 34 ] .
we observed that mho subjects had lower igf-1 levels than healthy nonobese subjects which goes in line with the negative association between igf-1 and bmi found by others [ 12 , 13 ] .
the relation between obesity and igf-1 is complex ; it is hypothesized that free igf-1 increases with body weight until it reaches a level that triggers a negative feedback that would suppress growth hormone secretion ( gh ) which in turn would result in decreased igf-1 production in the liver .
these results are parallel to those of marini et al . , who suggested that low igf-1 levels could contribute to early atherosclerosis in mho women compared with non - obese women .
on the other hand , increased risk of atherosclerosis among individuals with low igf-1 was previously reported .
in contrast , some found positive association between igf-1 and imt in men   and in both men and women .
another study in middle aged subjects showed that imt and igf-1 are positively associated in women and inversely in men .
this seems to be a conflict , however the relation between igf-1 system and cvd is complex , and there are many positive and negative associations .
both disorders of gh / igf-1 axis activity including gh deficiency characterized by low serum igf-1 and acromegaly accompanied by igf-1 excess are associated with increased intima thickness [ 36 , 37 ] , so , a probably u - shaped association between the gh / igf-1 axis activity and atherosclerosis was suggested though direct mechanisms of such a relation need to be elucidated .
some speculate that igf-1 is a proatherogenic by exerting an antiapoptotic effect on vascular smooth muscles and endothelial cells , and by being a promigratory factor , however , a detailed atheroprotective effect of igf-1 has been fully reviewed .
atherosclerosis is a chronic inflammatory disease initiated by oxidative stress , so the association of low igf-1 with early atherosclerosis in our study is consistent with its potential anti - inflammatory and antioxidant effects ; as well as its possible role in endothelial function through its stimulation of endothelial nitric oxide production [ 41 , 42 ] .
interestingly , physical activity is an important regulator of gh / igf system , also weight loss restored low levels of free igf-1 to normal , this further highlights the beneficial effect of life style based weight reduction in healthy obese .
our study has some limitations , first , the cross sectional design , second , the sample size being relatively small ; however , further prospective evaluation on larger scale study may be recommended .
third , cimt was assessed by one investigator ; however , a reasonable examination protocol was done by an expert radiologist . in conclusion ,
cimt is elevated and igf-1 is reduced in mho subjects , and cimt is independently associated with male gender , middle age , and igf-1 .
 
 background / aims . 
 the effect of benign obesity on subclinical cardiovascular disease is still questionable . 
 the purpose of this study was to assess carotid intima media thickness ( cimt ) , as a marker of subclinical atherosclerosis , and to evaluate its relation to age , sex , and igf-1 in metabolically healthy obese ( mho ) subjects . 
 methods . 
 a total of 75 mho subjects and 80 age , and sex matched healthy nonobese control subjects were included in the study . 
 body mass index ( bmi ) , waist circumference ( wc ) , blood pressure , fasting plasma glucose , fasting insulin , homa - ir , lipid profile , insulin like growth factor-1 ( igf-1 ) , and cimt were assessed in all subjects . 
 results . 
 mho subjects had significantly higher cimt and lower igf-1 than healthy nonobese controls . 
 mean cimt was significantly higher in mho men age subgroup range from 30 to 50 years than in their age range matched ( premenopausal ) mho women subgroup . in mho subjects , cimt was positively correlated with age , bmi , wc , sbp , homa - ir , tg , and ldl - c , and negatively correlated with igf-1 . 
 regression analysis revealed that middle age , male sex and igf-1 remained independently associated with cimt in mho subjects . 
 conclusion . 
 cimt is elevated and igf-1 is reduced in mho subjects , and cimt is independently associated with male gender , middle age , and igf-1 . 
 definition of healthy obesity may be broadened to include imt measurement . 