Our results confirm that a more adverse CV risk profile and stiffer arteries are found in young obese individuals with IR. However, IR, as measured by the HOMA-IR index, was not an independent determinant of any of our measures of arterial stiffness. Rather, obesity, BP and other CV risk factors appeared to be mediating the vascular compromise.
Many adult studies demonstrate a link between obesity and vascular dysfunction. Reduced distensibility in the brachial, femoral and carotid arteries was related to a larger trunk fat mass as measured by dual-energy x-ray absorptiometry (DEXA) in the Hoorn study, a large population-based cohort examining the relationships between glucose tolerance and CV disease [10
]. Zebekakis et al [11
] found a similar relationship in a somewhat younger population. In fact, the association between adiposity, as measured by BMI, and brachial distensibility was stronger in younger individuals (<40 years). In a similar study of middle-aged adults, researchers found elevated arterial stiffness (higher PWV) with greater BMI and waist–hip ratio [12
]. However, in the study by Zebekakis et al, the relationship between PWV and adiposity was independent of BP only for women [11
]. They suggested that a more precise measure of adiposity might have demonstrated a relationship for both sexes, as seen when abdominal visceral fat was measured with computed tomography (CT) in the Health, Aging, and Body Composition Study [13
]. Data linking AIx to adiposity are less clear, with some studies demonstrating no relationship [14
], while another found a link only after correction for other CV risk factors [15
]. Again, method of determining adiposity may play a role, as one investigator found body fat measured with bioelectrical impedance, but not BMI, to be associated with AIx [16
Few paediatric studies of arterial stiffness have been performed. However, our previous work[4
] has consistently demonstrated a relationship between BrachD and adiposity in children. Other studies using different methods to measure brachial artery function than employed in our research (wall tracker[18
]), also found obesity to be an important determinant. More studies have employed PWV to measure arterial stiffness in youth. The CV Risk in Young Finns Study showed a higher PWV measured in adulthood with increasing numbers of CV risk factors measured in childhood including obesity [19
]. Other investigators have been able to correlate BMI with PWV measured in childhood[20
] and one large study of 573 healthy children found the relationship to be independent of other CV risk factors [21
]. The single study that did not find a correlation[22
] was performed in a younger group of children (average age 10 years) who had a much lower BMI (mean 17 kg/m2
) than our cohort. Our data extend these observations by demonstrating an independent relationship between BMI and arterial stiffness in a larger group of young individuals with PWV measured in the central arterial distribution (carotid–femoral) which is more closely related to hard CV events (coronary death or myocardial infarction) in adults [2
Adults with diabetes have higher PWV than healthy controls [23
], although vascular damage may begin before progression to type 2 diabetes, as HOMA-IR was independently associated with peripheral arterial disease even in healthy individuals in the National Health and Nutrition Examination Survey (NHANES) [24
]. Although adult studies have found IR to be independently associated with PWV, the methods used differed substantially from those in our study, and included use of a device that measures brachial–ankle PWV [25
], which results in much higher absolute values than the traditional carotid–femoral PWV. Another investigator found that fasting glucose was an independent determinant of PWV but that the variable estimates for BP indicated a much stronger effect [26
], mirroring our results and suggesting a stronger role for BP than metabolic control in determining arterial stiffness. Fewer data relate diabetes and IR to brachial artery properties and AIx. Megnien et al found lower brachial compliance measured under isobaric conditions in diabetic individuals as compared with controls[27
] and fasting glucose negatively correlated with compliance. Although Henry et al found that individuals with impaired glucose tolerance had lower BrachD than normal controls [28
], his later work found no differences between individuals with or without metabolic syndrome when stratified by sex [29
]. For AIx, one study found no difference between persons with or without diabetes but they had examined a mixture of individuals with both type 1 and type 2 diabetes [23
]. Another found increased AIx in females with metabolic syndrome, but not in males [30
]. However, this study was conducted in hypertensive adults and did not adjust for the known sex differences in AIx, as was done in our models.
In Japanese children, HOMA-IR was found to be an independent determinant of brachial–ankle PWV [31
]. However, there were substantial differences between these studies and our own data beyond the PWV technique and race differences. Our participants were older and heavier, which may substantially influence HOMA-IR results. Using ultrasound to measure PWV, Gungor et al found increasing arterial stiffness in obese youth with further increase in type 2 diabetes [20
]. Although multiple regression found HOMA-IR to be an independent predictor, lean individuals were excluded from the analysis and BP and adiposity were not included in the model [20
]. Using an optical method to measure PWV, Schack-Nielsen et al did not find PWV to be associated with HOMA-IR [22
]. However, these 10 year old children were significantly younger and lighter than our study population. Again, data on the brachial artery and AIx in children are also limited. Whincup et al [18
] did see a relationship between IR and brachial distensibility, but only among the 13 to 15 year old group, and not the 9 to 11 year olds. The one study that examined AIx found no relation to glucose tolerance but included only 44 children, and may have been underpowered to demonstrate differences [32
]. Our study expands the observations on the relationship between IR and arterial stiffness to a population more representative of American youth.
Increased leptin levels have been associated with obesity in youth [33
]. Some investigators suggest that leptin/adiponectin ratio is a more sensitive indicator of IR than HOMA-IR [34
]. We found an inverse relationship between leptin level and PWV, although the effect size was quite small. Although some investigators have found a positive relationship between leptin and PWV [35
], others found no relationship with carotid intima–media thickness [36
], and in one large study, there was no relationship between these adipocytokines and coronary heart disease mortality [37
]. Additional studies are needed to further explore these findings.
The cross-sectional nature of this study does not allow determination of the time course for the development of the vascular associations seen. Therefore, we cannot prove that there is a decline in vascular function as an individual gains adiposity. Our obese and obese insulin-resistant groups also had a greater proportion of non-white individuals, which may have influenced our results. Another potential source of selection bias was our exclusion of lean insulin-resistant individuals. This type of individual constituted only 2.8% of the school-based population from which our participants were recruited, making it unlikely that there would have been sufficient numbers to demonstrate differences in arterial stiffness from the other groups. More precise methods for assessing adiposity and body fat distribution, such as DEXA or CT, were not feasible in this school-based cohort. Therefore, it is not possible to determine if body composition was an independent determinant of arterial stiffness. Finally, normal values for arterial stiffness across age, sex and race are not available for youths, limiting the usefulness of these measures in risk stratification.
We conclude that although obesity-related IR is associated with increased arterial stiffness, it is the more adverse CV risk profile that is actually driving the vascular compromise in non-diabetic, otherwise healthy, young people. The practice of ‘primordial prevention,’ which relies on prevention of acquisition of CV risk factors, especially aggressive early treatment of obesity, is needed to avoid the vascular dysfunction in youth that may lead to future heart attack and stroke.