Our study showed that adolescents and young adults with T2DM have significantly thicker cIMT than lean controls for the all carotid artery segments. This is not surprising since our subjects with T2DM had higher CV risk factor levels. More important is the confirmation that increased thickness of the common carotid and bulb can also be found in uncomplicated obesity. Furthermore, beta stiffness coefficient and YEM were higher in both obese and T2DM subjects as compared to lean, when examined in an analysis of variance. These data demonstrate that early changes in vascular structural and function can be demonstrated in youth with obesity prior to the development of carbohydrate intolerance. Additional compromise is demonstrated in patients with established T2DM.
As expected, levels of CV risk factors increased from the lean to obese to T2DM groups and traditional CV risk factors correlated with cIMT and stiffness. In multivariate analyses, group was an independent determinate of cIMT for the common carotid and beta stiffness coefficient. Classification as obese or T2DM was not an independent determinant of cIMT in the bulb or internal carotid or YEM. This suggests that the effect of obesity and T2DM may impart additional influences on common carotid structure and some measures of carotid function that are not entirely explained by traditional CV risk factors. In addition, obesity and T2DM may be modifying the effect of risk factors as seen by the greater effect of age on common carotid cIMT in the obese and T2DM as compared to the lean group.
Adult studies have demonstrated a strong association between obesity and cIMT. The Multi-Ethnic Study of Atherosclerosis examined a large cohort (N = 6814, 45 - 84 years) of CV disease free subjects and found obese subjects of both genders were more likely to have common and internal carotid cIMT greater than the 80th
Although the obese subjects were more likely to report hypertension or diabetes, the association between adiposity and cIMT persisted after adjustment for traditional CV risk factors.3
Developing adiposity in childhood has also been linked to carotid thickness as an adult.14
In the Muscatine Study, childhood BMI was a significant determinate of cIMT measured as an adult (33-42 years) for women.15
The Bogalusa Heart Study found that cumulative levels of BMI in childhood were associated with adult cIMT in both genders even after controlling for adult BMI.16
Cross-sectional studies have demonstrated a relationship between obesity and common carotid IMT during childhood.17-22
Iannuzi studied 100 children with BMI > 95th
percentile (CDC) who were healthy without any obesity-related comorbidities (hypertension, dyslipidemia, glucose intolerance or diabetes).23
Common carotid IMT was thicker in obese youth compared to age-matched controls even after controlling for traditional CV risk factors. However, when glucose was entered into the model instead of HOMA, the difference in cIMT by obesity group reached only marginal significance.23
In a similar study, Reinehr found glucose to be an independent determinate of cIMT in obese and lean children along with BMI, SBP and high sensitivity CRP.24
These data suggest a similar relationship between worsening carbohydrate intolerance and thicker cIMT as seen in adults. Mangee studied a larger cohort (N = 228) and also found increased cIMT in obese as compared to lean children. However, only the common carotid was evaluated and no multivariate modeling was performed.25
In a study of Chinese youth, both the internal and common carotid arteries were thicker in obese subjects. However, the bulb was not examined in the study nor was multivariate regression performed. Furthermore, the average BMI in this small study (N = 61, BMI 27.7 kg/m2
) was lower than in our cohort (BMI 36.5 kg/m2
) suggest that their findings may not be generalizable to more obese American youth.26
One recent study did measure all three carotid segments in lean and obese youth, but only on the left side. Furthermore, their multivariate models contained incomplete lipid data (only 12 of 30 controls) and did not include BP as a covariate.27
Our data extend the observations on the effect of obesity on all segments of the carotid artery and provide insight on independent determinants of cIMT in youth using multivariate models containing all traditional CV risk factors.
Similar to data on cIMT, truncal subcutaneous fat accumulation measured as an adolescent was associated with increased cSTIFF in adulthood (average age 36 years).28
In a larger study of healthy adults (N = 2255, age 24-39 years), the relationship remained even after adjusting for number of CV risk factors.29
Cross-sectional studies of children have also demonstrated increased cSTIFF in obese subjects with the metabolic syndrome as compared to obese children without this CV risk factor clustering even after adjusting for age, gender and CRP.30
Tounian, et al found obese youth to have stiffer carotid arteries when compared to lean controls but they did not find significant relationship between cSTIFF and CV risk factors.31
Our data includes a larger cohort than the study by Tounian which may explain our ability to demonstrate relationships between CV risk factors and carotid stiffness in both univariate and multivariate models. These data suggest that a spectrum of vascular abnormalities may develop as an individual develops obesity prior to progressing to metabolic derangement and final development of type 2 diabetes.
Substantial data are available describing vascular changes in adults with T2DM. Diabetic subjects have both thicker32, 33
carotid arteries than healthy controls. Thickness is affected by BP, age, duration of diabetes, glycemic control and degree of adiposity.32, 35
Insulin resistance modifies carotid stiffness in adults with T2DM.34
Arterial stiffness is also affected by carbohydrate intolerance. Data from the Atherosclerosis Risk in Communities Study show higher carotid stiffness with increasing concentrations of fasting glucose in non-diabetic middle aged subjects.36
This was also seen in the Rotterdam Study of older adults.37
Our observation of increasing severity of carotid abnormalities across the obese to the diabetic subjects also suggests a graded effect of diminishing metabolic control on vascular damage.
In youth, substantial evidence is available demonstrating abnormalities in carotid ultrasound in subjects with type 1 diabetes. Most are small studies with fewer than 100 subjects and the majority image only the common carotid artery.38-40
Although the majority demonstrate significantly thicker cIMT in youth with T1DM as compared to controls, many are unable to demonstrate relationships between CV risk factors and cIMT. This may be due to absence of risk factor data 41, 42
or study designs where subjects were intentionally or coincidentally matched by risk factor levels.43, 44
Similar to our data, a few studies did find univariate correlations between cIMT and BMI, BP and lipids but did not perform multivariate analyses to evaluate independent determinates.25, 45, 46
The narrow range of differences in BP and cholesterol levels between controls and children with T1DM is not surprising given the normal, low BMI levels in cases and controls in these papers. Our data is the first to examine the effect of T2DM on cIMT. Furthermore, it includes 2 controls (1 lean and 1 obese) for each subject with T2DM providing a wider range of CV risk factor levels increasing our power to demonstrate independent associations between T2DM, CV risk factors and cIMT.
Stiffer vessels are also found in youth with type 1 diabetes. Poor glycemic control as manifest by higher HbA1c levels, correlated with carotid distensibility in one study.47
Another found environmental agents such as exposure to tobacco or frequent respiratory infections to be related to carotid compliance.48
Our data are unique in showing the effect of T2DM on vascular compromise in a larger group of adolescents and young adults.
Our cross-sectional design does not allow us to determine the time sequence for development of vascular changes as an individual progresses from uncomplicated obesity to metabolic syndrome and finally type 2 diabetes. This cohort also has a somewhat narrow age range which may have limited our ability to detect increase in common carotid cIMT in the lean subjects. The T2DM group was also slightly older with higher BP and cholesterol levels than the lean and obese groups. However, multivariate analyses controlling for these covariates were performed to statistically control for these disparities. Although we found a significant difference in cIMT between groups, the absolute magnitude of the differences were small. Therefore the utility of cIMT measurement for risk stratification for pediatric patients may be diminished by imprecision of the methodology and biologic variability. Furthermore, usage of ultrasound screening is limited by lack of normative data across ages, genders and race/ethnicity. Further refinement of ultrasound techniques and collection of additional data in normal children is needed to advance the field.
We conclude that adolescents and young adults with obesity and T2DM diabetes are at risk for early atherosclerotic changes in the carotid arteries. The abnormalities are only partially explained by traditional CV risk factors such as age and BP, as presence of obesity or diabetes contributed independently to carotid structure and function. These findings are particularly disturbing as the prevalence of obesity-related metabolic syndrome and T2DM in youth is increasing across the globe49
and may lead to a parallel increase in adverse CV outcomes. Therefore, pediatric health care practitioners should continue to screen for abnormalities in CV risk factors especially in children with elevated BMI or T2DM. Comprehensive life-style interventions to reduce obesity must be applied now if we are to prevent a projected decline in life-expectancy for our youth.50