Our data demonstrate that arterial stiffness is increased in subjects with obesity-related T2DM compared to lean controls. We also demonstrated higher stiffness in obese diabetic as compared to non-diabetic obese subjects. These findings hold true for carotid-femoral PWV a measure of central arterial stiffness, BrachD which measures a peripheral muscular artery and AIx which is a mixed measure influenced by central stiffness and peripheral wave reflections. As expected, CV risk factor profile deteriorated from L to O to diabetic subjects, with central adiposity (android-gynoid ratio), blood pressure and metabolic control (TG, HDL-C and fasting insulin) displaying the greatest difference between T2DM subjects and the other groups. However, for most measures, status as an non-diabetic obese or obese diabetic subject remained an independent determinant of arterial stiffness even after correcting for risk factors. These data demonstrate there is pervasive vascular dysfunction associated with obesity and diabetes above and beyond what is expected from the contribution of traditional risk factors.
Adult studies consistently demonstrate increased PWV along the trunk in subjects with T2DM as compared to controls[18
] regardless of level of systolic blood pressure.[2
] This increase in central stiffness affects hard outcomes as demonstrated by the hazard ratio shown for all-cause and CV mortality of 1.08 (95% CI 1.03 to 1.14) for each 1 m/sec increase in PWV.[2
] Peripheral stiffness is also higher in diabetic patients, as demonstrated by lower brachial compliance, than controls even when measured at isobaric conditions controlling for baseline distending pressure.[20
] The mixed measure, AIx, is higher (stiffer) in diabetic versus control subjects[21
] with diabetes emerging as an independent determinant of AIx in multivariate analyses in adult men.[22
] Although Scuteri demonstrated higher PWV in insulin-resistant first-degree relatives of diabetic subjects (average age of 33 ± 7 years)[23
] and Haller found higher AIx in adolescents with type 1 diabetes mellitus,[24
] our data are the first to demonstrate increased arterial stiffness in young subjects with T2DM. Furthermore, our findings of increased PWV in the arm and leg of diabetic subjects as compared to non-diabetic controls suggests that early peripheral vascular disease may be identified in youth with T2DM.
Adiposity correlates strongly with PWV in adult diabetics.[25
] In non-diabetic adults, both BMI, a measure of overall adiposity, and waist-hip ratio, a measure of central adiposity, are strong independent determinants of PWV, explaining similar amounts of variance in arterial stiffness.[26
] Obesity has also been associated with brachial artery stiffness. Zebekakis et al[27
] studied over 1300 subjects aged 10 to 86 years (average 44 years) with an ultrasound-based wall-tracker technique. Consistently, a lower brachial distensibility was seen with increasing BMI across ages, even after adjusting for BP, lipids and blood glucose.[27
] The relationship between adiposity and AIx appears to be more complex. In one study of indigenous Australians, weight, waist circumference, BMI and fat mass were all determinants of AIx in multivariate analyses.[28
] However, the investigators did not find a difference in AIx by diabetic status which may relate to genetic differences in this population, limiting generalizability to our Caucasian and African-American cohort. In contrast, Greenfield et al[29
] found that only central fat, not total body fat measured by DXA was an independent determinant for AIx in females. In our data, height was a significant determinant, not central adiposity. Shorter individuals have wave reflection sites closer to the heart resulting in earlier arrival of reflected waves even at the same mean blood pressure[30
] thus it is important to include height in modeling. Differences among our data and the reports by Maple-Brown[28
] and Greenfield[29
] may be related to the inclusion of height in our models.
Previous work demonstrated correlations between obesity and arterial stiffness in youth. Gungor et al[3
] studied adolescents and found a higher BMI to correlate (correlation coefficient = 0.5) with PWV after controlling for SBP. A recent paper studying younger children (average age 10.1 ± 0.3 years) compared anthropometric measures of adiposity to those obtained with DXA to determine the strength of their relationship to arterial stiffness. The investigators found that all measures (BMI, waist circumference, percent body fat by DXA) were independently associated with PWV with similar strength (total R2
) after adjustment for other CV risk factors.[31
] However, in both of these studies, android-gynoid ratio, a measure of central adiposity, which we found to be more consistently and strongly correlated with PWV, was not evaluated.
Other measures of arterial stiffness, such as resting brachial artery distensibility are also correlated with adiposity. Whincup used a wall-tracker technique and found BMI, percentage body fat (estimated from bio-electrical impedance), sum of skinfolds, waist circumference and waist-hip ratio all to be correlated with brachial artery function.[32
] As in our data, the strength of the relationship was greater between BrachD and adiposity than for other CV risk factors (BP, lipids). Singhal also measured fat mass with bioelectrical impedance and found this measure of adiposity, but not BMI, skinfolds or waist-hip ratio, to be independently related to brachial distensibility after adjustment for CV risk factors.[33
] This relationship was only found in boys[33
] but these findings in a predominantly pre-term cohort may not be directly applicable to our study group. Our data, which include a variety of methods for measuring obesity extend the observations regarding the importance of central adiposity in determining arterial stiffness.
The cross-sectional nature of this study does not allow determination of the time course for the development of the vascular changes seen. Therefore, we can not determine which arterial sites are influenced first by CV risk factors and whether obesity or obesity-related diabetes has a more profound effect. Our O group also had a greater proportion of non-Caucasian subjects which may have influenced our results. Furthermore, the predominance of non-Caucasian subjects in all groups may limit application of our findings to other races/ethnicities. Finally, use of arterial stiffness measurements for risk-stratification in children is limited by lack of normal values across ages, sexes and race/ethnicities. Additional large studies in healthy youth are needed before inferences linking arterial stiffness measured in youth and future CV outcomes can be made.
Adolescents and young adults with obesity-related T2DM and those with obesity without diabetes have increased arterial stiffness. These abnormalities persist after controlling for factors such as BP and lipids, implying an augmented risk for development of target organ damage which is predisposing to future CV events. Heightened awareness of the adverse consequences of obesity and obesity-related T2DM should prompt health care providers to institute early and aggressive life-style interventions in adolescents with or at risk for overweight.