This work demonstrates that both weight loss and insulin reductions had direct and positive effects on arterial stiffness, and that the strongest effect occured in individuals who simultaneously lost weight and lowered their insulin levels. Specifically, weight loss and insulin reductions were individually associated with improvements in baPWV independent of cardiometabolic risk factors. The combined effect of weight loss and insulin reduction over 6-months had a greater impact on baPWV than weight loss or insulin reductions alone.
Weight loss has been previously shown to improve vascular stiffness [9
] although the mechanism underlying this association is unknown. Previous work from the SAVE trial has studied various predictors of changes in pulse-wave velocity [9
]. The current analysis was directed at studying the relationship between weight loss, improved insulin sensitivity, and subsequent changes in vascular stiffness. We found that the combined effects of weight loss and reduction in circulating insulin was independent of changes in other factors related to change in pulse-wave velocity [9
]. Weight loss affects a wide variety of physiologic measures, including insulin sensitivity and circulating insulin levels, in part, through improved insulin homeostasis [18
]. Hyperinsulinemia promotes the arteriosclerotic process by instigating vascular smooth muscle cells proliferation and migration in the vessel wall [18
]. Recently Yue et al., in a study of people with type 2 diabetes, found that poor glycemic control was associated with lower circulating levels of endothelial progenitor cells and higher ba
]. PWV is also associated with other measures of arterial architecture, including vascular thickness [9
]. Results from the ongoing Vaso Risk study [25
] have the potential to provide more detail on the relationship between diabetes, glycemic control and arterial stiffness.
The observed results differ by location within the arterial tree. Weight loss and insulin reduction were associated with reductions in ba
PWV, a mixed measure of stiffness, but not with changes in purely central or peripheral measures. These data suggest improvements in weight and insulin are likely to be systemic and can be seen in measures of the vasculature that incorporate both central and peripheral PWV. While central measures of PWV changed in response to the lifestyle intervention in SAVE, weight loss and insulin reductions were not associated with changes in these measures. The individual and combined effects of weight loss and insulin reductions were more pronounced in the mixed measure than the purely central and peripheral measures. Our findings suggest that using mixed measures of PWV that take into account both central and peripheral vascular changes is the best representation of the effects of weight and insulin change on arterial stiffness. These findings add to previous studies that show weight loss is associated with improvements in both central [5
] and mixed [9
] measures of arterial stiffness. The effects of weight loss and insulin declines are more apparent throughout the vasculature than in central and peripheral arterial beds alone.
It is possible that we only detected significant differences in ba
PWV because this mixed measure of arterial stiffness is more sensitive to short-term vascular remodeling. However, it is also possible that we did not see effects in cf
PWV as a result of its large variances at baseline and follow up, resulting in limited statistical power to detect small changes over time. The addition of carotid and femoral probes makes the PWV protocol more difficult to execute and may result in more error in the peripheral measures especially in obese individuals [27
]. In previous analysis, our group identified factors other than changes in insulin as potential predictors of cfPWV [9
]. Furthermore, the removal of potential outliers (thirty individuals with change in cf
cm/sec) had little effect on the results of these analyses and weight loss and insulin reduction still did not predict changes cf
In this analysis, adjustment for insulin change fully attenuated the association between weight loss and decreases in ba
PWV. This evidence builds on the findings of previous studies that show insulin levels and impaired fasting glucose are more related to peripheral measures of PWV than BMI, weight and weight loss. A study of 697 non-diabetic adults found increased ba
PWV in subjects with impaired fasting glucose, independent of BMI [28
]. While these results imply that there is a connection between impaired fasting glucose and mixed measures of arterial stiffness, their study did not measure fasting insulin levels and could not conclude that the effect of impaired glucose levels on ba
PWV were independent of insulin levels [28
]. Zhang et al., found that Chinese people with type 2 diabetes had increased central and peripheral PWV compared to controls, and fasting glucose was a determinant of peripheral artery stiffness. This study did not measure fasting insulin levels or relate these levels to neither fasting glucose levels or arterial stiffness [29
]. Recently, Rudofsky et al. reported the effects of 12
weeks of weight loss intervention in 21 obese and non-diabetic participants on PWV, measured by finger photoplethysmography [15
]. They showed that improvements in PWV were associated with improvements in HOMA-IR only, and not with weight loss.
The effect of weight loss and insulin reduction on ba
PWV was stronger in men. The differential effect of sex is likely explained by differences in the baseline characteristics of men and women recruited for the SAVE trial. At SAVE baseline, men had greater risk factors for CVD and diabetes and higher baseline PWV than women. As a result, the SAVE intervention had a greater impact on weight loss and cardiometabolic risk factors in men. In the first six months of the SAVE trial, men lost more weight than women (9.3
kg vs. 5.8
kg) and had more than twice the decrease in insulin (2.5 μU/mL vs. 1.0 μU/mL). Our findings suggest that the weight loss intervention was more successful in men than women, as has been reported previously in the literature [5
The relatively small numbers of men and African-Americans in the SAVE trail limits our ability to generalize to these groups and to stratify all analyses by gender or race, although adjustment for these factors was made. Additionally our study only focused on the 6-month change in weight, insulin and PWV. Consistent with other findings, the SAVE study found that weight loss plateaus between 6–12
months of follow up; consequently, we limited our analysis to 6-month data to avoid instances of weight re-gain in study subjects.
The SAVE trial provides longitudinal assessment of arterial stiffness and cardiometabolic risk factors. While the participants in SAVE were overweight or obese, they were generally healthy, without impaired fasting glucose or diabetes [8
]. The SAVE trial focuses on this segment of the population enabling the study of the effects of obesity and the early stages of insulin resistance prior to the onset of diabetes. Obese individuals with hyperinsulinemia are potentially ideal targets for such an intervention targeted to lower PWV. Our study shows that in terms of cardiovascular risk, people with hyperinsulinemia and obesity will likely show the most benefit from a weight loss intervention. Further, the measurement of regional PWV provides additional insight into the correlates of arterial stiffness along the vasculature, which a single assessment could not provide. Future studies of weight loss and changes in arterial stiffness should utilize additional measures of metabolic syndrome [31
] and diabetes risk factors [32
] to elucidate the relationships between weight loss, diabetes risk factors and arterial stiffness.