The results from the present study showed that physiologically measured sedentary time using individual calibration was associated with hyperinsulinemia measured 5.6 years later in healthy middle-aged Caucasian subjects. This association was independent of baseline confounders including age, sex, fat mass, fasting insulin, smoking status, follow-up time, and MVPA. Similar results were found when we modeled sedentary time as quartiles. Moreover, reliability estimates from a repeated-measures substudy of this cohort suggest that the true association between behavior and health is likely to be twice as strong as those observed (18
Our observations are consistent with previous cross-sectional findings using objective measurements of sedentary time suggesting that this behavior is associated with 2-h blood glucose (19
) and metabolic syndrome features (11
) in adults. Our results extend these previous cross-sectional observations by suggesting that sedentary time predicts higher levels of fasting insulin independent of time spent in MVPA and other confounding factors. This observation is, however, in contrast to recent prospective observations in high-risk individuals, where accelerometry-measured MVPA and not sedentary time predicted insulin resistance at follow-up (14
). Differences between studies are likely explained by differences in methodology for assessing sedentary time, duration of follow-up, and population (i.e., age, diabetes risk, and obesity status). Future studies are needed to determine whether objectively measured subcomponents of physical activity differentially predict insulin resistance and other metabolic outcomes caused by baseline age, obesity status, and diabetes risk.
The following study strengths and limitations should be considered. First, because the present study is observational, the extent to which causality can be inferred is less than that for a randomized controlled trial. However, our prospective study design, the relatively precise measure of our main exposure variable, and the possibility to control for many confounding factors support a causal independent positive association between sedentary time and the development of insulin resistance. Second, the use of individually calibrated heart rate monitoring for measurement of sedentary time is likely to be more accurate compared with self-report methods. Although this method is somewhat susceptible to heart rate fluctuations due to external factors (environmental and emotional influences), the individually defined FHR will greatly reduce misclassification of time spent sedentary. The thresholds used for defining sedentary time and MVPA are somewhat arbitrary. However, these intensity thresholds are feasible when using heart rate monitoring in large population-based studies (9
). Our estimate of time spent sedentary and at MVPA, based on the FHR and RHR, is adjusted relative to the fitness level of each individual because RHR is lower in more fit individuals. This means that our results may not be directly comparable with results obtained with other objective methods such as accelerometry. The confounding effect of aerobic fitness on our results is likely to be minimal. Indeed, additional adjustments for aerobic fitness did not change results for any of the models (data not shown). Third, the associations observed in this group of healthy middle-aged Caucasian subjects may not be generalizable to other populations that differ in age and physical activity. Volunteers more than 65 years of age at follow-up were not included due to safety precautions for the exercise test. However, our results were unchanged after excluding those with impaired fasting glucose, suggesting that this condition did not explain our findings. Fourth, other potential confounders not accounted for in the analyses, such as genotype, dietary habits, birth weight, early growth patterns, and pharmaceutical factors, may explain some of the observed associations. Also, although we adjusted for MVPA, we could not adjust for total PAEE because of collinearity. Finally, fasting insulin is not a direct measure of insulin resistance, but it has been shown consistently that fasting insulin is a robust surrogate for insulin resistance and is associated with the metabolic syndrome, diabetes, and their etiology (21
Using data from this cohort, we recently showed that sedentary time at baseline was not significantly associated with a wide range of obesity indicators at follow-up; interestingly, greater fat mass, waist circumference, and BMI at baseline significantly predicted sedentary time at follow-up (22
). This suggests that sedentary time may be differentially associated with various health outcomes and also urges the need for more prospective studies using objective methods for assessing the dose-response relationships between various subdimensions of physical activity with obesity, insulin resistance, and other chronic disease risk factors.
The results from this study may have important clinical implications. In a meta-analysis, Ruige et al. (23
) reported an increased risk of 18% (8–29%) for cardiovascular diseases per increment of 50 pmol/l in fasting insulin. Further, a recent meta-analysis demonstrated a linear association between fasting insulin levels and cardiovascular mortality independent of other risk factors (2
Pathways through which inactivity can lead to insulin resistance and its comorbidities include vascular changes. Vascular and endothelial dysfunction may contribute to reduced blood flow, decreased peripheral insulin-stimulated glucose uptake, and reduced glucose-stimulated insulin secretion (24
). A sedentary lifestyle also has a direct effect on inactivity-induced factors including deep venous thrombosis and poor lipid metabolism (25
In summary, this is the first study suggesting that increased time spent sedentary is prospectively associated with elevated fasting insulin levels regardless of the amount of time spent in MVPA in healthy middle-aged adults. From a public health perspective, these findings urge the need for recommendations aimed at reducing sedentary time in addition to those aimed at increasing MVPA.