We examined the interrelationships between inflammation, insulin resistance and PAD in this nationally representative sample population and found 1) that insulin resistance, indicated by HOMA-IR, is strongly associated with PAD and 2) that the presence of insulin resistance attenuates the association between CRP and PAD. Furthermore, this is the first study to illustrate the association of PAD and a direct measure of insulin resistance, HOMA-IR, a simple method that uses plasma insulin and glucose in a single fasting blood sample. HOMA-IR has previously only been reported in relation to cardiovascular6–8
and cerebrovascular disease.15–18
Indeed, we found a roughly 25% increased odds of PAD for each one-quartile increase in HOMA-IR, a finding that remained consistent despite adjustment for typical atherosclerotic risk factors, factors related to insulin resistance (i.e., body mass index), and glycemic control (hemoglobin A1c). In addition, although the trend across quartiles was marginally no longer statistically significant after adjusting for diabetes, the point estimates were essentially unchanged and subjects in the highest HOMA-IR quartile continued to have a nearly 2-fold increased odds of PAD. Using HOMA-IR as a continuous variable, we found a strong relationship between PAD and insulin resistance that persisted even after additional adjustment for diabetes or hemoglobin A1c. These data suggest that insulin resistance may have an association with peripheral arterial disease along the entire spectrum of insulin resistance and distinct from the impact of diabetes. Even after excluding subjects with diabetes, there were graded increases in PAD prevalence with increasing HOMA-IR quartiles, although the associations between HOMA-IR and PAD were no longer statistically significant. Our data support prior observations that PAD is associated with the metabolic syndrome11, 12, 36
and glucose intolerance13
, both surrogate markers of insulin resistance.
In contrast to the limited data on the association of insulin resistance and PAD, the link between inflammation and PAD has been well established. Our demonstration of a strong association between CRP and PAD is consistent with prior epidemiologic data and prospective studies linking inflammation with atherosclerosis in the coronary and peripheral arterial beds1–3, 19–23, 37
. However, much of the data on inflammation and atherosclerosis has been generated in healthy individuals. Less clear is whether this relationship persists in individuals with established cardiovascular risk factors, such as diabetes. Sakkinen et al. studied the relationship between CRP and myocardial infarction (MI) over a 20 year period and although they found a positive relationship between CRP and MI in the overall population, the association was abolished in individuals with diabetes.26
The same group also showed no significant relationship between CRP and stroke among patients with diabetes or hypertension.25
Prospective data from the Strong Heart Study in an American Indian population found no predictive value of CRP for incident cardiovascular events in diabetic individuals.38
In contrast, the Women’s Health Study2
found that CRP added prognostic information regarding cardiovascular events even in subjects with the metabolic syndrome, and a study by Schulze et al.27
found a strong relationship between CRP and cardiovascular events among men with diabetes. However, none of these studies focused specifically on peripheral arterial disease, and none directly examined the role of insulin resistance.
Given the conflicting data on the relationship of CRP and vascular disease among subjects with diabetes and metabolic syndrome, we explored the possibility that insulin resistance in particular might influence the relationship between CRP and PAD. Indeed, our analysis found a strong association between CRP and PAD among individuals who were insulin sensitive. However, this association was no longer evident in subjects with insulin resistance.
The attenuation of the relationship between CRP and PAD in the presence of insulin resistance may be explained in part by the close inter-relationship of inflammation and insulin resistance in vascular disease.28–30, 39
Extensive experimental data demonstrate that inflammation leads to impaired insulin metabolic signaling resulting in insulin resistance.39
Insulin resistance may in turn exacerbate inflammation via increased cytokine and adipo-chemokine expression (including tumor necrosis factor alpha (TNF-α), interleukin-6, leptin, monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and others), elevation of free fatty acid levels, and impaired endothelial nitric oxide synthase activity.39, 40
The reciprocal interaction of inflammation and insulin resistance creates a cycle of further increasing cardiovascular risk.
These findings also support the notion that atherogenesis results from the complex interplay of multiple atherosclerotic risk factors, each of variable influence in different vascular beds. In individuals with few risk factors, inflammation may have a relatively large contribution to the development of atherosclerosis. In contrast, in the presence of a potent cardiovascular risk factor, insulin resistance, the relative contribution of inflammation to the pathogenesis of atherosclerosis may be diminished. In our study, subjects with insulin resistance but without inflammation (CRP <1 mg/L) already had a high prevalence of PAD (5.5%) compared to those who were insulin sensitive and without inflammation (2.2%). Among insulin resistant subjects, the presence of inflammation then resulted in only a marginal increase in PAD prevalence (to 6.9% in the highest CRP category) that was not statistically significant. Whether these data imply that insulin resistance reduces the association of inflammation and PAD by a distinct effect on vascular function or simply by increasing inflammation, these data highlight the complexity of the interaction of these risk factors in PAD and suggest that the role of inflammation in PAD may be modified in individuals with insulin resistance.
Additionally, although there are common risk factors for the development of vascular disease, the impact of specific risk factors on the development of disease is not the same in the peripheral vascular bed as in the coronary or cerebrovascular circulations.41
Indeed, cigarette smoking, one of the strongest risk factors for the development of PAD, was shown in the Edinburgh Artery Study42
to have a greater impact on PAD (OR 1.8–5.6 for the risk of PAD in smokers vs. non-smokers) than on coronary artery disease (OR 1.1–1.6). In contrast, hypertension and hyperlipidemia, potent risk factors for coronary atherosclerosis, appear to have less impact on the development of PAD with a 10 mg/dL increase in total cholesterol conferring only a 10% increased risk of PAD.41
These findings suggest that individual risk factors may have varying impact in different vascular beds, and as such, a focused analysis of the impact of insulin resistance on PAD is warranted and may shed light on the differential pathophysiology of PAD compared to CAD and cerebrovascular disease.
These pathophysiologic differences may in part explain the differences observed between our results and the findings of the Women’s Health Study and a study by Schulze et al. which suggest that CRP adds prognostic information regarding incident cardiovascular disease in subjects with the metabolic syndrome2
at baseline. Our results also stand in contrast to a cross-sectional study from Vu et al.43
in a smaller NHANES cohort suggesting that CRP remains associated with PAD even in patients with metabolic syndrome or diabetes, although not in those with established cardiovascular disease. The discrepancy is explained in part by differences in statistical methodology (the authors used the group with low CRP and no established disease as the reference population for all comparisons), and use of metabolic syndrome as opposed to a direct measure of insulin resistance.
These data are derived from a nationally representative cohort and therefore are generalizable to the US adult population. The ABI method has been demonstrated to have excellent sensitivity and specificity for the diagnosis of PAD.10
Despite these strengths, potential limitations of the present study merit consideration. In NHANES, the ABI was calculated using the blood pressure in only one arm, raising the potential for misclassification by not excluding the possibility of subclavian stenosis. Additionally, our analysis was limited to the subset of participants with ABI measurements who had a fasting blood sample drawn, reducing our sample size and potentially limiting power. However, our final sample population was nonetheless substantial, consisting of more than 3200 individuals in whom there were 256 cases of PAD. We are also limited by the lack of established threshold values of HOMA-IR for indicating presence or absence of insulin resistance. Prior studies have used quartiles8
and given the lack established guidelines, we elected to use standard median and quartile cut-points in our analysis.
Additionally, there are notable differences in clinical variables by HOMA-IR quartile; even with multivariable models, there may be confounding that may not be adequately accounted for in our statistical models. Finally, the cross-sectional nature of our study does not allow us to draw conclusions regarding causality, and prospective studies would be required to clarify any temporal relationship and to delineate the true causal relationships between inflammation, insulin resistance, and PAD.
In summary, insulin resistance is strongly and independently associated with PAD. The presence of insulin resistance attenuates the association of inflammation with PAD. These data establish a role of insulin resistance in PAD and suggest that future studies are warranted to better understand the complex interplay of inflammation and insulin resistance in peripheral arterial disease.