Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis

Abstract

Objective: The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA.

Methods: The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines.

Results: Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05).

Conclusion: Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.

Figure 1

Independent Association between Adipocytokines and Insulin Resistance (HOMA) (Panel A) and Coronary Calcium (Panel B) TCVR: Traditional Cardiovascular Risk Factors. See methods for adjustment method details. A: Beta (95%CI) refers to the multiple linear regression coefficients for the effect of log-adipocytokine per IQR difference in increment with 95% CI on log-HOMA.B: Results are ORs for coronary calcium score per IQR log-adipocytokine increment with 95% CI estimated by a proportional odds logistic regression model.

Figure 2

Interaction Plot Shows that High Leptin Concentrations Attenuate the Effect of Insulin Resistance on Severity of Coronary Calcification Interaction p=0.02. Each curve for probability of severity of calcification by log (HOMA) is estimated using the median of each tertile of log(leptin). The interaction was adjusted for age, sex, race, BMI, inflammatory mediators, and cardiovascular risk factors using a proportional odds logistic regression model.