Role of the IKKbeta/NF-kappaB inflammatory pathway, free fatty acids, and adiposity in insulin resistance in Hispanic Americans

Various lines of evidence have demonstrated a role for inflammation in insulin resistance. Obesity is considered a state of chronic inflammation and is associated with insulin resistance and increased levels of free fatty acids (FFAs). FFAs can activate the IKKbeta/NF-kappaB inflammatory pathway and can disrupt the normal insulin signaling pathway.;The overall goal of this research was to further explore the role that inflammation plays in insulin resistance, including examining the roles of circulating FFAs and their relationship to genetic variants in genes in the IKKbeta/NF-kappaB inflammatory pathway and adiposity. In 815 Hispanic individuals in the Insulin Resistance Atherosclerosis (IRAS) Family Study, we measured FFAs in a fasting blood sample, insulin sensitivity (SI) by frequently sampled intravenous glucose tolerance test, areas of visceral and subcutaneous adipose tissue (VAT and SAT) by computed tomography, and collected genetic data on genes in the IKKbeta/NF-kappaB pathway.;Increasing levels of body mass index (BMI), VAT, and SAT were associated with increasing levels of circulating FFAs (BMI: p = 0.024; VAT: p = 2.33 x 10-3; SAT: p = 0.018) adjusting for age, sex, clinic site, and admixture. Increasing levels of circulating FFAs were associated with decreasing SI (p = 8.10 x 10-11). Increasing BMI, VAT, and SAT were also associated with decreasing SI (BMI: p = 4.98 x 10-71; VAT: p = 4.98 x 10-71; SAT: p = 4.21 x 10-62), but this relationship was not significantly mediated by FFAs.;Two SNPs in TLR2 were associated with levels of circulating FFAs (rs6835636: p = 5.69 x 10-3; rs13150331: p = 9.52 x 10 -3). TLR4 SNP rs10116253 showed evidence of interaction with FFAs (p = 0.025). For each copy of the minor allele, increasing levels of FFAs had a greater impact on levels of SI.;In summary, levels of circulating FFAs are associated with increasing adiposity and decreasing SI, but they do not mediate the association between adiposity and SI in this cohort. These results indicate that FFAs may contribute to insulin resistance independent of adiposity and provide corroborating evidence that genetic variation in the TLR2 and TL4 genes may mediate insulin resistance in humans.