The prevalence of atherosclerotic cardiovascular disease is higher in patients with type 2 diabetes, a disorder characterized by hyperinsulinemia and insulin resistance. The role of hyperinsulinemia as an independent participant in the atherogenic process has been controversial. In the current study, we tested the effect of insulin and the insulin sensitizer, adiponectin, on human macrophage foam cell formation. We found that both insulin and adiponectin increased the expression of the type 2 scavenger receptor CD36 by approximately twofold and decreased the expression of the ATP-binding cassette transporter ABCA1 by >80%. In both cases regulation was post-transcriptional. As a consequence of these changes, we found that oxidized LDL (oxLDL) uptake was increased by 80% and cholesterol efflux to apolipoprotein A1 (apoA1) was decreased by ∼25%. This led to two-to threefold more cholesterol accumulation over a 16-h period. As reported previously in studies of murine systems, scavenger receptor-A (SR-A) expression on human macrophages was downregulated by insulin and adiponectin. Insulin and adiponectin did not affect oxLDL-induced secretion of monocyte attractant protein-1 (MCP-1) and interleukin-6 (IL-6). These studies suggest that hyperinsulinemia could promote macrophage foam cell formation and thus may contribute to atherosclerosis in patients with type 2 diabetes.
Bibliographical noteFunding Information:
We are grateful to David Schmitt, Dr Xin-Min Li and Robert Koeth in Dr Stanley Hazen’s laboratory at the Cleveland Clinic for helping us perform the cholesterol efflux assay and GC-MS. This study was supported by NIH P01 HL087018 (RLS) and a KL2 award (SK) from the Case Western Reserve University Clinical Translational Research Award UL1RR024989.
- foam cell