Macrophage-foam cell formation in streptozotocin-induced diabetic mice: Stimulatory effect of glucose

Background: Diabetes is associated with an increased risk for atherosclerosis. We investigated the effect of diabetes induction on atherogenesis and on macrophage-foam cell formation. Methods and results: Atherosclerotic apolipoprotein-E-deficient mice were converted into diabetic mice by streptozotocin injection. Aortic atherosclerotic lesion area was significantly enhanced by 67% and 106% in mice that were diabetic for 1 and 3 months, respectively, compared to the non-diabetic mice. Moreover, mouse peritoneal macrophages (MPM) from diabetic mice for 1 and 3 months exhibit higher lipid peroxides content by 55% and 63%, respectively, in association with the MPM glucose content. Oxidized LDL (Ox-LDL) uptake by MPM obtained from diabetic mice for 1 and 3 months was significantly increased by 36% and 45%, respectively, in association with the increased macrophage cholesterol content. To determine whether the accelerated foam cell formation in diabetic mice could result from a direct effect of glucose on macrophages, J-774-A.1 macrophages were incubated with increasing glucose concentrations (2.5–62 mM). Glucose-enriched macrophages exhibit dose-dependent higher peroxides content up to 7.5-fold and increased Ox-LDL cellular uptake associated with up-regulation of the scavenger receptor CD36 at the mRNA level. Conclusion: Induction of diabetes in atherosclerotic mice led to an accelerated atherosclerosis and macrophage-derived foam cell formation, probably by involving a glucose-dependent related mechanism.