High Glucose Concentration Increases Macrophage Cholesterol Biosynthesis in Diabetes Through Activation of the Sterol Regulatory Element Binding Protein 1 (SREBP1): Inhibitory Effect of Insulin

Diabetes activates atherogenesis and macrophage foam cell formation. This study's goal was to determine whether insulin counteracts diabetes-induced macrophage foam cell formation, as well as to determine transcriptional mechanisms involved in this effect. Insulin injection to diabetic mice reduced macrophage lipid peroxides levels, Ox-LDL uptake, and CD36 mRNA levels by 40% 29%, and by 41% respectively, compared to age-matched untreated diabetic mice. These results were further assessed using an in vitro system. Addition of insulin to glucose-enriched cells led to a significant decrease in cellular lipid peroxidation by 43% compared to cells incubated with high concentrations of glucose with no insulin. This effect was correlated with a reduction in NADPH oxidase activity. Macrophage cholesterol biosynthesis was then studied in cells from diabetic mice treated with insulin and in glucose-enriched macrophages incubated with insulin. Insulin treatment of diabetic mice significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression. and protein expression by 81%, 54%, and 31% respectively, compared to macrophages isolated from nontreated diabetic mice. Similarly, insulin incubation with glucose-enriched macrophages significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 84%, 42%, and 18%, respectively, compared to macrophages incubated with high glucose but without insulin. These effects were mediated by glucose and insulin ability to regulate the transcription factor SREBP-1. Whereas glucose uppregulated SREBP-1 expression and maturation, insulin blocked SREBP1 cleavage, leading to reduced mature form of the transcription factor in the nucleus. In conclusion, this study presents important novel insights on the events connecting diabetes and glucose stimulation of macrophage foam cell formation leading to atherosclerosis. Most important, the inhibitory effects of insulin on diabetes-mediated (and high glucose-induced) increased cholesterol synthesis were shown to involve modulation of SREBP-1 expression and its maturation.