SUN-084 Aged Insulin Resistant Macrophages Reveal Dysregulated Cholesterol Biosynthesis, Pro-Inflammatory Gene Expression, and Reduced Foam Cell Formation

Insulin resistance is the central defining feature of type 2 diabetes and increases with age. People with type 2 diabetes are at a significantly increased risk of developing atherosclerosis. Macrophages are phagocytotic leukocytes which play a central role in the development of type 2 diabetes and atherosclerosis. Despite their relevance however, the effect of insulin and insulin resistance on macrophages regarding their inflammatory status and role in atherosclerosis remain unclear. Our aim was to determine the inflammatory gene expression profile in aged insulin resistant macrophages and how this may impact foam cell formation - a key step in the development of atherosclerosis. Genome-wide transcript array analysis was performed on bone marrow derived macrophages from aged insulin resistant mice (n=3) gained through chronic hyper-stimulation of the PI3K arm of the insulin signalling pathway via hematopoietic SHIP2 knock-down (h-SHIP2(KD)). The transcriptome of aged h-SHIP2(KD) insulin resistant macrophages become reprogrammed, differentially expressing more than 4000 genes (≥2fold, P=≤ 0.05. Pathway analysis revealed that the most significantly altered intracellular signalling pathways include upregulation of interferon signalling pathwyas, components of the inflammasome (for example increased mRNA expression Nlrp3: 1.75-fold, P=0.05, Casp4: 4.31-fold, P=0.05) and changes in cholesterol biosynthesis genes (for example Fdps: 2.56-fold, P=0.05, Idi1: 3.13-fold, P=0.05, Sqle: 3.87-fold, P=0.05, Cyp51: 4.47-fold, P=0.05, Dhcr: 4.72-fold, P=0.05). Exposure of these h-SHIP2(KD) macrophages to acetylated LDL revealed a decreased capacity to form foam cells compared to WT controls (Mean staining intensity 2818 vs 4730 units respectively, P=0.03, n=3). These data support the emerging role of insulin a modulator of inflammation and that insulin resistance in macrophages is protective against foam cell formation. Our transcriptome expression data revealed novel targets which may be exploited for new therapies.