This study states that Cardiovascular risk in diabetes remains elevated despite glucose lowering therapies. We hypothesised that hyperglycaemia induces trained immunity in macrophages, promoting persistent pro-atherogenic characteristics. Bone marrow derived macrophages from control and mice with diabetes were grown in physiological glucose (5 mM) and subject to RNA-sequencing (n=6), ATAC-sequencing (n=6) and ChIP-sequencing (n=6) for determination of hyperglycaemia-induced trained immunity. Bone marrow transplantation from mice with (n=9) or without (n=6) diabetes into [normoglycaemic] Ldlr -/- mice was used to assess its functional significance in vivo. Evidence of hyperglycaemia-induced trained immunity was sought in human peripheral blood mononuclear cells (PBMCs) from patients with diabetes (n=8) compared with case controls (n=16) and in human atherosclerotic plaque macrophages excised by laser capture microdissection. In macrophages, high extracellular glucose promoted pro-inflammatory gene expression and pro-atherogenic functional characteristics, through glycolysis-dependent mechanisms. Bone marrow-derived macrophages (BMDM) from diabetic mice, retained these characteristics, even when cultured in physiological glucose, indicating hyperglycaemia-induced trained immunity. Bone marrow transplantation from diabetic mice into [normoglycaemic] Ldlr -/- mice increased aortic root atherosclerosis, confirming a disease-relevant and persistent form of trained innate immunity.

Reference link-