Hyperglycemia Drives an Activated, Lipid-Laden Nonclassical Monocyte Phenotype in Diabetes

The presence of lipid-loaded macrophages in the artery wall and kidney characterizes diabetic atherosclerotic cardiovascular disease and diabetic kidney disease, respectively. Monocytes, the bone marrow–derived precursors of macrophages, accumulate lipids in response to hypercholesterolemia; however, whether diabetes directly alters monocyte lipid loading remains unclear. Using unbiased proteomics, we show that diabetes profoundly affects circulating monocytes, leading to upregulation of glucose metabolism pathways and suppression of cholesterol homeostasis pathways, indicative of lipid loading, particularly in nonclassical monocytes. Functional analyses confirmed that nonclassical monocytes exhibit increased glucose uptake and a lipid-loaded phenotype in three distinct mouse models of diabetes and that they are also more lipid-loaded in people living with diabetes. The increased lipid loading of nonclassical monocytes was due not only to dyslipidemia but also to elevated glucose levels. Finally, we find that nonclassical monocytes traffic to the kidney and contribute to a foamy population of kidney macrophages in a mouse model of diabetes. Together, these findings suggest that hyperglycemia in diabetes drives the reprogramming of nonclassical monocytes, leading to lipid loading and the accumulation of lipid-loaded macrophages in the kidney. Article Highlights Although monocytes can accumulate lipids, whether diabetes alters monocyte lipid loading is unknown. Nonclassical monocytes accumulate more lipids via a process that is partly regulated by hyperglycemia in people with diabetes and in three different mouse models of diabetes. Increased lipid loading promotes a more activated monocyte phenotype. Nonclassical monocytes contribute to the accumulation of foamy kidney macrophages in a mouse model of diabetic kidney disease.