Cholesterol metabolism and its role in type 2 diabetes mellitus development

Abstract Cholesterol has increasingly been recognized for its pivotal role in the regulation of glucose metabolism. It influences the pathophysiological processes of type 2 diabetes mellitus (T2DM) by affecting pancreatic β-cell function and promoting insulin resistance. Potential mechanisms include alterations in Ca 2 ⁺ homeostasis, activation of the PERK-eIF2α signaling pathway, Golgi stress, as well as modulation of inflammation, oxidative stress, bile acids metabolism, and gut microbiota composition. While observational studies consistently demonstrate significant associations between cholesterol and its metabolic markers with T2DM, the findings from randomized controlled trials and Mendelian randomization studies remain inconsistent. This review provides an overview of cholesterol metabolism, examines the biological mechanisms linking cholesterol dysmetabolism to T2DM, and summaries the current evidence from population-based studies regarding the relationship between cholesterol metabolism and risk of T2DM.