The current study demonstrates, for the first time in literature, that diabetic hypercholesterolaemic Ins2+/Akita: ApoE−/− mice are characterized by increased arterial stiffness, in a manner associated with up‐regulation of hypertonicity‐responsive factors, such as AQ1 and NFAT5, along with genes implicated in early inflammation and atherosclerosis, such as VCAM‐1; cytoskeletal remodelling, such as F‐actin and ASMA; endothelial dysfunction, such as iNOS and eNOS; and ROS generation, such as NADPH oxidase. This evidence concerns the gene APOE and atherosclerosis.