Apolipoprotein E (APOE) is a multifunctional protein crucial in lipid metabolism, influencing the homeostasis of cholesterol and diverse cellular processes, including glucose metabolism. Its main isoforms (ε2, ε3, and ε4) have distinct health implications, including their role in the development and progression of Type 2 diabetes mellitus (T2DM). It is estimated that the presence of the ε4 allele in the APOE gene influences the risk of obesity, insulin resistance, and hyperglycemia and reduces brain glucose uptake, in addition to affecting the synthesis and transport of cholesterol, processes closely linked to metabolic function. Experimental models demonstrate that changes in APOE functionality can lead to insulin resistance and metabolic dysfunction, suggesting its role in glycemic regulation. Given these influences, potential therapeutic targets include modulation of APOE expression, anti-inflammatory interventions, and personalized nutritional strategies. Despite advances, more studies are still needed to validate APOE as a viable therapeutic target for glycemic control and prevention of complications associated with T2DM.