This narrative review, therefore, aims to recapitulate, within an historical perspective encompassing approximately 70 years, the major scientific milestones and hypothesis on the etiopathogenesis of type 2 diabetes, with a specific focus on the putative overestimation of the role of insulin resistance and an underestimation of the role of chronic positive energy balance in the etiopathogenesis of type 2 diabetes. This evidence concerns the gene INS and type 2 diabetes mellitus.