Of note, both excess of FAs and obesity, which are leading risk factors for diabetes, can specifically increase the levels of p66Shc protein, as well as its activation through phosphorylation in Ser36, in cells and tissues involved in glucose homeostasis, such as insulin-secreting pancreatic beta-cells [29,30,42], adipocytes [43], and hepatocytes [44], thus causing cellular stress, apoptosis, cellular dysfunction, and insulin resistance, therefore favoring the pathogenesis of diabetes. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.