Indeed, while Ranieri SC et al. identified p66Shc as a major mediator of insulin resistance and T2D in leptin-deficient (ob/ob) mice [43], Ciciliot S et al. demonstrated that reduced p66Shc levels were protective against obesity, without preventing insulin resistance, ectopic fat accumulation, or glucose intolerance, in the same mouse model and in humans [49]. The gene discussed is LEP; the disease is Insulin resistance.