In this regard, moreover, it appears that first-degree relatives of type 2 diabetic humans have an abnormality (? inborn) in insulin signaling and action in muscle that: (a) is unrelated to obesity; (b) does not involve signaling to and through Akt to a major substrate, AS160 [11]; and (c) may set the stage for development of T2DM, perhaps with another insult, such as caloric excess. Here, AKT1 is linked to obesity due to melanocortin 4 receptor deficiency.