Metformin was reported to restore insulin resistance via 5′-AMP-activated protein kinase (AMPK)-mediated downregulation of PTEN.107 Notably, loss of PTEN could lead to obesity with preserved insulin sensitivity.108 PTEN haploinsufficiency in humans increases the risk of obesity as a monogenic factor but decreases the risk of T2D because of enhanced insulin sensitivity.109 As the largest insulin-sensitive organ, skeletal muscle has a significant role in glucose and lipid homeostasis. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.