The outcome of metabolism-related T2DM is quite simple: hyperglycemia resulting from declined insulin sensitivity owing to the reduction of functional β-cell mass, with obesity being a powerful driver in its development and progression, including strengthened genetic/epigenetic vulnerability, microenvironmental changes impairing insulin signaling, deteriorated β-cell function, and dysregulated microbiome-gut-brain axis. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.