INS and obesity due to melanocortin 4 receptor deficiency: Insulin secretion and enhanced insulin sensitivity is critical to avoid pathological weight loss and to store energy in adipose tissue.29 However, sustained hyperglycemia that accompanies severe obesity exhausts pancreatic beta cells, inducing their apoptosis and decreasing insulin secretion.30, 31 While untreated db/db mice fed a HF diet showed significantly decreased endogenous insulin levels (Fig. 2b), plasma insulin levels in TA-1887-treated mice were relatively stable, as was beta cell mass, possibly due to loss of glucotoxicity via increased urinary glucose excretion.