Plenary and keynote abstracts

Abstract

The increasing prevalence of obesity, prediabetes and type 2 diabetes (T2D) emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications to prevent conversion to T2D. Recent reports indicate that former obesity medication, 5-hydroxytryptamine (5-HT, serotonin)2C receptor (5-HT 2C R) agonist lorcaserin improves glycemic control in association with weight loss in obese patients with T2D. We examined whether lorca-serin has a direct effect on insulin sensitivity and how this effect is achieved. We clarify that lorcaserin dose-dependently improves glycemic control in a mouse model of T2D without altering body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neuro-chemical mediator of lorcaserin’s glucoregulatory effects, via activation of brain pro-opiomelanocortin (POMC) peptides. We observed that lorcaserin reduces hepatic glucose production and improves insulin sensitivity. The recent large scale clinical trial CAMELLIA-TIMI 61 revealed that lorcaserin prevented conversion to T2D and improved T2D and supports the translational relevance this medication for prediabetes and T2D treatment. Taken together, these data suggest that lorcaserin’s action within the brain represents a mechanistically novel treatment for prediabetes and T2D: findings of significance to a prevalent global disease.