Role of serotonin in body weight, insulin secretion and glycaemic control

Abstract: Obesity and type 2 diabetes are key healthcare challenges of the 21st century. Subsequent to its discovery in 1948, serotonin (5‐hydroxytryptamine; 5‐HT) has emerged as a principal modulator of energy homeostasis and body weight, prompting it to be a target of weight loss medications (eg, fenfluramine, d‐fenfluramine, fenfluramine‐phentermine and sibutramine). The potential risk of off‐target effects led to these medications being withdrawn from clinical use and spurred drug discovery into 5‐HT receptor selective ligands. The serotonin 2C receptor (5‐HT2CR) is the primary receptor through which 5‐HT impacts feeding and body weight and 5‐HT2CR agonist lorcaserin was released for obesity treatment in 2012. Obese patients with type 2 diabetes prescribed medications that produce weight loss commonly observe improvements in type 2 diabetes. However, recent research has provided compelling evidence that 5‐HT2CR agonists produce effects on blood glucose and insulin sensitivity independent of weight loss. As such, neuroactive 5‐HT2CR agonists are a potential new category of type 2 diabetes medications. 5‐HT is also expressed within pancreatic β cells, is co‐released with insulin and may have a role in modulating insulin secretion. This review highlights the latest advances in the function of 5‐HT in body weight, insulin release and glycaemic control.