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

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 The potential risk of off-target effects led to these medications being withdrawn from clinical use and spurred drug discovery into 5-HT receptor selective ligands.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-HT2C R) is the primary receptor through which 5-HT impacts feeding and body weight and 5-HT2C R 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-HT2C R agonists produce effects on blood glucose and insulin sensitivity independent of weight loss. As such, neuroactive 5-HT2C R 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.