GLP1R:
GLP-1R (Glucagon-Like Peptide-1 Receptor, a member of the B1 class GPCRs, mediates the physiological functions of glucagon-like peptide-1 (GLP-1). Its core function is to stimulate insulin secretion, inhibit glucagon, delay gastric emptying, and reduce appetite. As a popular target for the treatment of type 2 diabetes and obesity, the activation of GLP1R can simulate the natural regulatory mechanism of the "intestinal-brain-pancreas axis", becoming the focus of drug research for metabolic diseases. Monomeric drugs (such as Semaglutide) may cause gastrointestinal side effects (nausea, vomiting) when used for a long time, and have limited effects on fat metabolism and energy consumption.
GCGR:
GCGR (glucagon receptor) is a type B GPCR. Initially, it was described as a glucagon-binding entity linked to the function of adenylate cyclase. GCGR promotes glycogenolysis, fat oxidation, and energy consumption in the liver, but excessive activation can lead to hyperglycemia. When combined with GLP-1R, it can counteract the risk of elevated blood sugar levels and enhance the weight loss effect.
GIPR:
GIPR (Glucose-dependent Insulinotropic Peptide Receptor) belongs to the GPCR (G protein-coupled receptor) family of secretin (class B1). It mainly mediates the physiological functions of glucose-dependent insulinotropic peptide (GIP), playing a significant role in insulin secretion regulation, fat metabolism, and energy homeostasis. Previously, GIPR was believed to promote fat storage, but recent studies have shown that its combination with GLP-1R can improve fat distribution (reducing visceral fat) and enhance insulin sensitivity.
Physiological and pathological significance
G protein-coupled receptors (GPCRs) are the largest membrane protein family in the human body. They regulate key physiological functions through peptide hormones such as glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic peptide (GIP). GLP-1R promotes insulin secretion, slows gastric emptying, and enhances satiety, which helps lower blood sugar and reduce weight. GIPR is activated by GIP and can promote insulin secretion and affect fat deposition, thereby influencing energy balance. GCGR promotes glycogenolysis and glucose production through glucagon, maintaining blood sugar levels. Targeting these receptors has led to the development of GLP-1R agonists, GIPR/GLP-1R dual agonists, and GIPR/GLP-1R/GCGR triple agonists, which help control and reduce weight and provide a comprehensive treatment option for diabetes and obesity.
From the laboratory to the clinic
Currently, the US Food and Drug Administration (FDA) has approved several drugs targeting GLP-1R, GIPR and GCGR for the treatment of type 2 diabetes and obesity and other diseases. These drugs include GLP-1 receptor agonists, such as semaglutide, liraglutide, dulaglutide, PEG-Loxenatide, and tirzepatide (a GIPR/GLP-1R dual agonist). Additionally, several clinical trials are underway. For instance, retatrutide, a triple agonist targeting GIPR/GLP-1R/GCGR, Survodutide, a dual agonist targeting GCGR/GLP-1R, and IONIS-GCGR Rx, a drug targeting GCGR, are currently in phase 2 clinical trials.
