Glucose-dependent insulinotropic peptide and beyond: co-agonist innovations in the treatment of metabolic diseases

Glucose-dependent insulinotropic peptide (GIP), a key incretin hormone, has emerged as a pivotal therapeutic target in metabolic disorders. Historically, its therapeutic potential in type 2 diabetes mellitus (T2DM) has been underestimated owing to GIP resistance and its limited acute effects on glycemic control and body weight regulation. However, emerging evidence has demonstrated that GIP resistance is reversible through sustained glycemic improvement, thereby restoring its physiological effectiveness. With the development of gut hormone co-agonists, the potential of GIP in the treatment of metabolic diseases has been reevaluated. The study of GIP and its co-agonists such as glucagon-like peptide-1 (GLP-1), revealed that its mechanism of action in regulating blood glucose, fat metabolism, and bone metabolism is complex and diverse. A better understanding of GIP evolution can help in designing more effective GIP-based treatment strategies. In this review, we summarize the physiological functions of GIP, systematically explores its diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects of GIP analogs.