Abstract
Glucose-dependent insulinotropic polypeptide (GIP), once the overlooked sibling of the incretin family, is now experiencing a research renaissance. Historically, its therapeutic development was hindered by a seemingly diminished insulinotropic effect in type 2 diabetes (T2DM), its paradoxical stimulation of glucagon during hyperglycemia, and translational gaps between rodent and human physiology. This review highlights the renewed interest in GIP, driven by a deeper understanding of its pleiotropic actions. GIP stimulates glucose-dependent insulin secretion and, uniquely, also stimulates glucagon secretion during hyperglycemia. Emerging evidence suggests this glucagon release may subsequently enhance insulin secretion through intra-islet α-β cell communication, revealing a more complex role in glucose homeostasis than previously appreciated. Beyond the pancreas, GIP promotes lipid storage in adipose tissue, reduces ectopic fat deposition, modulates bone remodeling, influences cardiovascular lipid metabolism, and exhibits neuroprotective properties. Preclinical and clinical studies indicate that GIP-based therapies can improve glycemic control, alleviate obesity-related inflammation, and enhance insulin sensitivity. Notably, GIP exhibits synergistic effects with GLP-1, exemplified by the dual receptor agonist Tirzepatide, which has demonstrated superior efficacy in clinical trials. Compared to the selective GLP-1 receptor agonist semaglutide (1 mg), the highest dose (15 mg) of tirzepatide achieved a greater reduction in glycated hemoglobin (-2.30 vs -1.86 percentage points) and body weight (an additional 5.5 kg reduction) over 40 weeks. Furthermore, GIP and its analogs show promise in ameliorating pathology and cognitive deficits in neurodegenerative models like Alzheimer's disease, suggesting a potential new therapeutic avenue for central nervous system disorders. This review synthesizes the evolving narrative of GIP from a challenging target to a multifaceted therapeutic agent and identifies key research gaps, particularly in understanding its tissue-specific signaling and optimizing its synergy within multi-agonist therapies for metabolic and neurodegenerative diseases.