Context-dependent functions of insulin, IGF, and GLP signaling in inflammatory bowel disease: linking metabolism, immunity, and intestinal homeostasis.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic relapsing inflammatory disorder of the gastrointestinal tract characterized by dysregulated immune responses, impaired epithelial barrier function, and alterations in the gut microbiota. Although considerable progress has been made in understanding the immunopathogenesis of IBD, increasing evidence indicates that metabolic signaling pathways are integral regulators of intestinal inflammation, tissue repair, and disease progression. Among these, insulin, insulin-like growth factors (IGFs), and glucagon-like peptides (GLPs) constitute an interconnected immunometabolic network that links nutrient sensing, energy metabolism, epithelial regeneration, and immune homeostasis. Insulin signaling plays context-dependent roles in IBD by regulating glucose metabolism, epithelial repair, inflammatory responses, and interactions with the gut microbiota and bile acid metabolism. While insulin promotes mucosal healing and barrier restoration in intestinal epithelial cells, excessive activation of insulin signaling in immune cells may exacerbate chronic inflammation through epigenetic and cytokine-mediated mechanisms. The IGF axis is also profoundly altered during active IBD, with systemic suppression of IGF-1 and IGFBP-3 accompanying disease activity, whereas local IGF signaling promotes epithelial regeneration, wound healing, and immune regulation. In addition, IGF-binding proteins (IGFBPs) function as active modulators of inflammation, fibrosis, and colitis-associated colorectal cancer in an isoform-specific manner. GLP signaling further integrates metabolism with intestinal immunity; GLP-1 receptor agonists exhibit anti-inflammatory, metabolic, and microbiota-modulating effects, whereas GLP-2 primarily enhances epithelial proliferation, barrier integrity, and mucosal repair. Emerging preclinical and observational clinical studies suggest that GLP-based therapies may improve disease outcomes, although prospective randomized trials are still required. This review summarizes current knowledge regarding the biological functions and molecular mechanisms of insulin, IGFs, IGFBPs, and GLPs in IBD, highlighting their coordinated roles in regulating metabolism, immunity, epithelial homeostasis, and tissue remodeling. A better understanding of these interconnected signaling pathways may facilitate the development of novel immunometabolic therapeutic strategies aimed at promoting mucosal healing, limiting chronic inflammation, and improving long-term outcomes in patients with IBD.