Gut-pancreas-metabolism axis: emerging anti-diabetic roles of gut-derived bioactive molecules

The rising global burden of diabetes mellitus necessitates exploration of mechanisms beyond classical pancreatic dysfunction. The gut-pancreas-metabolism axis has emerged as a central regulatory network linking gut microbiota, enteroendocrine signaling, immune modulation, and pancreatic function in glucose homeostasis. Gut-derived bioactive metabolites, including short-chain fatty acids, bile acid derivatives, indole compounds, lipopolysaccharide fragments, and microbial peptides, significantly influence insulin secretion, insulin sensitivity, inflammation, and energy metabolism. These metabolites regulate key pathways such as AMP-activated protein kinase, PI3K/Akt signaling, G-protein-coupled receptor activation, and inflammatory cascades, thereby contributing to β-cell preservation and metabolic balance. Dysbiosis-associated shifts in microbial metabolite profiles are strongly associated with insulin resistance, impaired incretin responses, and chronic low-grade inflammation in type 2 diabetes. This review summarizes recent mechanistic advances in the gut-pancreas-metabolism axis and highlights the therapeutic potential of microbiota-derived bioactive compounds. Furthermore, it discusses emerging translational strategies, including probiotics, prebiotics, postbiotics, and dietary modulation of the gut microbiome, as adjunctive approaches for diabetes management. Targeting this axis provides promising opportunities for precision-based metabolic therapy in diabetes care.