Gut-pancreas-metabolism axis and its bioactive molecules emerge as key anti-diabetic regulators.

The escalating global burden of diabetes mellitus necessitates innovative therapeutic approaches beyond conventional pancreatic interventions. The gut-pancreas-metabolism axis has gained prominence as a crucial regulatory network, integrating the gut microbiota, enteroendocrine signaling, and immune modulation to maintain glucose homeostasis. Current standard-of-care often overlooks the profound impact of gut-derived factors, leading to suboptimal management of insulin resistance and chronic low-grade inflammation. Understanding this axis reveals a critical gap in addressing the multifaceted pathology of diabetes, particularly the interplay between gut health and systemic metabolic function.

This review systematically synthesizes recent mechanistic advances concerning the gut-pancreas-metabolism axis. It explores the influence of various gut-derived bioactive metabolites, including short-chain fatty acids, bile acid derivatives, indole compounds, lipopolysaccharide fragments, and microbial peptides, on glucose homeostasis. The authors discuss their roles in insulin secretion, insulin sensitivity, inflammation, and energy metabolism, highlighting therapeutic potential and emerging translational strategies for diabetes management. The review also examines the impact of dysbiosis-associated shifts in microbial metabolite profiles on metabolic health.

Gut-derived bioactive metabolites, such as short-chain fatty acids, bile acid derivatives, and indole compounds, significantly influence insulin secretion and sensitivity. These molecules regulate key pathways including AMP-activated protein kinase, PI3K/Akt signaling, and G-protein-coupled receptor activation, contributing to β-cell preservation and metabolic balance. Dysbiosis-associated shifts in microbial metabolite profiles are strongly linked to insulin resistance, impaired incretin responses, and chronic low-grade inflammation in type 2 diabetes. The review highlights that specific microbial peptides can modulate immune responses and metabolic pathways. > The review emphasizes that targeting the gut-pancreas-metabolism axis offers promising opportunities for precision-based metabolic therapy in diabetes care, leveraging the intricate connections between gut health and systemic metabolism.