Food-Derived Antidiabetic Peptides as Multi-Target Systemic Regulators: A Comprehensive Review of Sources,...

Food-derived bioactive peptides have become a research hotspot in diabetes nutritional intervention due to their high safety, wide availability, and multi-target activities. This review addresses this by proposing a systems biology integration framework that defines these peptides as pleiotropic regulators of the gut microbiota-immune inflammation-metabolic signaling network, offering a novel systems-level perspective beyond previous reviews focused on single enzymes or pathways. The framework consists of three synergistic tiers. Tier 1 inhibits α-amylase, α-glucosidase or dipeptidyl peptidase-IV (DPP-IV) to control postprandial blood glucose. Tier 2 corrects insulin resistance by modulating phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), activating nuclear factor erythroid 2-related factor 2 (Nrf2), and suppressing nuclear factor kappa-B (NF-κB). Tier 3 uses the gut as a hub to remotely coordinate metabolism via the gut-liver and gut-pancreas axes. The review also systematically summarizes the major sources and preparation methods of food-derived antidiabetic peptides, analyzes their advantages including multi-target network regulation, safety, and sustainability, as well as challenges such as oral bioavailability, insufficient clinical evidence, processing stability, and regulatory hurdles. Finally, it outlines future directions focusing on three actionable priorities: AI-assisted design, oral delivery systems, and high-quality clinical studies. This framework offers a new perspective for applying food-derived peptides in precision nutrition intervention for diabetes.