Abstract

Background Oligopeptides derived from dietary sources are regarded as ideal functional ingredients for nutritional interventions in diabetes due to their favorable bioavailability, target specificity, and safety profiles. Gynura divaricata (GD), a medicinal food plant, has shown hypoglycemic properties; however, the potential of GD-derived oligopeptides in glycemic control and their mechanistic underpinnings remain largely unexplored. Purpose This study aimed to investigate the anti-diabetic efficacy of GD oligopeptides and elucidate their mechanisms of action, particularly via the gut-microbiota-brain axis, in a streptozotocin (STZ)/high-fat diet-induced diabetic mouse model. Methods The therapeutic effects of GD oligopeptides were assessed through longitudinal blood glucose monitoring and systemic biochemical profiling. Organ-specific protection was evaluated via histopathological examination of the liver, pancreas, intestine, and brain. The influence on gluconeogenesis was analyzed by quantifying key glycogen metabolic proteins. Gut microbiota composition was assessed by sequencing, short-chain fatty acids (SCFAs) were measured, and appetite/energy metabolism regulators in the brain were detected. And a subset of diabetic mice was subjected to broad-spectrum antibiotic treatment to validate the effcst of gut microbes. Bioactive peptides were identified using LC-ESI-MS/MS, and molecular docking was performed to evaluate binding affinity to AKT. Results GD oligopeptides significantly ameliorated hyperglycemia, dyslipidemia, and insulin resistance in diabetic mice. They enhanced hepatic glycogen synthesis and suppressed gluconeogenesis through activation of the AKT/FoxO1 pathway, and reduced pancreatic apoptosis via modulation of Bcl-2/Bax expression. A total of 37 bioactive peptides were identified, with molecular docking confirming strong binding between GD oligopeptides and AKT. Importantly, GD oligopeptides restored intestinal barrier integrity, enriched SCFA-p