Endophytic microorganisms as sustainable sources of antidiabetic metabolites: biochemical mechanisms, bioprospecting strategies, and translational challenges

Abstract Diabetes mellitus affects over 589 million adults globally, with projections exceeding 900 million by 2050. Conventional antidiabetic therapies are limited by adverse effects, high cost, and single-target pharmacology. Endophytic microorganisms, fungi and bacteria residing asymptomatically within plant tissues, represent an underexplored yet structurally diverse reservoir of bioactive metabolites developed through co-evolutionary adaptation with their hosts. This scoping review aimed to systematically map the breadth and depth of available evidence on: (1) the antidiabetic biochemical mechanisms of endophyte-derived metabolites; (2) bioprospecting and biotechnological discovery strategies; and (3) key translational barriers to clinical application, to identify research priorities and knowledge gaps. A systematic search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and ScienceDirect covering January 2016 to March 2026, supplemented by hand-searching of reference lists. The Boolean search strategy combined endophyte-specific, antidiabetic, and metabolite-related terms. Studies were screened against explicit inclusion and exclusion criteria following PRISMA for Scoping Reviews (PRISMA-ScR) guidelines. A total of 747 records were identified; following duplicate removal and two-stage screening, 123 studies were included in the final synthesis. Included studies documented seven principal antidiabetic mechanisms of endophyte-derived metabolites: (1) inhibition of α-glucosidase and α-amylase; (2) enhancement of GLUT4 translocation via the IRS1/PI3K/Akt/GSK3β axis; (3) AMPK activation suppressing hepatic gluconeogenesis; (4) PPARγ agonism improving insulin sensitivity; (5) antioxidant protection of pancreatic β-cells from ROS-induced apoptosis; (6) anti-inflammatory modulation of TNF-α, IL-6, and IL-1β via NF-κB/MAPK pathways; and (7) multi-target engagement. Bioprospecting strategies, including OSMAC, genomic mining, co-culture systems, and AI-assisted discovery, are accelerating compound identification. Key translational barriers include inconsistent metabolite yields, strain instability, regulatory complexity, and unresolved intellectual property disputes. Endophytic microorganisms constitute a compelling and sustainable source of multi-target antidiabetic compounds. This review provides the first PRISMA-ScR compliant synthesis of the field, offering clinicians, natural product researchers, pharmaceutical scientists, and policymakers a rigorous evidence base for prioritising endophyte-derived lead compounds for preclinical and clinical development. Substantial knowledge gaps remain in the in vivo validation, clinical translation, and equitable access frameworks for microbial resources from biodiverse regions.