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

Year: 2026

Type: article

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.

Source: 3 Biotech

DOI: 10.1007/s13205-026-04928-3

Authors: Sherif B. Adeyemi, Mercy A. Alabi, Hafizah Y. Chenia, Tricia Lin, Johnson Lin

Institutions: University of Ilorin, University of KwaZulu-Natal, Stellenbosch University, Tallaght University Hospital

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,090