Abstract
Diabetes mellitus (DM), a chronic metabolic disorder characterized by persistent hyperglycemia, poses a significant global health burden. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal plants such as Coptidis Rhizoma, has shown therapeutic promise for DM and its complications. Preclinical and clinical studies have revealed that BBR exerts multi-target effects, including remodeling the gut microbiome, promoting insulin secretion, ameliorating insulin resistance, and inhibiting hepatic gluconeogenesis. Its protective mechanisms against diabetic complications, such as nephropathy, cardiomyopathy, and retinopathy, involve modulating key pathways like AMPK/SIRT1, PI3K/Akt, and TGF-[Formula: see text]/Smad, which attenuate oxidative stress, inflammation, and fibrosis. Despite its low oral bioavailability, a wide array of formulation strategies, including polymer nanocarriers, lipid-based nanocarriers, mixed micelles, and absorption enhancer, have improved systemic exposure in preclinical models, although clinical translation remains limited. This review synthesizes evidence from the past decade spanning preclinical mechanisms, randomized controlled trials, pharmacokinetics and nanoformulation strategies, concluding that BBR is a promising candidate for complementary therapy, although the supporting clinical evidence remains limited. Further studies are warranted to clarify its mechanisms, and optimize its delivery. In particular, larger and longer-term trials, along with systematic pharmacokinetic–pharmacodynamic studies of BBR and its metabolites, are needed to confirm its efficacy and long-term safety.