Screening of <i>Lactococcus lactis</i> strains with hypoglycemic effects and evaluation of their protective mechanisms against glucose-induced type 2 diabetes in zebrafish

Type 2 diabetes mellitus (T2DM) is a major global health challenge, and probiotics represent a potential therapeutic avenue. In this study, three strains of probiotics with α-glucosidase inhibitory activity were screened <i>in vitro</i>, and the inhibitory effect of <i>Pediococcus acidilactici</i> SWU-HY34 (HY34) was the strongest, reaching 35.2%, which was further evaluated <i>in vivo</i> using a hyperglycemia silkworm model and zebrafish diabetes model. Strain HY34 effectively reduced blood glucose levels in diabetic zebrafish (<i>p</i> < 0.05), suppressed the mRNA expression of pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), alleviated liver tissue damage (<i>p</i> < 0.05), and also improved lipid profiles by decreasing triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol levels (LDL) (<i>p</i> < 0.05), while increasing high-density lipoprotein (HDL) levels (<i>p</i> < 0.05). Furthermore, HY34 ameliorated diabetes-induced dyslipidemia and mitigated oxidative stress by enhancing antioxidant enzyme activity. The mechanism by which HY34 improves metabolic health and alleviates diabetes may involve modulating the gut microbiota composition and the production of beneficial metabolites in zebrafish. These results suggest that probiotics, such as HY34, could be further explored for the development of novel hypoglycemic drugs.