Lactiplantibacillus plantarum Ln4 attenuates streptozotocin and high-fat diet-induced Type-2 diabetes

Type-2 diabetes mellitus (T2DM) is an expanding global concern with limited efficacy of conventional therapies. Probiotics have gained attention for their ability to modulate gut microbiota and glucose homeostasis. This study evaluated the therapeutic potential of Lactiplantibacillus plantarum Ln4 at LOW (5 × 10 8 CFU/day) and HIGH (5 × 10 9 CFU/day) doses in an STZ/HFD-induced diabetic mouse model, compared with metformin (200 mg/kg). STZ/HFD induction resulted in reduced body and muscle weight, increased food and water intake, elevated fasting blood glucose, OGTT, AUC, HOMA-IR, liver weight, and dysregulated metabolic biomarkers. Ln4 administration significantly reversed these alterations, normalized serum adiponectin, insulin, GLP-1, and HbA1c levels, and improved lipid profile, oxidative stress markers, and histopathological changes in liver and skeletal muscle. Mechanistically, Ln4 restored GLUT-2, GLUT-4, GCK, IRS/PI3K/Akt, AMPK, and GSK3β signaling while suppressing PEPCK and PTP1B expression. Overall, L. plantarum Ln4 effectively ameliorated hyperglycemia and dyslipidemia, showing efficacy comparable to metformin. Lactiplantibacillus plantarum Ln4 mitigates STZ/HFD-induced T2DM in mice by improving glucose metabolism and enhancing insulin sensitivity. Ln4 treatment elevated GLP-1 and adiponectin levels, upregulated GLUT2/4, GCK, and key signaling pathways (IRS/PI3K/Akt, AMPK), while suppressing PEPCK and PTP1B. These changes reversed hyperglycemia, dyslipidemia, and tissue injury, comparable to metformin. CB, citrate buffer; STZ, streptozotocin; HFD, high fat diet; 64 NFD, normal-fat diet; PBS, phosphate buffered saline; Met, metformin; LOW and HIGH, Lactiplantibacillus plantarum Ln4; CFU, colony forming unit; GAS, gastrocnemius; SOL, soleus; EDL, extensor digitorum longus; TA, tibialis anterior; GLP-1, glucagon-like peptide-1; HbA1C, glycated hemoglobin; MDA, malondialdehyde; ALT, alanine transaminase; AST, aspartate transaminase; TG, triglyceride; TC, total cholesterol; GLUT, glucose transporter; PEPCK, phosphoenolpyruvate carboxykinase; GCK, glucokinase; IRS-1, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; AMPK, 5′ adenosine monophosphate-activated protein kinase; GSK3β, glycogen synthase kinase-3 beta; PTP1B, protein tyrosine phosphatase 1B; H IHC, immunohistochemistry; p, phosphorylated form; FA, fatty acid; and ADP, adiponectin. • Lactiplantibacillus plantarum Ln4 alleviated STZ/HFD-induced T2DM in mice. • Ln4 showed efficacy comparable to Met in normalizing TG, TC, and liver enzymes. • Ln4 increased adiponectin and GLP-1 and reduced HbA1c and histopathological injury. • Ln4 modulated GLUTs, GCK and IRS/PI3K/Akt, AMPK, GSK3β pathways.