Jiangtang Xiaozhi formula alleviates type 2 diabetes mellitus by improving islet beta-cell dedifferentiation: a network pharmacology-based study.

<h4>Objective</h4>To investigate the underlying therapeutic mechanisms of Jiangtang Xiaozhi formula (JTXZF, )) in the treatment of type 2 diabetes mellitus (T2DM).<h4>Methods</h4>The effects of JTXZF on T2DM were evaluated using a db/db mouse model. Potential targets of JTXZF in ameliorating T2DM-related pancreatic beta-cell dedifferentiation were initially predicted using network pharmacology. A beta-cell dedifferentiation model was established in Min6 cells <i>via</i>palmitic acid (PA) intervention. The impact of JTXZF on beta-cell dedifferentiation was assessed through Western blot (WB), immunofluorescence staining, real-time quantitative polymerase chain reaction (RT-qPCR), and siRNA transfection, focusing on the modulation of the phosphatidylinositol 3-kinase/protein kinase B/forkhead box O1 (PI3K/AKT/FoxO1) signalling pathway <i>via</i>insulin-like growth factor 1 (IGF-1). Transmission electron microscopy was employed to examine changes in mitochondrial morphology in Min6 cells, and mitochondrial dysfunction(definition) was evaluated using WB and RT-qPCR to assess the intervention effect of JTXZF on beta-cell dedifferentiation.<h4>Results</h4>JTXZF improved insulin sensitivity and lipid metabolism, enhanced IGF-1 expression regulating the PI3K/AKT/FoxO1 signalling pathway, upregulated the beta-cell marker transcription factor pancreatic and duodenal homeobox 1, and downregulated the progenitor cell marker neurogenin-3 as well as the pluripotency transcription factor octamer-binding transcription factor 4, thereby inhibiting PA-induced beta-cell dedifferentiation. Additionally, JTXZF appeared to improve beta-cell dedifferentiation mechanisms, possibly by increasing mitofusin 2(Mfn2) expression to alleviate mitochondrial dysfunction.<h4>Conclusion</h4>JTXZF modulates the PI3K/AKT/FoxO1 signalling pathway <i>via</i>IGF-1, thereby improving islet beta-cell dedifferentiation in T2DM, and may also regulate Mfn2 expression to mitigate mitochondrial dysfunction.