Polysaccharide from Momordica charantia L. Alleviates Type 2 Diabetes Mellitus in Mice by Activating the IRS1/PI3K/Akt and AMPK Signaling Pathways and Regulating the Gut Microbiota

Developing effective therapies for type 2 diabetes mellitus (T2DM) remains a critical global health priority. This study explored the novel antidiabetic potential of MCPS-3, a polysaccharide derived from Momordica charantia L., and its underlying mechanisms in a high-fat diet and streptozotocin-induced T2DM mouse model. Our results indicated that MCPS-3 treatment significantly reduced serum glucose levels, improved glucose tolerance, and enhanced insulin sensitivity, alongside increased glycogen storage and improved liver enzyme activities. It also alleviated diabetes-induced damage in the pancreas, liver, and kidneys and improved serum lipid profiles by lowering triglycerides and LDL-C while increasing HDL-C levels. Mechanistic studies revealed that MCPS-3 activated the IRS1/PI3K/AKT and AMPK pathways, essential for glucose and lipid regulation. Importantly, MCPS-3 treatment restored gut microbial balance by increasing microbial diversity and shifting the composition of harmful and beneficial bacteria. Metabolomic analysis further identified changes in 46 metabolites, implicating pathways related to steroid and lipid metabolism. These findings underscore the multifaceted nature of MCPS-3′s antidiabetic effects, including its role as a modulator of gut microbiota and metabolic pathways, and support its potential as a therapeutic agent for improving metabolic health in T2DM.