Piperine cocrystals ameliorates type 2 diabetes by regulating glycolipid metabolism and reshaping gut microbiota in mice

Type 2 diabetes (T2DM), a chronic metabolic disorder driven by insulin resistance or deficiency, necessitates novel therapeutic strategies. Piperine (PIP), a bioactive alkaloid from Piper nigrum and Piper longum , exhibits antidiabetic potential but suffers from poor solubility and bioavailability. This study developed two cocrystals, PIP-3,5-DHBA·H 2 O and PIP-2,6-DHBA, to address these limitations. Structural characterization via SCXRD, PXRD, DSC-TGA, FT-IR, and optical microscopy confirmed cocrystal formation. Pharmacokinetic and therapeutic evaluations focused on PIP-3,5-DHBA·H 2 O in STZ-induced diabetic C57BL/6J mice over 10 weeks, assessing metabolic parameters, pancreatic histopathology, and gut microbiota. Results revealed enhanced solubility for both cocrystals, with PIP-3,5-DHBA·H 2 O displaying superior bioavailability (2.8-fold increases in C max and AUC 0–24 ). Treatment significantly reduced fasting glucose, TG, TC, and LDL-C while elevating HDL-C. Gut microbiota analysis demonstrated decreased Firmicutes / Bacteroidetes ratio and enriched beneficial genera ( Coprococcus , Akkermansia ). Mechanistically, the cocrystal improved β-cell function and metabolic regulation. These findings validate cocrystallization as a viable strategy to overcome PIP's physicochemical limitations, offering a dual-functional approach for T2DM management through enhanced bioavailability, metabolic restoration, and microbiome modulation.