Dual AMPK activation and TXNIP suppression underlie the superior anti-diabetic action of rosiglitazone-metformin co-crystal (RZM): evidence from preclinical models

This study investigates the anti-diabetic potential of rosiglitazone-metformin adduct (RZM), a 1:1 molar co-crystal complex, in spontaneous diabetic KK mice and streptozotocin-induced diabetic rats. Diabetic models were divided into four groups: vehicle control, physical mixture (R + M), low-dose RZM, and high-dose RZM. Metabolic parameters including fasting glucose and lipid profiles were assessed over time, alongside hepatic histopathology and molecular analyses of AMPK/TXNIP pathways. <i>In vitro</i> validation employed high glucose-exposed MIN6 and INS-1 β-cells. RZM treatment significantly reduced hyperglycaemia, enhanced glucose tolerance, and ameliorated dyslipidemia, with dose-dependent efficacy. Histopathology demonstrated RZM's hepatoprotective effects through reduced steatosis and inflammation. Mechanistically, RZM activated AMPK phosphorylation while suppressing TXNIP overexpression in both pancreatic β-cells and metabolic tissues, a conserved pathway confirmed across species and <i>in vitro</i> models. Compared to conventional combination therapy, the stoichiometrically optimised RZM formulation exhibited superior glycemic control and liver protection <i>via</i> coordinated AMPK-TXNIP modulation. These findings establish RZM as a dual-targeting agent with translatable therapeutic advantages, providing preclinical evidence for its development as a next-generation antidiabetic drug through synergistic pathway regulation.