Abstract: Objective To investigate the pharmacological efficacy of the peptide-based drug BR0336 injection in a male C57BL/6 mouse model of T2DM combined with NASH induced by STZ-HFD. Methods Neonatal male mice were induced with streptozotocin to establish a T2DM model and fed a high-fat diet from one month of age. They were randomly assigned to the model group, TZP-0.15 mg∙kg^-1 control group, and BR0336-0.05 mg∙kg^-1, 0.15 mg∙kg^-1, 0.5 mg∙kg^-1 groups based on fasting blood glucose levels and body weight. Such parameters as body weight, food intake, fasting blood glucose, serum insulin, HbA1C%, liver function and blood lipid profiles of mice were recorded. Additionally, histopathological NAS and fibrosis analysis of liver tissues was conducted. Results BR0336 at various doses could significantly reduce body weight, food intake, fasting blood glucose, insulin levels and HbA1c% of model mice, and decrease liver NAS scores and fibrosis rates. Furthermore, BR0336 could protect liver function and improve dyslipidemia in model mice. Compared with the positive control group, an equivalent dose of BR0336 exhibited superior effects in terms of food intake, insulin levels, liver function and blood lipid profiles, and significantly delayed the progression of NASH and fibrosis. Conclusion BR0336 has a significant therapeutic effect against hyperglycemia and lipid metabolism disorders in model mice of STZ-HFD-induced T2DM combined NASH.

Key words: BR0336, T2DM, NASH model, mice, GLP-1/GIP double receptor agonist, pharmacodynamics