design of a dual agonist of exendin-4 and fgf21 as a potential treatment for type 2 diabetes mellitus and obesity

Background: fibroblast growth factor 21 (fgf21) is a metabolic, endocrine hormone regulating insulin sensitivity, energy expenditure, and lipid metabolism. it has significant potential as a therapeutic drug for treating type 2 diabetes and obesity. however, the clinical efficacy of fgf21 analogs is limited due to their instability and short half-life. glucagon-like peptide 1 (glp-1) receptor agonists have been recognized as effective medications for type 2 diabetes mellitus and obesity over the past two decades. methods: this study designed a new long-acting dual-agonist, exendin-4/fgf21, utilizing albumin-binding-designed ankyrin repeat proteins (darpins) as carriers. the purified fusion proteins were subcutaneously injected into mice for pharmacokinetic and biological activity studies. results: ex-darp-fgf21 had a high binding affinity for human serum albumin (hsa) in vitro and a prolonged half-life of 27.6 hours in vivo. bioactivity results reveal that ex-darp-fgf21 significantly reduced blood glucose levels in healthy mice. moreover, compared to ex-darp alone, the ex-darp-fgf21 dual agonist displayed enhanced blood glucose lowering bioactivity and superior body weight management in the diet-induced obesity (dio) mouse model. conclusions: these results indicate that the long-acting dual agonist of exendin-4 and fgf21 holds considerable potential as a treatment for type 2 diabetes mellitus (t2dm) and obesity in the future.