AIM: In order to quantitatively examine the improvement of insulin sensitivity (IS) in patients with type 2 diabetes mellitus (T2DM) when exendin-4-IgG4-Fc (E4F4) was given for 12 weeks, the present study was conducted to establish E4F4 population oral glucose minimal models based on the meal tolerance test (MTT) data of E4F4 pre- and post-dosing, and to analyze whether low-dose (2.7 mg) administration for 12 weeks significantly improved insulin sensitivity in patients with T2DM. METHODS: Blood glucose and insulin concentrations were collected among 16 subjects in the study who completed MTT before or after dosing. Nonlinear mixed-effects model construction for the population oral glucose minimal models was performed using NONMEN 7.2 software using pre- and post-dosing data, respectively. The insulin sensitivity parameters obtained from the models before and after the administration of the drug were statistically analyzed using GraphPad Prism 8.0. RESULTS: Nonparametric test of IS before and after dosing showed statistical difference (P=0.02), and insulin sensitivity after dosing was significantly higher than the baseline value before dosing. CONCLUSION: 12 weeks of low-dose E4F4 treatment in patients with type 2 diabetes mellitus resulted in an improvement in insulin sensitivity. This study provides a pharmacodynamic basis for the efficacy of this novel biologic.