AAC2-hINS treatment improved physical activity and cognitive performance in STZ and genetic mouse models of T1D. (a) Activity of mice in XYZ directions in STZ mice was measured during the active dark period using CLAMS. Student’s t-test. (b) Spontaneous alteration (% SA) in STZ mice was measured 3–4 weeks post treatment. One-way ANOVA. (c) Representative images of protein expression of hINS (brown staining, yellow arrows) in the hippocampus of STZ mice treated with Veh, hINS, AAC2, AAC2-hINS (n = 3/group). (d) Activity of mice in XYZ directions in Ins2Akita mice (n = 5/group) was measured during the active dark period using CLAMS. Student’s t-test. (e,f) Barnes Maze test was performed with Ins2Akita mice after 7 weeks post-treatment (n = 5/group). In the training period (Day 1~5), latency (e) and a number of errors (f) were measured. Differences were compared for each day by Student’s independent t-test. Significant differences between control and AAC2-hINS-treated mice on days 4 and 5 were p = 0.004 and 0.02, respectively. At baseline, the control group presented significantly more errors compared to the AAC2-hINS treated group (p = 0.01). (g) Hole escape time at day 6 (Q3 in same Barnes Maze experiment). Overall comparison p = 0.026.