Fig. 5: TXNIP overexpression in diabetic mice abolishes the blood glucose-lowering effect of metformin by reducing its enhancement of intestinal GLUT1 expression and glucotonic effect.

a IPGTT data for vehicle- and metformin-treated transgenic mice. Metformin-treated nontransgenic C57BL/6 mice (n = 5) exhibited better glucose tolerance than both vehicle-treated mice (n = 4) and metformin-treated mice overexpressing TXNIP (n = 5, analysis of variance multiple t-test for multiple-comparison correction; *P < 0.05 was used to compare CON-NT and CON-MET, ^#P < 0.05, and ^##P < 0.01 was used to compare CON-MET and TXMIP-MET) and corresponding AUCs. b Representative images of small-intestinal and colon FDG autoradiography of metformin-treated and vehicle-treated mice after PBS lavage. Areas of higher FDG accumulation are red in color. c The right graph shows the quantitative analysis of FDG uptake in post-washing intestinal tissue autoradiography images. Metformin-treated mice exhibited higher FDG uptake in the ileum and colon compared with both vehicle-treated mice and metformin-treated mice with TXNIP overexpression. The left graph shows the analysis of PBS washings from the colon. PBS washings from metformin-treated mice contained significantly more FDG than those from vehicle-treated mice or metformin-treated mice overexpressing TXNIP, indicating greater FDG excretion. d Representative images of the total protein levels of TXNIP demonstrate a significant overexpression of TXNIP in the group compared with the control group, indicating robust TXNIP upregulation in the ileum and colon. The graph shows a significant increase in TXNIP expression between control and TXNIP-overexpressing groups, providing evidence of robust TXNIP upregulation. e Representative images of the expression analysis of GLUT1 in membrane proteins revealing a significant increase in GLUT1 expression in the mouse intestine after metformin treatment, whereas a decrease was observed in mice overexpressing TXNIP, in both the ileum and colon. All data are presented as the mean ± s.e.m. Data in a and c–e were analyzed using two-tailed Student’s t-tests; *P < 0.05, **P < 0.01, ***P < 0.001. NS, nonsignificant.