Extended Data Fig. 9: Intestinal mitochondrial complex I inhibition is necessary for metformin to improve intraperitoneal pyruvate tolerance.
From: Metformin inhibits mitochondrial complex I in intestinal epithelium to promote glycaemic control
(a) Pyruvate tolerance test in which 200 mg kg−1 metformin was delivered by oral gavage 30 minutes before the intraperitoneal injection of pyruvate (2 g kg−1) in overnight-fasted mice on standard diet. (b) Incremental area under the curve of (a); Vil-Crevehicle n = 15, Vil-Cre:NDI1vehicle n = 14, Vil-Cremetformin n = 16, Vil-Cre:NDI1metformin n = 13. (c) Pyruvate tolerance test in which 200 mg kg−1 metformin was delivered by oral gavage 30 minutes before the intraperitoneal injection of pyruvate (2 g kg−1) in overnight-fasted mice on high-fat diet. (d) Incremental area under the curve of (c); Vil-Crevehicle n = 13, Vil-Cre:NDI1vehicle n = 17, Vil-Cremetformin n = 16, Vil-Cre:NDI1metformin n = 14. SD = standard diet; HFD = high-fat diet (60% lard); IP = intraperitoneal; iAUC = incremental area under the curve (arbitrary units). (e) Metabolomics heatmap of liver one hour after orally administered vehicle (water) or metformin (200 mg kg−1) in overnight fasted mice; n = 5 per condition. All mice were male. For SD-fed mice, pyruvate tolerance tests were performed on 7–10-week-old animals and the liver metabolomics was performed on 9-12-week-old animals. For HFD-fed mice, HFD was started at 8 weeks of age and pyruvate tolerance tests were performed after 8-10 weeks of HFD feeding. Data are presented as mean ± SEM. Statistical significance was determined by Two-way ANOVA with Bonferroni’s correction for multiple comparisons. *P < 0.05, **P < 0.01, ***P < 0.001.
