Fig. 2

Metformin-induced decreases in plasma arginine and citrulline are associated with the down-regulation of immune response-related genes in postmenopausal women. (a) Functional analysis on the Spearman´s rank correlation between breast tissue gene expression changes (post-treatment vs., baseline) and plasma level changes (post-treatment vs. baseline) of the amino acid arginine revealed down-regulation of fat cell differentiation and endothelial proliferation and migration in the postmenopausal women treated with metformin compared to placebo. (b) Functional analysis on the Spearman´s rank correlation between breast tissue gene expression changes and plasma level changes of the amino acid citrulline revealed down-regulation of immune cell activation, proliferation and differentiation, and increased mammary gland morphogenesis in the postmenopausal women treated with metformin compared to those treated with placebo. The bar plots in panels A and B show the top 20 highly enriched pathways in placebo-treated and metformin-treated postmenopausal women, respectively. The bars represent the NESs. The significantly enriched pathways are shown as adjusted p-value < 0.01.