Agradecimentos: This study was supported by funding from INCT Obesidade e Diabetes CNPq (465693/2014-8) and FAPESP (2014/50907-5). G.Z.R. received a fellowship from PNPD/CAPES (88882.305918/2018-1). This research used facilities of the Brazilian Biosciences National Laboratory (LNBio), part of the Brazilian Centre for Research in Energy and Materials (CNPEM), a private non-profit organization under the supervision of the Brazilian Ministry for Science, Technology, and Innovations (MCTI). The NMR Laboratory staff is acknowl-edged for their assistance during the experiments. We also would like to thank Maria Cristina de Souza and Marielza Crosgnac Feres Lot—from Gasometria/HC, Josimo Garcia from Cyclobrás, and LACTAD/UNICAMP for providing assistance and/or materials during the experiments Ver menos

Abstract: Metformin is the most prescribed drug for DM2, but its site and mechanism of action are still not well established. Here, we investigated the effects of metformin on basolateral intestinal glucose uptake (BIGU), and its consequences on hepatic glucose production (HGP). In diabetic patients and mice, the primary site of metformin action was the gut, increasing BIGU, evaluated through PET-CT. In mice and CaCo2 cells, this increase in BIGU resulted from an increase in GLUT1 and GLUT2, secondary to ATF4 and AMPK. In hyperglycemia, metformin increased the lactate (reducing pH and bicarbonate in portal vein) and acetate production in the gut, modulating liver pyruvate carboxylase, MPC1/2, and FBP1, establishing a gut-liver crosstalk that reduces HGP. In normoglycemia, metformin-induced increases in BIGU is accompanied by hypoglycemia in the portal vein, generating a counter-regulatory mechanism that avoids reductions or even increases HGP. In summary, metformin increases BIGU and through gut-liver crosstalk influences HGP Ver menos