Open AccessLet-7 underlies metformin-induced inhibition of hepatic glucose production
Author(s) -
Di Xie,
Fan Chen,
Yuanyuan Zhang,
Bei Shi,
Jiahui Song,
Kiran Chaudhari,
Shao-Hua Yang,
Gary J. Zhang,
Xiangrong Sun,
Hugh S. Taylor,
Da Li,
Yingqun Huang
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2122217119
Subject(s) - metformin , glucose homeostasis , hepatocyte nuclear factors , diabetes mellitus , endocrinology , medicine , hepatocyte , gene isoform , pharmacology , biology , chemistry , insulin resistance , transcription factor , in vitro , biochemistry , gene
Significance A clear mechanistic understanding of metformin’s antidiabetic effects is lacking. This is because suprapharmacological concentrations of metformin have been used in most studies. Using mouse models and human primary hepatocytes, we show that metformin, at clinically relevant doses, suppresses hepatic glucose production by activating a conserved regulatory pathway encompassing let-7, TET3, and a fetal isoform of hepatocyte nuclear factor 4 alpha (HNF4α). We demonstrate that metformin no longer has potent antidiabetic actions in a liver-specific let-7 loss-of-function mouse model and that hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis. Our results thus reveal an important role of the hepatic let-7/TET3/HNF4α axis in mediating the therapeutic effects of metformin and suggest that targeting this axis may be a potential therapeutic for diabetes.