Details

Autor(en) / Beteiligte

• Xie, Di
• Chen, Fan
• Zhang, Yuanyuan
• Shi, Bei
• Song, Jiahui
• Chaudhari, Kiran
• Yang, Shao-Hua
• Zhang, Gary J
• Sun, Xiaoli
• Taylor, Hugh S
• Li, Da
• Huang, Yingqun

Titel

Let-7 underlies metformin-induced inhibition of hepatic glucose production

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2022-04, Vol.119 (14), p.e2122217119-e2122217119

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• SignificanceA 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.