@article{1122f1a681044424b70648eee596b9df,
title = "Let-7 underlies metformin-induced inhibition of hepatic glucose production",
abstract = "Metformin, the frontline antidiabetic drug, has gained increasing attention for the prevention and treatment of aging, cancer, and cardiovascular disease. Yet a clear mechanistic understanding of its action is still lacking, largely due to the suprapharmacological concentrations of metformin used in most studies. Here, we report an inhibition of glucose production by primary hepatocytes from dietary and genetic mouse models of type 2 diabetes (T2D) using metformin at clinically relevant concentrations. Mechanistically, metformin up-regulates microRNA let-7 that in turn down-regulates TET3, evoking a change in the ratio of hepatocyte nuclear factor 4 alpha (HNF4α) isoforms and subsequent inhibition of key gluconeogenic genes. Importantly, this let-7–mediated mechanism is faithfully recapitulated in mice with T2D chronically treated with therapeutic doses of metformin. Furthermore, hepatic delivery of let-7 ameliorates hyperglycemia and improves glucose homeostasis in diabetic mice, whereas liver-specific inhibition of let-7 abrogates these beneficial effects of metformin. Moreover, let-7 overexpression decreases glucose production from primary hepatocytes from obese humans. Thus, we propose the reactivation of a let-7–dependent pathway that is pathologically repressed in the liver of diabetes as a major mechanism of metformin action and that liver-specific delivery of let-7 represents a potential therapeutic for T2D. Our findings are also pertinent to the development of therapeutic strategies for other chronic diseases.",
keywords = "Let-7, TET3, diabetes, liver, metformin",
author = "Di Xie and Fan Chen and Yuanyuan Zhang and Bei Shi and Jiahui Song and Kiran Chaudhari and Yang, {Shao Hua} and Zhang, {Gary J.} and Xiaoli Sun and Taylor, {Hugh S.} and Da Li and Yingqun Huang",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Kathy Harry at the Yale Liver Center for isolating mouse primary hepatocytes. Research reported in this publication was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH (DK119386 and DK124321 to Y.H.); grants from the National Natural Science Foundation of China (No. 82071607), the LiaoNing Revitalization Talents Program (No. XLYC1907071), and the Fok Ying Tung Education Foundation (No. 151039) to D.L.; and a grant from the National Institute of Neurological Disorders and Stroke (R01NS109583) to S.-H.Y. Y.H. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: We thank Kathy Harry at the Yale Liver Center for isolating mouse primary hepatocytes. Research reported in this publication was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH (DK119386 and DK124321 to Y.H.); grants from the National Natural Science Foundation of China (No. 82071607), the LiaoNing Revitalization Talents Program (No. XLYC1907071), and the Fok Ying Tung Education Foundation (No. 151039) to D.L.; and a grant from the National Institute of Neurological Disorders and Stroke (R01NS109583) to S.-H.Y. Y.H. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",
year = "2022",
month = apr,
day = "5",
doi = "10.1073/pnas.2122217119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "14",
}