Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.

By M. Foretz, S. Hébrard, J. Leclerc, Elham Zarrinpashneh, M. Soty, G. Mithieux, K. Sakamoto, F. Andreelli, B. Viollet. Journal of Clinical Investigation, 2010

1,226 citations recorded by the source corpus.

Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/4d79b84814994b68fdf5827e39af5e62297b4059

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Citations in the corpus

Metformin: from mechanisms of action to therapies. (2014, background): “It has been reported that this transient inhibition of complex 1 induces a drop in cellular energy charge, a measure of the energetic state of the cell defined as ([ATP] + 0.5[ADP])/ ([ATP] + [ADP] + [AMP]) (Foretz et al., 2010; Stephenne et al., 2011).”
Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress (2010, background): “Activation of AMPK and subsequent inhibition of mTORC1 occurs in response to these drugs, but the contribution of this signaling pathway to the antidiabetic effects of the drugs remains unclear (Foretz et al., 2010; Shaw et al., 2005).”
CREB and the CRTC co-activators: sensors for hormonal and metabolic signals (2011, background): “However, the glucose-lowering effects of metformin appear to be largely preserved in mice even with a combined knockout of both AMPK catalytic subunits (α1 and α2), suggesting the presence of additional regulatory targets for this small molecul”
AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, neutral): “Nature Reviews Molecular Cell Biology, 13(4), 251-262.”
Metformin as a Tool to Target Aging (2016, neutral): “…oxygen species (ROS) (Batandier et al., 2006; Bridges et al., 2014; Zheng et al., 2012), activation of AMP-activated kinase (AMPK) (Cho et al., 2015; Duca et al., 2015; Foretz et al., 2010; Lien et al., 2014; Lu et al., 2015; Zheng et al., 2012), and reduction in DNA damage (Algire et al., 2012).”
The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, neutral): “, although it remains controversial whether AMPK is absolutely required for the glucose-lowering effects of metformi”
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “2005] or mouse hepatocytes with a double AMPK-a1/-a2 knockout treated with the metabolic poison metformin [Foretz et al. 2010]), the increases in ADP:ATP and AMP:ATP in response to metabolic stress are much greater, indicating that AMPK is acting to preserve energy homeostasis in the wild-type cells”
The mechanisms of action of metformin (2017, background): “Since ACC phosphorylation is abolished by AMPK knockout [31], the long-term insulin-sensitising effects of metformin appear to be mediated entirely by AMPK.”
Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality. (2015, background): “However, studies on the metabolic effects of metformin demonstrated that metformin inhibits gluconeogenesis in an LKB1- and AMPKindependent fashion (57).”
Cellular and Molecular Mechanisms of Metformin Action (2020, background): “Additionally, these studies are challenged by conflicting data showing that metformin does not alter hepatic energy charge and does not require AMPK activation to exert its therapeutic effects in vivo (59, 124).”