Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice

Fujita, Yoshihito; Hosokawa, Munetaka; Fujimoto, Shimpei; Mukai, Eri; Abulizi, Abudukadier; Obara, Akio; Ogura, Mariko; Nakamura, Yasuhiko; Toyoda, Kentaro; Nagashima, Kazuaki; Seino, Yutaka; Inagaki, Nobuya

doi:10.1007/s00125-010-1729-5

Cited by 34 publications

(23 citation statements)

References 38 publications

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“…Although arctigenin activated AMPK in skeletal muscle and liver, it showed no effect on the activation of recombinant AMPK kinase, suggesting that arctigenin activated AMPK indirectly. LKB1 and CaMKK are two upstream kinases of AMPK [34], and a recent study showed that ONOO − played a critical role in AMPK activation by metformin in liver and that endothelial NOS was required for metformin action in vitro and in vivo [35]. However, our results showed that arctigenin activated AMPK independently of LKB1, CaMKK, and the ONOO − or NOS pathways.…”

Section: Discussioncontrasting

confidence: 68%

Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice

Huang

Gong

et al. 2011

Diabetologia

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Aims/hypothesis Arctigenin is a natural compound that had never been previously demonstrated to have a glucoselowering effect. Here it was found to activate AMPactivated protein kinase (AMPK), and the mechanism by which this occurred, as well as the effects on glucose and lipid metabolism were investigated. Methods 2-Deoxyglucose uptake and AMPK phosphorylation were examined in L6 myotubes and isolated skeletal muscle. Gluconeogenesis and lipid synthesis were evaluated in rat primary hepatocytes. The acute and chronic effects of arctigenin on metabolic abnormalities were observed in C57BL/6J and ob/ob mice. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye, JC-1. Analysis of respiration of L6 myotubes or isolated mitochondria was conducted in a channel oxygen system. Results Arctigenin increased AMPK phosphorylation and stimulated glucose uptake in L6 myotubes and isolated skeletal muscles. In primary hepatocytes, it decreased gluconeogenesis and lipid synthesis. The enhancement of glucose uptake and suppression of hepatic gluconeogenesis and lipid synthesis by arctigenin were prevented by blockade of AMPK activation. The respiration of L6 myotubes or isolated mitochondria was inhibited by arctigenin with a specific effect on respiratory complex I. A single oral dose of arctigenin reduced gluconeogenesis in C57BL/6J mice. Chronic oral administration of arctigenin lowered blood glucose and improved lipid metabolism in ob/ob mice. Conclusions/interpretation This study demonstrates a new role for arctigenin as a potent indirect activator of AMPK via inhibition of respiratory complex I, with beneficial effects on metabolic disorders in ob/ob mice. This highlights the potential value of arctigenin as a possible treatment of type 2 diabetes.

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Section: Discussioncontrasting

confidence: 68%

Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice

Huang

Gong

et al. 2011

Diabetologia

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“…Metformin and epigallocatechin-3-gallate suppress hepatic gluconeogenesis by ROS-mediated AMPK activation in the liver (50). By using genetic models, many groups have demonstrated the acute requirement of ROS for AMPK activation, which has many beneficial metabolic effects (47,51,52). Based on the significant inhibition of AMPK and glucose uptake by NAC, we suggest that ROS generation by emodin plays an important role in the activation AMPK.…”

Section: Discussionmentioning

confidence: 88%

Emodin Regulates Glucose Utilization by Activating AMP-activated Protein Kinase*

Song

Kim

Ghim

et al. 2013

Journal of Biological Chemistry

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Background: AMPK activation improves glucose tolerance and insulin sensitivity. Results: Emodin increases glucose uptake in skeletal muscle and lowers blood glucose levels via AMPK activation. Conclusion: Administration of emodin leads to increased glucose tolerance and insulin sensitivity in vivo. Significance: Our results highlight the potential value of emodin as a drug for the treatment of diabetes.

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“…Although these initial conclusions were later refuted by the authors [16], the absence of clear data linking the mitochondrial effect of metformin to activation of hepatic AMPK still nurtures confusion. Thus, an alternative AMP-independent hypothesis involving mitochondrial-derived peroxynitrite was recently proposed, prolonging the controversy [17]. Taken together, a clarification of the mechanism by which metformin activates hepatic AMPK is required, especially in humans.…”

Section: Introductionmentioning

confidence: 99%

Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status

et al. 2011

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Aim/hypothesisThe glucose-lowering drug metformin has been shown to activate hepatic AMP-activated protein kinase (AMPK), a master kinase regulating cellular energy homeostasis. However, the underlying mechanisms remain controversial and have never been investigated in primary human hepatocytes.MethodsHepatocytes isolated from rat, mouse and human livers were treated with various concentrations of metformin. Isoform-specific AMPKα abundance and activity, as well as intracellular adenine nucleotide levels and mitochondrial oxygen consumption rates were determined at different time points.ResultsMetformin dose- and time-dependently increased AMPK activity in rat and human hepatocytes, an effect associated with a significant rise in cellular AMP:ATP ratio. Surprisingly, we found that AMPKα2 activity was undetectable in human compared with rat hepatocytes, while AMPKα1 activities were comparable. Accordingly, metformin only increased AMPKα1 activity in human hepatocytes, although both AMPKα isoforms were activated in rat hepatocytes. Analysis of mRNA expression and protein levels confirmed that only AMPKα1 is present in human hepatocytes; it also showed that the distribution of β and γ regulatory subunits differed between species. Finally, we demonstrated that the increase in AMP:ATP ratio in hepatocytes from liver-specific Ampkα1/2 (also known as Prkaa1/2) knockout mice and humans is due to a similar and specific inhibition of the mitochondrial respiratory-chain complex 1 by metformin.Conclusions/interpretationActivation of hepatic AMPK by metformin results from a decrease in cellular energy status owing to metformin’s AMPK-independent inhibition of the mitochondrial respiratory-chain complex 1. The unique profile of AMPK subunits found in human hepatocytes should be considered when developing new pharmacological agents to target the kinase.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2311-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice

Cited by 34 publications

References 38 publications

Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice

Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice

Emodin Regulates Glucose Utilization by Activating AMP-activated Protein Kinase*

Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status

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