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

Stéphenne, Xavier; Foretz, Marc; Taleux, Nellie; Zon, Gerard C. van der; Sokal, Étienne; Hue, Louis; Viollet, Benoı̂t; Guigas, Bruno

doi:10.1007/s00125-011-2311-5

Cited by 240 publications

(208 citation statements)

References 50 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…It has been shown that metformin activates AMPK through LKB1 because LKB1 is the up-stream kinase regulating the phosphorylation of the AMPK catalytic α subunit at T172, a crucial phosphorylation site for AMPK activity [26] . Alternatively, it has been proposed that metformin activates AMPK via inhibiting mitochondrial complex 1 and consequently increasing the ADP/ATP ratio, a basic stimulating factor for AMPK activity [27,28] . In this study, we observed that AMPK phosphorylation was apparently inhibited by LPS administration, especially in the liver, a major tissue target for the glucose-lowering effect of metformin.…”

Section: Discussionmentioning

confidence: 99%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

View full text Add to dashboard Cite

Aim: Accumulating evidence shows that lipopolysaccharides (LPS) derived from gut gram-negative bacteria can be absorbed, leading to endotoxemia that triggers systemic inflammation and insulin resistance. In this study we examined whether metformin attenuated endotoxemia, thus improving insulin signaling in high-fat diet fed mice. Methods: Mice were fed a high-fat diet for 18 weeks to induce insulin resistance. One group of the mice was treated with oral metformin (100 mg·kg -1 ·d -1 ) for 4 weeks. Another group was treated with LPS (50 μg·kg -1 ·d -1 , sc) for 5 days followed by the oral metformin for 10 d. Other two groups received a combination of antibiotics for 7 d or a combination of antibiotics for 7 d followed by the oral metformin for 4 weeks, respectively. Glucose metabolism and insulin signaling in liver and muscle were evaluated, the abundance of gut bacteria, gut permeability and serum LPS levels were measured. Results: In high-fat fed mice, metformin restored the tight junction protein occludin-1 levels in gut, reversed the elevated gut permeability and serum LPS levels, and increased the abundance of beneficial bacteria Lactobacillus and Akkermansia muciniphila. Metformin also increased PKB Ser473 and AMPK T172 phosphorylation, decreased MDA contents and redox-sensitive PTEN protein levels, activated the anti-oxidative Nrf2 system, and increased IκBα in liver and muscle of the mice. Treatment with exogenous LPS abolished the beneficial effects of metformin on glucose metabolism, insulin signaling and oxidative stress in liver and muscle of the mice. Treatment with antibiotics alone produced similar effects as metformin did. Furthermore, the beneficial effects of antibiotics were addictive to those of metformin. Conclusion: Metformin administration attenuates endotoxemia and enhances insulin signaling in high-fat fed mice, which contributes to its anti-diabetic effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The successfully established diabetic KK-Ay mice ( n = 41) were randomly divided into four groups: vehicle group (saline treatment, n = 10); SMR-treated groups (50 mg/kg/day, n = 10; 100 mg/kg/day, n = 11). As we all known, metformin is a commonly used anti-diabetic drug which has been demonstrated can increasing GLUT4 expression and translocation through activating AMPK pathway [28,29]. So we choose metformin as a positive control drug (200 mg/kg/day, n = 10).…”

Section: Methodsmentioning

confidence: 99%

Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter

Wang

Yang

et al. 2017

Food & Nutrition Research

View full text Add to dashboard Cite

The present study investigated the anti-diabetic activity and potential mechanism of stigmasterol (SMR), which is a kind of phytosterols derived from the edible soybean oil in vitro and in vivo. SMR displayed a mild GLUT4 translocation activity by 1.44-fold in L6 cells. L6 cells were treated with different concentration of SMR, showing significant effects on the enhancing glucose uptake. SMR administrated orally to the KK-Ay mice significantly alleviated their insulin resistance and oral glucose tolerance with reducing fasting blood-glucose levels and blood lipid indexes such as triglyceride and cholesterol. Moreover, the GLUT4 expression in L6 cells, skeletal muscle and white adipose tissue had been also enhanced. In this paper we conclude that, stigmasterol seems to have potential beneficial effects on the treatment of type 2 diabetes mellitus with the probable mechanism of targeting GLUT4 glucose transporter included increasing GLUT4 translocation and expression.

show abstract

“…In mammals, metformin is generally believed to act through the activation of AMPK, one of the main regulators of cellular energy homeostasis (2,(14)(15)(16), but recent research suggests the existence of AMPK-independent mechanisms as well (17,18). More upstream, metformin is thought to activate AMPK through partial inhibition of complex I of the electron transport chain (ETC) and a resultant increase in the AMP/ATP ratio (19)(20)(21), although again, not all data support this theory (16,22).…”

mentioning

confidence: 99%

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Haes

Frooninckx

Assche

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

301

212

View full text Add to dashboard Cite

The antiglycemic drug metformin, widely prescribed as first-line treatment of type II diabetes mellitus, has lifespan-extending properties. Precisely how this is achieved remains unclear. Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance. We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

show abstract

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

Cited by 240 publications

References 50 publications

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling

Anti-diabetic activity of stigmasterol from soybean oil by targeting the GLUT4 glucose transporter

Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

Contact Info

Product

Resources

About