Role of AMP-activated protein kinase in mechanism of metformin action
Gaochao Zhou,Robert W. Myers,Ying Li,Yuli Chen,Xiaolan Shen,Judy Fenyk-Melody,Margaret Wu,John Ventre,Thomas W. Doebber,Nobuharu Fujii,Nicolas Musi,Michael F. Hirshman,Laurie J. Goodyear,David E. Moller +13 more
TLDR
It is reported that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed.Abstract:
Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.read more
Citations
More filters
Journal ArticleDOI
The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis
Anthony Sanchez,Robin Candau,Robin Candau,Alfredo Csibi,Allan F. Pagano,Allan F. Pagano,Audrey Raibon,Henri Bernardi +7 more
TL;DR: AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.
Journal ArticleDOI
Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease.
Nikita Katila,Sunil Bhurtel,Sina Shadfar,Sunil Srivastav,Sabita Neupane,Uttam Ojha,Gil-Saeng Jeong,Dong-Young Choi +7 more
TL;DR: The results indicate that metformin provides neuroprotection against MPTP neurotoxicity, which might be mediated by inhibition of α-synuclein phosphorylation and induction of neurotrophic factors.
Journal ArticleDOI
Antidiabetic properties of polysaccharide- and polyphenolic-enriched fractions from the brown seaweed Ascophyllum nodosum.
Junzeng ZhangJ. Zhang,Christa Tiller,Jingkai ShenJ. Shen,Can WangC. Wang,Gabrielle S. Girouard,Dorothy DennisD. Dennis,Colin J. Barrow,Mingsan MiaoM. Miao,H. Stephen Ewart +8 more
TL;DR: Mice treated with PPE and PPE-F1 had decreased blood total cholesterol and glycated serum protein levels compared with untreated diabetic mice, whereas PPE also normalized the reduction in liver glycogen level that occurred in diabetic animals.
Journal ArticleDOI
Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7.
Jingqi Fang,Jiping Yang,Xun Wu,Gangming Zhang,Tao Li,Xi'e Wang,Hong Zhang,Chih-chen Wang,Guang-Hui Liu,Guang-Hui Liu,Lei Wang +10 more
TL;DR: It is reported that a low dose of metformin upregulates the endoplasmic reticulum‐localized glutathione peroxidase 7 (GPx7) and increases the nuclear accumulation of nuclear factor erythroid 2‐related factor 2 (Nrf2), which binds to the antioxidant response elements in the GPX7 gene promoter to induce its expression.
Journal ArticleDOI
Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study
Thomas Bryrup,Cæcilie W. Thomsen,Timo Kern,Kristine H. Allin,Kristine H. Allin,Ivan Brandslund,Niklas Rye Jørgensen,Henrik Vestergaard,Henrik Vestergaard,Torben Hansen,Torben Hansen,Tue H. Hansen,Oluf Pedersen,Trine Nielsen +13 more
TL;DR: The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes and suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following meetformin intake.
References
More filters
Journal ArticleDOI
Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain
TL;DR: It is concluded that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues.
Journal ArticleDOI
The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis.
J. Denis McGarry,N. F. Brown +1 more
TL;DR: Key developments of the last 20 years that have led to the current understanding of the physiology of the CPT system, the structure of theCPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population are reviewed.
Journal ArticleDOI
The AMP‐Activated Protein Kinase
D. Grahame Hardie,David Carling +1 more
TL;DR: The central hypothesis is that the AMP-activated protein kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress, and protects the cell by switching off ATP-consuming pathways and switching on alternative pathways for ATP generation.
Journal ArticleDOI
Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.
Mohamad Y. El-Mir,Véronique Nogueira,Eric Fontaine,Nicole Avéret,Michel Rigoulet,Xavier Leverve +5 more
TL;DR: The results suggest the existence of a new cell-signaling pathway targeted to the respiratory chain complex I with a persistent effect after cessation of the signaling process.
Journal ArticleDOI
Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
TL;DR: Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis, and also seems to induce weight loss, preferentially involving adipose tissue.