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
Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data.
Lorenzo Nesti,Andrea Natali +1 more
TL;DR: The overall evidence emerging from both clinical trials and real world registry is in favor of a protective effect of metformin with respect to both coronary events and progression to heart failure.
Journal ArticleDOI
Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD).
TL;DR: Evidence supporting a key role for SREBPs in NAFLD is presented and it is suggested that further studies are urgently needed to evaluate modulation of SREBP activity as a potential new treatment forNAFLD.
Journal ArticleDOI
Regulation of Snf1 Protein Kinase in Response to Environmental Stress
Seung-Pyo Hong,Marian Carlson +1 more
TL;DR: It was shown that Snf1 protein kinase is regulated differently during adaptation of cells to NaCl and alkaline pH with respect to both temporal regulation of activation and subcellular localization, which could contribute to specificity of the stress responses.
Journal ArticleDOI
Metformin Alters Upper Small Intestinal Microbiota that Impact a Glucose-SGLT1-Sensing Glucoregulatory Pathway.
Paige V. Bauer,Paige V. Bauer,Frank A. Duca,T.M. Zaved Waise,Brittany A. Rasmussen,Brittany A. Rasmussen,Mona A. Abraham,Mona A. Abraham,Helen J. Dranse,Akshita Puri,Catherine A. O’Brien,Catherine A. O’Brien,Tony K.T. Lam +12 more
TL;DR: It is demonstrated that metformin alters upper small intestinal microbiota and impacts a glucose-SGLT1-sensing glucoregulatory pathway and triggers an SGLT 1-dependent pathway to lower glucose production in rodents.
Journal ArticleDOI
AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing’s syndrome
Mirjam Christ-Crain,Blerina Kola,Francesca Lolli,Csaba Fekete,Dalma Seboek,Gábor Wittmann,Daniel Feltrin,Susana Igreja,Sharon Ajodha,Judith Harvey-White,George Kunos,Beat Müller,François P. Pralong,Gregory Aubert,Giorgio Arnaldi,Gilberta Giacchetti,Marco Boscaro,Ashley B. Grossman,Márta Korbonits +18 more
TL;DR: Metformin, a known AMPK regulator, prevented the corticosteroidinduced effects on AMPK in human adipocytes and rat hypothalamic neurons, suggesting that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.
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.