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Year : 2014  |  Volume : 1  |  Issue : 2  |  Page : 125-126

Insights into the molecular actions of metformin and the future targets for research

ICMR Advanced Centre of Reverse Pharmacology in Traditional Medicine, Kasturba Health Society-Medical Research Centre, Mumbai, Maharashtra, India

Date of Web Publication12-Jun-2014

Correspondence Address:
Hiteshi Dhami-Shah
Kasturba Health Society-Medical Research Centre, ICMR Advanced Centre of Reverse Pharmacology in Traditional Medicine. 17 K.D Road, Vile Parle West, Mumbai - 400 056, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2347-9906.134434

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How to cite this article:
Dhami-Shah H. Insights into the molecular actions of metformin and the future targets for research. J Obes Metab Res 2014;1:125-6

How to cite this URL:
Dhami-Shah H. Insights into the molecular actions of metformin and the future targets for research. J Obes Metab Res [serial online] 2014 [cited 2021 May 15];1:125-6. Available from: https://www.jomrjournal.org/text.asp?2014/1/2/125/134434

Metformin, besides being a widely prescribed antidiabetic drug, has shown its beneficial role in treating polycystic ovarian syndrome, steatohepatitis, HIV-linked metabolic abnormalities as well as prevention of cancer. The current issue of JOMR has several interesting articles on metformin. The clinical use of metformin preceded by decades the understanding of its molecular mechanisms of action. Recent data have provided insights into the novel mechanisms, which are emerging to explain the diverse effects of metformin. The research also suggests possible future targets for drug discovery and development. A research digest is attempted to highlight several of such molecular targets.

Stephenne X, Foretz M, Taleux N, Van der Zon GC, Sokal E, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011;54:3101-110.

This study aimed at understanding the mechanism of action involved in activating hepatic adenosine monophosphate-activated protein kinase (AMPK) by metformin, on hepatocytes of rat, mouse, and human origin. Activity of AMPK subunits (α1, α2, β, and γ), intracellular adenine nucleotide levels and mitochondrial oxygen consumption rates were analyzed at different time points, with several doses. There was an increase in AMPK activity in the rat as well as the human hepatocytes. There was a significant hike in cellular AMP: Adenosine triphosphate (ATP) ratio in human hepatocytes from liver specific AMPKαα1/2. The resultant decrease in the cellular energy status is ascribed to an independent inhibition by metformin of mitochondrial respiratory chain complex I. Hence, AMPK subunits found in human hepatocytes can provide targets for new drug discovery.

Hyun B, Shin S, Lee A, Lee S, Song Y, Ha NJ, Cho KH, Kim K. Metformin down-regulates TNF-α Secretion via Suppression of Scavenger Receptors in Macrophages. Immune Netw 2013;13(4):123-32.

The mechanism of the antiinflammatory activity of metformin was studied in RAW 264.7 cells, peritoneal macrophages and in type 2 diabetes in C57BL/6N mice. The lipopolysaccharide induced cytokines release and nuclear factor kappa B translocation, the expression of scavenger receptors CD36 and SR-A, were studied. Metformin, in a dose-dependent manner decreased production of nitric oxide and pro-inflammatory cytokines, interleukin (IL)-β, IL-6 and tumor necrosis factor-alpha [TNF-α]) through down-regulation in macrophages. TNF-α protein as well as mRNA expression were reduced in obese mice and in macrophages. The protein expression of antiinflammatory cytokines, IL-4 and IL-10 was enhanced. The novel mechanisms of the antiinflammatory activity of metformin offer new targets for drug discovery, particularly with active plant molecules.

Theriault J, Palmer H, Pittman D. Inhibition of the unfolded protein response by metformin in renal proximal tubular epithelial cells. Biochem Biophys Res Commun 2011;409(3):500-5.

Metformin is transported to the surface of renal proximal tubular epithelial cells by organic cation transporters. This putative renoprotective effect of metformin was examined on the expression of unfolded protein response UPR-related markers (GRP94 and CHOP) induced by glucosamine (GlcN), 2-deoxyglucose (2-DOG) and tunicamycin in the renal proximal tubular epithelial cells. Metformin inhibited UPR-related marker expression induced by GlcN and 2-DOG. Metformin was AMPK independent. The study opens up further potential for research in investigating the beneficial effect of metformin on kidney function.

Cai H, Zhang G, Chen W, Zhang B, Zhang J, Chang J, Tang C, Qi Y, Yin X. Metformin protects the myocardium against isoproterenol-induced injury in rats through alleviating endoplasmic reticulum stress. Pharmazie 2014;69(1):64-9.

In the rat model of isoproterenol (ISO)-induced myocardial injury, pretreatment with metformin significantly reduced mortality. There was also a decrease in the plasma lactate dehydrogenase activity as well as in myocardial malondialdehyde. Metformin also diminished hemodynamic disturbance, myocardial damage, and apoptosis. As the western blot analysis showed suppression of endoplasmic reticulum stress with an increase in phosphorylation of AMPK, the protective effect against ISO injury was ascribed to AMPK activation. The proposed cardioprotective role in rats has not been correlated clinically. This would require a longitudinal study on the cardiovascular risk factors in patients treated with metformin.

Buler M, Aatsinki S-M, Izzi V, Hakkola J. Metformin Reduces Hepatic Expression of SIRT3, the Mitochondrial Deacetylase Controlling Energy Metabolism. PLOS One. 2012;7(11):e49863.

Sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, regulates the electron transport chain and maintains the basal ATP yield. The study hypothesized that the antihyperglycemic effect of metformin could be by an inhibition of the mitochondrial ATP production. This response was through down regulation of SIRT3 expression in primary hepatocytes. It was shown that metformin decrease mitochondrial SIRT3 protein levels by enhancing acetylation of several mitochondrial proteins. Since the suppression of ATP production inhibits hepatic glucose production, SIRT3 down-regulation serves as a proposed novel path for the therapeutic action of metformin.


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