Metformin: From diabetes to cancer to prolongation of life
The surprising findings of Metformin
The metformin molecule dates back over a century, but its clinical use started in the ‘50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with an improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, acting on the insulin receptors and mitochondria, most likely by activating the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid-lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life length is the object of large ongoing studies and several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation, and miRNAs. An activity on age-associated inflammation (inflammation) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to the reduction of cells with the senescent-associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson’s disease. Telomere prolongation may be related to the activity of mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.
Metformin is well known for control of type II Diabetes Mellitus. Metformin is taken by mouth, once a day and eliminates injection.
It is classified as a GLP 1 and exhibits other metabolic effects. It can also decrease lipids, and reduce the risks of cancer.
Metabolic Mechanism of Action of Metformin (graphic)
Metformin and Lipid-Lowering Effects
A cholesterol-lowering activity, specifically on the atherogenic low-density lipoprotein (LDL) fraction, has been reported for metformin from the early clinical studies, indicating a (-12 %) LDL-cholesterol reduction versus no change with the sulphonylurea
Mitochondrial activity of metformin
The major target of the pleiotropic effects of metformin and other biguanides is mitochondria. The early reports already indicated that the drug reduces cellular respiration by specific inhibition of the mitochondrial respiratory chain.
Metformin and cancer
An unexpected anti-cancer activity of metformin was the result of an early epidemiological study essentially indicating that metformin-treated diabetics had a significantly lower cancer burden versus diabetics treated with other agents. This observation was confirmed by several other reports. This potential benefit of metformin is in contrast with the apparently raised cancer risk following insulin-based therapies. Although non-confirmatory data have been reported two independent meta-analyses comparing metformin to other treatments reported 30–40 % reductions in cancer incidence in metformin-treated T2D
Diabetes has a clear association with increased cancer risk, particularly in insulin-treated individuals
Metformin use has been shown to reduce the frequency of specific cancers, in particular breast cancer, and to be an effective radiosensitizer in the treatment of this most frequent tumor
Metformin appears to provide additional benefit for the treatment of e.g., cisplatin-treated cancers and the use of metformin has been associated with a clear reduction of cancer risk versus other antidiabetics
Metformin and aging
Identification of the hallmarks of aging allowed us to identify those most sensitive to metformin. Among these, the activation of AMPK and SIRT1 and down-regulation of the insulin-IGF1 signaling and m-TORC1 are involved in the beneficial effects of metformin on energy metabolism[171]. Activation of AMPK via the liver kinase B1 (LKB1) mediates the prolonged lifespan in mice and C. elegans [172].
The inflammatory process is a major target of metformin. Suppression of the proinflammatory cytokines of the NF-kB pathway is associated with reduced mortality in older diabetics treated with metformin [173]. The activity of metformin on dysfunctional mitochondria with aging is well predictable from the drug’s mechanism on oxidative stress [174], possibly delaying mitochondrial biogenesis and senescence by AMPK-mediated H3K79 methylation acting through the SIRT1-DOT1L axis [175].
.
No comments:
Post a Comment