Metformin—mode of action and clinical implications for diabetes and cancer

Abstract

Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

“…S2). Because metformin has also been reported to be associated with cellular oxidative stress (Algire et al., 2012; Pernicova & Korbonits, 2014), we then examined the transcript levels of 11 antioxidant genes associated with oxidative stress (Li et al., 2015; Rhee, Woo, Kil & Bae, 2012; Turpaev, 2002) after 6 hr of metformin treatment. Of these genes, GPX7 and HO‐1 (HMOX1) were the most strongly upregulated (Figure 2a), suggesting the potential involvement of these two genes in regulating aging and/or homeostasis in HDFs.…”

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

“…Among others, the targets included several membrane transporters known to be involved in metformin pharmacokinetics including solute carrier family 22 members SLC22A1/OCT1 and SLC22A/OCT2, the main transporters for metformin uptake and clearance, respectively, and multidrug and toxin extrusion protein MATE1/SLC47A1, which mediates metformin secretion (Pernicova & Korbonits, 2014). Other transporters included several members of the uptake organic anion transporting polypeptides (OATP) family (SLC21/SLCO) such as SLCO1B1/OATP1B1, SLCO2B1/OATP2B1, and SLCO1B3/OATP1B3, which are known to transport statins, antibiotics, chemotherapeutics, antihistaminic drugs, and diuretics (König, Müller & Fromm, 2013).…”

“…Metformin is a highly hydrophilic drug and is understood to require transporters to cross membranes (Pernicova & Korbonits, 2014). Consistent with this view, our ligand‐based VP, involving in silico screening, accurately predicted up to eight different membrane transporters interacting with metformin.…”

Transporters Involved in Metformin Pharmacokinetics and Treatment Response

“…In particular, the liver is a major site of action for metformin, which reduces hepatic glucose production 1,3,32 . OCT1 and OCT3 are expressed on the sinusoidal membrane of hepatocytes and play a major role in the uptake of metformin from blood into the hepatocytes 59 .…”

“…Metformin and its structurally related analog, phenfomin, are derivatives of guanidine, which was discovered in the extracts of the plant Galega officinalis (French Lilac) in the 1920s 1 . Metformin improves peripheral and liver sensitivity to insulin, reduces glucose production in the liver, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases appetite, and causes weight reduction 2 .…”