Cellular and Molecular Mechanisms of Metformin Action

Abstract

Metformin is a first-line therapy for the treatment for type 2 diabetes due to its robust glucose-lowering effects, well-established safety profile and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (> 1mM) metformin concentrations which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox dependent mechanism of metformin action. Here, we review the current literature regarding metformin’s cellular and molecular mechanisms of action

Nuts and bolts of the salt-inducible kinases (SIKs)

“…The AMP-activated protein kinase (AMPK) is one of the most studied protein kinases, the huge interest in this enzyme stemming from the discovery that it is a key sensor of cellular energy charge and one of the intracellular targets of metformin (also called glucophage), the drug used most commonly to treat Type 2 diabetes [1][2][3]. For this reason, interest in AMPK has tended to overshadow the other members of the same subfamily, which are equally interesting and are collectively termed the AMPK-related kinases.…”

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease

“…Among the biguanide family of compounds, metformin was initially of little clinical interest, due to its low potency requiring high doses of the compound to be effective. However, metformin showed a higher safety profile than its counterparts, such as phenformin or buformin, which were discarded for clinical use because they produced lactic acidosis (reviewed in [1]). Metformin is currently the most commonly prescribed drug for type 2 diabetes (T2D), and is taken by an estimated 150 million people worldwide.…”

“…It has the advantage over other non-insulin-based diabetes therapies of reducing blood glucose levels without inducing hypoglycemia. Due to its superior safety profile, it has become the first-line treatment for T2D, and is now featured on the World Health Organization's essential medicines list [1][2][3]. However, although metformin is usually well tolerated, it does have some side effects.…”

“…Numerous reports on the possible metformin mechanisms of action have been published, and some contradictory results have been shown due to differences in the cellular system used in the analyses, or because different doses of metformin were used (reviewed in [1]). Thus, different mechanisms of action have been described depending on the dose used in rats and mice: (1) suprapharmacological metformin doses (>250 mg/kg/day) achieved >1 mM plasma metformin concentration; and (2) regular pharmacological treatment (50-100 mg/kg/day) achieved 50-100 µM metformin concentration, which corresponds to the regular human dose men-tioned above [1][2][3]. Thus, depending on the dose, the mechanism of action of metformin can be explained by it affecting different signaling pathways (see below).…”

Effect of Add-On Therapy of Sodium-Glucose Cotransporter 2 Inhibitors and Dipeptidyl Peptidase 4 Inhibitors on Adipokines in Type 2 Diabetes Mellitus

“…2021;13 (6):355-362 metabolism by blocking mitochondrial glycerophosphate dehydrogenase. Metformin alters the intestinal microbes in humans, but its significance in glucose metabolism is still unclear [9][10][11].…”