The mechanisms of action of metformin

Abstract

Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by this mechanism and there is increasing evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin has been shown to act via both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms; by inhibition of mitochondrial respiration but also perhaps by inhibition of mitochondrial glycerophosphate dehydrogenase, and a mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting its multiple modes of action. More work is required to truly understand how this drug works in its target population: individuals with type 2 diabetes.

Keywords: AMPK; Biguanide; Diabetes; Metformin; Review.

Fig. 1

Chemical structures of galegine, metformin and phenformin. Metformin and phenformin are synthetic derivatives of galegine. Chemically, (a) galegine (also known as isoprenylguanidine), is an isoprenyl derivative of guanidine, while (b) metformin (dimethylbiguanide) and (c) phenformin (phenethylbiguanide) are biguanides containing two coupled molecules of guanidine with additional substitutions

Fig. 2

The multiple mechanism via which metformin affects liver metabolism. Note that the possible effect of metformin on mitochondrial glycerophosphate dehydrogenase [7] has not been included. (1) Uptake of metformin into hepatocytes is catalysed by the organic cation transporter-1 (OCT1) [11]. Being positively charged, the drug accumulates in cells and, further, in the mitochondria because of the membrane potentials across the plasma membrane and the mitochondrial inner membrane [14]. (2) Metformin inhibits Complex I, preventing mitochondrial ATP production and, thus, increasing cytoplasmic ADP:ATP and AMP:ATP ratios (the latter by displacement of the adenylate kinase reaction); these changes activate AMPK [17]. (3) Alternatively, AMPK may be activated by a lysosomal mechanism, not shown in detail here but requiring Axin and late endosomal/lysosomal adaptor, MAPK and mTOR activator 1 (LAMTOR1) [27]. (4) Increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase (FBPase), resulting in the acute inhibition of gluconeogenesis [30], while also inhibiting adenylate cyclase and lowering cAMP production [32]. (5) Activated AMPK phosphorylates the ACC1 and ACC2 isoforms of ACC, inhibiting fat synthesis and promoting fat oxidation instead, thus reducing hepatic lipid stores and enhancing hepatic insulin sensitivity [34]. (6) AMPK also phosphorylates and activates the cAMP-specific 3′,5′-cyclic phosphodiesterase 4B (PDE4B), thus lowering cAMP by another mechanism [33]. (7) Glucagon-induced increases in cAMP activate cAMP-dependent protein kinase A (PKA), causing a switch from glycolysis to gluconeogenesis via phosphorylation and inactivation of PFKFB1, causing a decrease in fructose-2,6-bisphosphate (F2,6BP), an allosteric activator of phosphofructokinase (PFK) and inhibitor of fructose-1,6-bisphosphatase (FBPase). (8) PKA also phosphorylates and inactivates the liver isoform of the glycolytic enzyme pyruvate kinase (Pyr K) and (9) phosphorylates the transcription factor cAMP response element binding protein (CREB), thus inducing transcription of the genes encoding the gluconeogenic enzymes PEPCK and G6Pase. (10) Phosphorylation of CREB-regulated transcriptional co-activator-2 (CRTC2) by AMPK, or by AMPK-related kinases such as salt-inducible kinase 2 (SIK2), causes CRTC2 to be retained in the cytoplasm, antagonising the effects of PKA on the transcription of PEPCK and G6Pase [61, 62]. PKA inhibits SIK2 by direct phosphorylation at multiple sites [62]. Ac-CoA, acetyl-CoA; BPG, 1,3-bisphosphoglycerate; DHAP, dihydroxyacetone phosphate; FBP, fructose 1,6-bisphosphate; F6P, fructose 6-phosphate; G3P, glyceraldehyde 3-phosphate; G6P, glucose 6-phosphate; Ma-CoA, malonyl-CoA; OAA, oxaloacetate; PEP, phosphoenolpyruvate; 3PG, 3-phosphoglycerate

Fig. 3

Actions of metformin on metabolism and inflammation. Responses to metformin in the blood, liver and intestines are shown schematically. In the blood, in observational studies, NLR is suppressed in humans with type 2 diabetes, whilst in randomised placebo-controlled trials, cytokines, including C-C motif chemokine 11 (CCL11, also known as eotaxin-1), are also shown to be suppressed with metformin treatment. Other results indicate effects of this drug on monocytes and macrophages, affecting monocyte differentiation into macrophages and proinflammatory (proinflam) cytokine secretion. In the intestines, gut metabolism, incretin (GLP-1) secretion and the microbiome are modified upon metformin use. Further, there is evidence for gut-mediated mechanism for metformin action via gut–brain–liver crosstalk, which indirectly regulates hepatic glucose output. In the liver, metformin decreases lipogenesis and gluconeogenesis, as a result of its impact on molecular signalling and on mitochondrial function. HGP; hepatic glucose production; mTOR, mammalian target of rapamycin