Lakhasly

Metformin acts as a metabolic inhibitor and alters both whole-body and cellular energy metabolism.Hopefully, the knowledge gained from dissecting the pathways that metformin acts on will propel the development of multiple novel therapies.Laboratory evidence of the antimitotic action of metformin is promising, although results from epidemiological studies remain controversial.80 The combination of tumour genetics, patient metabolic profile and the cellular microenvironment determine the antitumour effect of metformin treatment.This mechanism is probably the main mode through which metformin lowers hepatic glucose output.Review criteria

Metformin acts as a metabolic inhibitor and alters both whole-body and cellular energy metabolism. It is primarily used in patients with type 2 diabetes mellitus, and its main mechanism of action in this disease setting is inhibition of hepatic gluconeogenesis. Metformin interacts with complex I in the mitochondrial electron transport chain, thereby lowering cellular ATP levels and causing AMP accumulation. AMP binds to the P-site of adenylate cyclase and inhibits its action in response to glucagon, thereby disrupting downstream cAMP–PKA signalling. As a result, the activity of enzymes of the gluconeogenic pathway is inhibited in favour of glycolysis. This mechanism is probably the main mode through which metformin lowers hepatic glucose output.

In addition, the reduction in energy charge leads to AMPK activation and downregulation of gluconeogenic gene expression. Although AMPK activation is dispensable for the glucose-lowering effect of metformin, it probably triggers important insulin-sensitizing and lipid-modulating mechanisms. Much of the regulatory components of this model of metformin action, as well as parameters that determine its kinetics (such as the rate of dissociation of AMP from the P-site of adenylate cyclase) and specificity remain undefined.

Laboratory evidence of the antimitotic action of metformin is promising, although results from epidemiological studies remain controversial.80 The combination of tumour genetics, patient metabolic profile and the cellular microenvironment determine the antitumour effect of metformin treatment. Focussed use of metformin to specifically target metabolic differences between normal and abnormal signalling offers a vast, though challenging, therapeutic potential. The metabolic similarities between activated proinflammatory cells and cancer cells suggest that metabolic inhibitors may modulate immune cells. The immune system could thus be a mediator of some of the pleiotropic benefits of metformin. Many details of metformin action remain to be discovered, and the risk of harm must be considered when designing new metformin-based therapies. Hopefully, the knowledge gained from dissecting the pathways that metformin acts on will propel the development of multiple novel therapies.

Review criteria