Introduction

1. Metformin-mode of action and clinical implications for diabetes and cancerNat Rev Endocrinol. 2014 Mar;10(3):143-56.

2. The biguanide metformin has been used for its glucose-lowering effect since 1957 in Europe and since 1995 in the USA • Yet despite being the most frequently prescribed antidiabetic treatment worldwide, its mechanism of action remains largely elusive • Pernicova et al. discuss the updated understanding of the molecular mechanisms through which metformin acts on metabolism, mainly focussing on liver gluconeogenesis, and on tumourigenesis • In addition, the potential implications of new discoveries about metformin molecular targets for the development of antidiabetic and anticancer therapies is also reviewed Introduction

3. Metformin and diabetes mellitus • The glucose-lowering, insulin-sensitizing agent metformin works mainly by reducing gluconeogenesis and opposing glucagon-mediated signalling in the liver and, to a lesser extent, by increasing glucose uptake in skeletal muscle • The primary site of metformin action is the mitochondrion • The antihyperglycaemic effect of metformin is probably owing to defective protein kinase A signalling • Metformin affects lipid metabolism primarily via 5'-AMP-activated protein kinase (AMPK) activation

4. Metformin and diabetes mellitus • Biguanides are recognized as indirect activators of AMPK • For about a decade, AMPK was the assumed prime mediator of metformin action • Metformin can activate AMPK by promoting AMP accumulation • However, reservations regarding the hypothesis of AMPK being the main driving force behind reduced hepatic gluconeogenesis have been accumulating over years, primarily owing to a lack of correlation between gluconeogenic gene expression and hepatic glucose output

5. Metformin and diabetes mellitus • The AMPK model was seriously challenged when metformin lowered glucose production in the liver of transgenic mice that lacked AMPK or its upstream activator LKB1 • The proposed role of metformin in glucagon signalling (increased AMP reduces cAMP levels) has supported the AMPK‑independent antihyperglycaemic action of metformin • Nevertheless, a number of metformin effects are still attributed to AMPK

6. Miller et al. suggested that metformin-induced changes in energy charge have contributory effects on gluconeogenesis, independent of cAMP and AMPK signalling The molecular targets of metformin include the mitochondrial complex I and other enzymes modulated by the altered energy charge, notably adenylate cyclase (inhibited by increased AMP levels), affecting glucagon signalling, and AMPK (stimulated by the increased AMP:ATP ratio) Metformin and diabetes mellitus

7. Metformin and cancer • In 2005, a report associated metformin use with a reduced incidence of cancer, putting the drug into the cancer research spotlight • Diabetes mellitus has been associated with a 1.2–2.0-fold increase in cancer incidence • A report in 2010 suggested that metformin reduces this risk by approximately 40% compared with any other antidiabetic treatment • However, a population-based analysis has failed to show an association between improved survival and metformin use in diabetic patients with breast cancer aged >65 years

8. Metformin and cancer • Mechanisms by which metformin attenuates tumourigenesis and has chemoprotective properties are not well-defined • An important limitation of many experimental studies is that metformin inhibits cell proliferation in vitro at supraphysiological concentrations, which are generally thought to be unachievable in patients • Moreover, many factors influence availability and response to metformin in tissue

9. Metformin and cancer

10. Future therapeutic directions • The AMP-binding P‑site on adenylate cyclase has been proposed as a new therapeutic target in insulin resistance and type 2 diabetes mellitus • Glucagon receptor is expressed in various tissues, and the cAMP–PKA pathway is involved in a plethora of signalling pathways, highlighting the need for a specific targeting strategy • Interaction of various pathways and drugs and their contribution to the pleiotropic effects attributed to metformin will probably remain a topic of debate in the future

11. Conclusions • 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 • Laboratory evidence of the antimitotic action of metformin is promising, although results from epidemiological studies remain controversial

12. Conclusions • The combination of tumour genetics, patient metabolic profile and the cellular microenvironment determine the antitumour effect of metformin treatment • 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