Editors' ChoiceType 2 Diabetes

Revisiting Metformin

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Science Translational Medicine  13 Feb 2013:
Vol. 5, Issue 172, pp. 172ec31
DOI: 10.1126/scitranslmed.3005833

Metformin, an oral antidiabetic drug in the biguanide class, is the preferred medicine of choice for the treatment of type 2 diabetes (T2D) and has become the most widely prescribed antidiabetic drug in the world. Yet, the molecular mechanisms of metformin action are still unclear. Now, Miller et al. have discovered that metformin inhibits glucagon activity, thus leading to a reduction in blood glucose levels.

Glucagon is a peptide hormone that raises blood glucose levels by promoting gluconeogenesis and glycogenolysis in the liver. It was previously thought that metformin functioned through activation of adenosine 5´-monophosphate (AMP)–activated protein kinase (AMPK). But, because biguanides, including metformin, work through inhibition of liver glucose production, the authors hypothesized that metformin might suppress the glucagon signaling pathways rather than AMPK pathways. Indeed, treating mouse liver cells with biguanides prevented glucagon-induced activation of adenylyl cyclase, leading to reduction of cyclic AMP (cAMP) levels and suppression of protein kinase A (PKA) activity. Because biguanide treatment did not reduce glucose output in hepatocytes in which PKA is inactivated, the cAMP-PKA pathway seems to be crucial for biguanide-mediated glucagon signal inhibition. In AMPK-deficient conditions, biguanides still regulated glucagon metabolism, suggesting that metformin acts in an AMPK-independent manner. Importantly, oral treatment of mice with metformin stopped glucagon-dependent increase in cAMP levels and PKA activation and thus suppressed hepatic glucose production. These data indicate that biguanides actually block the cAMP-PKA pathway in vivo. This study by Miller and colleagues sheds light on metformin’s mechanism of action. Further analysis of this pathway may facilitate the design of more effective metformin-like therapeutics for the treatment of insulin resistance and T2D.

R. A. Miller et al., Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature, published online 6 January 2013 (10.1038/nature11808). [PubMed]

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