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Dissecting the actions of widely used diabetes drugs

Nature Medicine volume 19, pages 272–273 (2013)Cite this article

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Roger H Unger & Eric D Berglund

The mechanism of action of biguanides has remained elusive, despite their long-standing use to treat type 2 diabetes. Miller et al.1 now may have finally resolved this issue with their work confirming earlier reports that biguanides, by preventing glucagon-stimulated rises in hepatic cyclic AMP (cAMP) concentrations, reduce the inappropriately high hepatic glucose production that is caused by glucagon-stimulated gluconeogenesis in hepatocytes. Increased cAMP concentrations activate protein kinase A (PKA), leading to phosphorylation of downstream target enzymes that mediate the glucagon-driven glucose production2 that characterizes poorly controlled diabetes. Miller et al.1 showed that biguanides block glucagon-stimulated PKA activation but they cannot block PKA activation caused by a cAMP analog, thus localizing the site of the inhibitory action to a glucagon-responsive site on the cAMP-producing enzyme adenylyl cyclase.

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Competing interests

A.D.C. is a consultant for Merck, Eli Lilly and Novo Nordisk. He also receives research support from Novo Nordisk and Eli Lilly. The other authors declare no conflict of interest.

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Dissecting the actions of widely used diabetes drugs. Nat Med 19, 272–273 (2013). https://doi.org/10.1038/nm.3123

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