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Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase

2018; Nature Portfolio; Volume: 24; Issue: 9 Linguagem: Inglês

10.1038/s41591-018-0159-7

1546-170X

Roger W. Hunter, Curtis C. Hughey, Louise Lantier, Elias Sundelin, Mark Peggie, Elton Zeqiraj, Frank Sicheri, Niels Jessen, David H. Wasserman, Kei Sakamoto,

Glycogen Storage Diseases and Myoclonus

Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P