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Publication
Metformin reduces liver glucose production by inhibition of
fructose-1-6-bisphosphatase.
Authors Hunter RW, Hughey CC, Lantier L, Sundelin EI, Peggie M, Zeqiraj E, Sicheri F,
Jessen N, Wasserman DH, Sakamoto K
Submitted By Submitted Externally on 11/5/2018
Status Published
Journal Nature medicine
Year 2018
Date Published 9/1/2018
Volume : Pages 24 : 1395 - 1406
PubMed Reference 30150719
Abstract 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-P2), and
knock-in (KI) of this mutant in mice significantly reduces their response to
metformin treatment. We observe this during a metformin tolerance test and in a
metformin-euglycemic clamp that we have developed. The antihyperglycemic effect
of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly
blunted compared to wild-type controls. Collectively, we show a new mechanism of
action for metformin and provide further evidence that molecular targeting of
FBP1 can have antihyperglycemic effects.




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