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

  • Hunter RW Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
  • Hughey CC Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA.
  • Lantier L Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA.
  • Sundelin EI Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark.
  • Peggie M MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK.
  • Zeqiraj E Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Sicheri F Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • Jessen N Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark.
  • Wasserman DH Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA.
  • Sakamoto K Nestlé Institute of Health Sciences SA, Lausanne, Switzerland. kei.sakamoto@rd.nestle.com.
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  • 2018-08-29
Published in:
  • Nature medicine. - 2018
Adenosine Monophosphate
Aminoimidazole Carboxamide
Animals
Base Sequence
Chickens
Disease Models, Animal
Fructose-Bisphosphatase
Glucose
Glucose Intolerance
Homeostasis
Humans
Hypoglycemia
Liver
Metformin
Mice, Inbred C57BL
Mutation
Obesity
Prodrugs
Ribonucleotides
English 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.
Language
  • English
Open access status
green
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https://sonar.ch/global/documents/185802
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