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Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease

Elias Immanuel Ordell Sundelin, Lars Christian Gormsen, Sara Heebøll, Mikkel Holm Vendelbo, Steen Jakobsen, Ole Lajord Munk, Søren Feddersen, Kim Brøsen, Stephen Jacques Hamilton-Dutoit, Steen Bønløkke Pedersen, Henning Grønbaek, Niels Jessen
British Journal of Clinical Pharmacology 2019 April 11

AIM: Metformin is first line treatment of type 2 diabetes mellitus and reduce cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is suggested to be the liver, where metformin distribution depends on facilitated transport by polyspecific transmembrane organic cation transporters (OCTs). Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with strong associations to insulin resistance and the metabolic syndrome but if NAFLD affects metformin biodistribution to the liver is not known. In this study, the primary aim was to investigate in vivo hepatic uptake of metformin dynamically in humans with variable degrees of liver affection. As secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies.

METHODS: 18 patients with biopsy-proven NAFLD were investigated using 11C- metformin PET/CT technique. Gene transcripts of OCTs were determined by real time PCR.

RESULTS: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and NASH (Vd 2.38 ± 0.56 vs 2.10 ± 0.39, p=0.3). There was no association between hepatic exposure to metformin and the degree of inflammation or fibrosis, and no clear correlation between metformin distribution and OCT gene transcription.

CONCLUSION: Metformin is distributed to the liver in patients with NAFLD and the distribution is not impaired by inflammation or fibrosis. The findings implicate that metformin action in liver in patients with NAFLD may be preserved.


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