Steen Jakobsen

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

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Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease. / Sundelin, Elias Immanuel Ordell; Gormsen, Lars Christian; Heebøll, Sara; Vendelbo, Mikkel Holm; Jakobsen, Steen; Munk, Ole Lajord; Feddersen, Søren; Brøsen, Kim; Hamilton-Dutoit, Stephen Jacques; Pedersen, Steen Bønløkke; Grønbaek, Henning; Jessen, Niels.

In: British Journal of Clinical Pharmacology, Vol. 85, No. 8, 2019, p. 1761-1770.

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@article{9cb7da68efe84220845dfcfcb4f6eb7f,
title = "Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease",
abstract = "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.",
keywords = "metformin, non-alcoholic fatty liver disease, organic cation transporters, pharmacokinetics",
author = "Sundelin, {Elias Immanuel Ordell} and Gormsen, {Lars Christian} and Sara Heeb{\o}ll and Vendelbo, {Mikkel Holm} and Steen Jakobsen and Munk, {Ole Lajord} and S{\o}ren Feddersen and Kim Br{\o}sen and Hamilton-Dutoit, {Stephen Jacques} and Pedersen, {Steen B{\o}nl{\o}kke} and Henning Gr{\o}nbaek and Niels Jessen",
note = "{\circledC} 2019 The British Pharmacological Society.",
year = "2019",
doi = "10.1111/bcp.13962",
language = "English",
volume = "85",
pages = "1761--1770",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "8",

}

RIS

TY - JOUR

T1 - Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease

AU - Sundelin, Elias Immanuel Ordell

AU - Gormsen, Lars Christian

AU - Heebøll, Sara

AU - Vendelbo, Mikkel Holm

AU - Jakobsen, Steen

AU - Munk, Ole Lajord

AU - Feddersen, Søren

AU - Brøsen, Kim

AU - Hamilton-Dutoit, Stephen Jacques

AU - Pedersen, Steen Bønløkke

AU - Grønbaek, Henning

AU - Jessen, Niels

N1 - © 2019 The British Pharmacological Society.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - metformin

KW - non-alcoholic fatty liver disease

KW - organic cation transporters

KW - pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=85067448581&partnerID=8YFLogxK

U2 - 10.1111/bcp.13962

DO - 10.1111/bcp.13962

M3 - Journal article

VL - 85

SP - 1761

EP - 1770

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 8

ER -