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*

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Resumé

Aims: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought 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 whether 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 a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. Methods: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). Results: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (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 imply that metformin action in liver in patients with NAFLD may be preserved.

OriginalsprogEngelsk
TidsskriftBritish Journal of Clinical Pharmacology
Vol/bind85
Udgave nummer8
Sider (fra-til)1761-1770
ISSN0306-5251
DOI
StatusUdgivet - aug. 2019

Fingeraftryk

Liver
Cations
Type 2 Diabetes Mellitus
Insulin Resistance
Western World
Fatty Liver
Liver Diseases
Real-Time Polymerase Chain Reaction

Bibliografisk note

This article is protected by copyright. All rights reserved.

Citer dette

Sundelin, E. I. O., Gormsen, L. C., Heebøll, S., Vendelbo, M. H., Jakobsen, S., Munk, O. L., ... Jessen, N. (2019). Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease. British Journal of Clinical Pharmacology, 85(8), 1761-1770. https://doi.org/10.1111/bcp.13962
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. / Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease. I: British Journal of Clinical Pharmacology. 2019 ; Bind 85, Nr. 8. s. 1761-1770.
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title = "Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease",
abstract = "Aims: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought 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 whether 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 a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. Methods: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). Results: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (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 imply 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 = "This article is protected by copyright. All rights reserved.",
year = "2019",
month = "8",
doi = "10.1111/bcp.13962",
language = "English",
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Sundelin, EIO, Gormsen, LC, Heebøll, S, Vendelbo, MH, Jakobsen, S, Munk, OL, Feddersen, S, Brøsen, K, Hamilton-Dutoit, SJ, Pedersen, SB, Grønbaek, H & Jessen, N 2019, 'Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease', British Journal of Clinical Pharmacology, bind 85, nr. 8, s. 1761-1770. https://doi.org/10.1111/bcp.13962

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.

I: British Journal of Clinical Pharmacology, Bind 85, Nr. 8, 08.2019, s. 1761-1770.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 - This article is protected by copyright. All rights reserved.

PY - 2019/8

Y1 - 2019/8

N2 - Aims: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought 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 whether 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 a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. Methods: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). Results: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (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 imply that metformin action in liver in patients with NAFLD may be preserved.

AB - Aims: Metformin is first-line treatment of type 2 diabetes mellitus and reduces cardiovascular events in patients with insulin resistance and type 2 diabetes. Target tissue for metformin action is thought 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 whether 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 a secondary aim, we wished to correlate hepatic metformin distribution with OCT gene transcription determined in diagnostic liver biopsies. Methods: Eighteen patients with biopsy-proven NAFLD were investigated using 11C-metformin PET/CT technique. Gene transcripts of OCTs were determined by real-time polymerase chain reaction (PCR). Results: We observed similar hepatic volume of distribution of metformin between patients with simple steatosis and non-alcoholic steatohepatitis (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 imply 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

U2 - 10.1111/bcp.13962

DO - 10.1111/bcp.13962

M3 - Journal article

C2 - 30973968

VL - 85

SP - 1761

EP - 1770

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 8

ER -

Sundelin EIO, Gormsen LC, Heebøll S, Vendelbo MH, Jakobsen S, Munk OL et al. Hepatic exposure of metformin in patients with non-alcoholic fatty liver disease. British Journal of Clinical Pharmacology. 2019 aug;85(8):1761-1770. https://doi.org/10.1111/bcp.13962