Elias Immanuel Ordell Sundelin1, Lars Christian Gormsen2, Sara Heebøll3, Mikkel Holm Vendelbo2,4, Steen Jakobsen2, Ole Lajord Munk2, Søren Feddersen5,6, Kim Brøsen5,7, Stephen Jacques Hamilton-Dutoit8, Steen Bønløkke Pedersen9,10, Henning Grønbaek3, Niels Jessen1,4,10,11. 1. Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Aarhus University Hospital, Denmark. 2. Department of Nuclear Medicine & PET Center, Aarhus University Hospital, Denmark. 3. Department of Gastroenterology & Hepatology, Aarhus University Hospital, Denmark. 4. Department of Biomedicine, Aarhus University, Denmark. 5. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Denmark. 6. Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 7. Department of Public Health, Clinical Pharmacology, University of Southern Denmark, Denmark. 8. Department of Pathology, Aarhus University Hospital, Denmark. 9. Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark. 10. Steno Diabetes Center Aarhus, Aarhus University Hospital, Denmark. 11. Department of Clinical Pharmacology, Aarhus University Hospital, Denmark.
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.
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.
Authors: Naga Chalasani; Zobair Younossi; Joel E Lavine; Anna Mae Diehl; Elizabeth M Brunt; Kenneth Cusi; Michael Charlton; Arun J Sanyal Journal: Hepatology Date: 2012-06 Impact factor: 17.425
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Authors: Lars C Gormsen; Elias Immanuel Sundelin; Jonas Brorson Jensen; Mikkel Holm Vendelbo; Steen Jakobsen; Ole Lajord Munk; Mette Marie Hougaard Christensen; Kim Brøsen; Jørgen Frøkiær; Niels Jessen Journal: J Nucl Med Date: 2016-07-28 Impact factor: 10.057
Authors: José María Moreno-Navarrete; Francisco J Ortega; José-Ignacio Rodríguez-Hermosa; Mònica Sabater; Gerard Pardo; Wifredo Ricart; José Manuel Fernández-Real Journal: Diabetes Date: 2010-10-18 Impact factor: 9.461
Authors: 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 Journal: Br J Clin Pharmacol Date: 2019-06-18 Impact factor: 4.335