TY - JOUR

T1 - Metformin does not Affect Postabsorptive Hepatic Free Fatty Acid Uptake, Oxidation or Resecretion in Humans

T2 - A 3-months Placebo Controlled Clinical Trial in Patients with Type 2 Diabetes and Healthy Controls

AU - Gormsen, Lars C

AU - Søndergaard, Esben

AU - Christensen, Nana L

AU - Jakobsen, Steen

AU - Nielsen, Erik H T

AU - Munk, Ole L

AU - Tolbod, Lars P

AU - Jessen, Niels

AU - Nielsen, Søren

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/6

Y1 - 2018/6

N2 - AIMS: Metformin is due to its well-documented glucose lowering effect the most commonly used drug in patients with T2D. However, metformin have also in pre-clinical studies been shown to improve lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from reesterification and resecretion as triglycerides.MATERIALS AND METHODS: To explore whether these pre-clinical findings can be translated to a human setting, we performed a 3-month randomized, placebo controlled, parallel-group clinical trial in patients with T2D (24 patients) and healthy controls (12 subjects). T2D subjects received either placebo (PLA) or 1000 mg metformin bid. (MET) whereas healthy subjects were all treated with metformin (CONT). Hepatic fatty acid metabolism was measured by [11C]palmitate PET, hepatic triglyceride secretion and peripheral oxidation by ex-vivo labelled [1-14C]VLDL-TG and VLDL-particle size by TG/ApoB ratio. Body composition was assessed by DXA and whole body lipid oxidation by indirect calorimetry.RESULTS: Metformin treatment for three months produced the anticipated decrease in FPG in the MET group [FPG (mM): 7.9±1.8 (study day 1) vs. 6.4±1.1 (study day 2)] whereas patients in the PLA group and healthy controls had similar FPG levels before and after the trial (mixed model group vs. time interaction, p=0.003). However, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation.CONCLUSION: The observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis.

AB - AIMS: Metformin is due to its well-documented glucose lowering effect the most commonly used drug in patients with T2D. However, metformin have also in pre-clinical studies been shown to improve lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from reesterification and resecretion as triglycerides.MATERIALS AND METHODS: To explore whether these pre-clinical findings can be translated to a human setting, we performed a 3-month randomized, placebo controlled, parallel-group clinical trial in patients with T2D (24 patients) and healthy controls (12 subjects). T2D subjects received either placebo (PLA) or 1000 mg metformin bid. (MET) whereas healthy subjects were all treated with metformin (CONT). Hepatic fatty acid metabolism was measured by [11C]palmitate PET, hepatic triglyceride secretion and peripheral oxidation by ex-vivo labelled [1-14C]VLDL-TG and VLDL-particle size by TG/ApoB ratio. Body composition was assessed by DXA and whole body lipid oxidation by indirect calorimetry.RESULTS: Metformin treatment for three months produced the anticipated decrease in FPG in the MET group [FPG (mM): 7.9±1.8 (study day 1) vs. 6.4±1.1 (study day 2)] whereas patients in the PLA group and healthy controls had similar FPG levels before and after the trial (mixed model group vs. time interaction, p=0.003). However, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation.CONCLUSION: The observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis.

U2 - 10.1111/dom.13244

DO - 10.1111/dom.13244

M3 - Journal article

C2 - 29405635

VL - 20

SP - 1435

EP - 1444

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 6

ER -