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Physiology and Biochemistry

Four weeks treatment with the GLP-1 receptor analogue liraglutide lowers liver fat and concomitantly circulating glucagon in individuals with overweight

Abstract

We investigated the effect of pharmacologically induced weight loss on markers of glucagon resistance in individuals with overweight during treatment with the glucagon-like peptide-1 receptor agonist liraglutide. We performed an open-label study in 14 men with overweight (age 38 ± 11 years, BMI 32 ± 4 kg/m2) without simultaneously diabetes. Subjects were treated with liraglutide, initiated and titrated with 0.6 mg/day/week to reach the final dose of 3.0 mg/day. Subjects were examined at baseline, during titration (Week 4), after 2 weeks of steady state (Week 6) of final dosing of liraglutide and 3 weeks after discontinuation of liraglutide (follow-up). Study participants lost 3.3 ± 1.9 kg (3%) total body weight during the first 4 weeks of treatment with liraglutide. Simultaneously, liver fat content decreased from 12.4 ± 11.6% to 10.2 ± 11.1%, p = 0.025, whereas fat content in the spleen and subcutaneous tissue was unaltered. Markers of glucagon resistance, including plasma glucagon and the glucagon-alanine-index, also decreased significantly during treatment, but total and individual plasma amino acid concentrations did not. Insulin resistance (HOMA-IR) was unchanged during treatment, whereas insulin clearance increased. Treatment with the GLP-1 receptor analogue liraglutide decreased liver fat content, and simultaneously attenuated glucagon concentrations and the glucagon-alanine index in individuals with overweight without diabetes.

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Fig. 1: Effect of liraglutide on liver fat, spleen fat and the glucagon-alanine index.

Data availability

The data generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors acknowledge Christine Rasmussen and Fie Johanne Andreasen (Department of Clinical Biochemistry, Rigshospitalet) for technical assistance. Furthermore, we thank Annette Witt (Department of Endocrinology, Hvidovre) for logistics and assistance with titration of study medicine and finally we thank Birgitte Vilsbøll/Lotte Lund from Good Clinical Practice (GCP-Unit, University of Copenhagen) for discussions and inputs on the protocol. Finally, we thank Prof. Liselotte Højgaard (Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet) and Dr. Linda Hilsted (Department of Clinical Biochemistry, Rigshospitalet) for their support.

Funding

The study was supported by unrestricted grants from the Novo Nordisk Foundation and Rigshospitalet. NJWA is supported by NNF Excellence Emerging Investigator Grant – Endocrinology and Metabolism (Application No. NNF19OC0055001), EFSD Future Leader Award (NNF21SA0072746) and DFF Sapere Aude (1052-00003B). Novo Nordisk Foundation Center for Protein Research is supported financially by the Novo Nordisk Foundation (Grant agreement NNF14CC0001). The funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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Contributions

MSS, HHJ and NJWA conception of research; MSS, HHJ and NJWA design of research; MSS, CM, and SM recruited study participants; MSS, and CM conducted the clinical visits and monitored treatment; HHJ, MLH, AEH, SHK, TLK, AL, AK, and JL designed and performed MR imaging; NJWA performed and analyzed biochemical analyses; MSS, and NJWA performed statistical analyses and interpreted results of experiments; MSS prepared figures; MSS, and NJWA drafted manuscript and HHJ, CM, KNB-M, MLH, AEH, CFD, SHK, TLK, AL, AK, SM, JL and JJH edited and revised manuscript; All authors approved final version of manuscript.

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Correspondence to Nicolai J. Wewer Albrechtsen.

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Competing interests

NJWA has received speaker fees from MSD and Mercodia and research support from Novo Nordisk A/S, Janssen Pharmaceuticals and Mercodia.CFD has received consultancy/lecture fees from Boehringer Ingelheim, Lilly, Merck/MSD, Novo Nordisk and Novartis. SM has received research grants from Novo Nordisk and Boehringer Ingelheim; lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi Aventis; and is a member of advisory boards of AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi Aventis. JJH has served on advisory panels for GlaxoSmithKline, Novo Nordisk, Zealand Pharma, AstraZeneca, MSD, Intarcia and Hanmi and acts as a consultant for Novo Nordisk, and has received research support from Merck, Sharp & Dohme. All other authors have nothing to disclosure.

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Svane, M.S., Johannesen, H.H., Hansen, A.E. et al. Four weeks treatment with the GLP-1 receptor analogue liraglutide lowers liver fat and concomitantly circulating glucagon in individuals with overweight. Int J Obes (2022). https://doi.org/10.1038/s41366-022-01207-y

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