Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats

Aytaç Gül; Hüseyin Özkan; Mehmet Güvenç; Tuğba Çalışır

doi:10.17944/interdiscip.1782720

Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats

Abstract

Objective: Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist widely used in type 2 diabetes mellitus and has well-documented metabolic and cardiovascular benefits. However, its acute hepatic and metabolic effects in healthy conditions remain poorly understood. This study aimed to investigate the dose-dependent acute effects of liraglutide on hepatic and metabolic biochemical parameters in rats. Methods: Twenty-eight female Wistar albino rats were randomly assigned to four groups: control (PBS), and low (50 μg/kg), medium (100 μg/kg), or high dose (300 μg/kg) liraglutide. After 12 hours of fasting, a single subcutaneous injection was administered, and blood samples were collected 6 hours later for biochemical analysis of hepatic and metabolic parameters. Group differences were assessed by one-way ANOVA with Tukey’s post hoc test, and correlation analyses were performed within each group. Results: Significant dose-dependent effects of liraglutide on hepatic enzymes and metabolic parameters were detected. Also, significant group effects were observed for alanine aminotransferase (ALT) (p = 0.034), aspartate aminotransferase (AST) (p = 0.026), glucose (p < 0.001), triglycerides (p = 0.021), and albumin (p = 0.020). ALT was elevated at low dose but not at higher doses. AST was reduced in medium- and high-dose groups. Glucose increased progressively across all treated groups, while triglycerides decreased, and albumin increased at high dose. Alkaline phosphatase (ALP), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), lactate dehydrogenase (LDH), and total protein showed similar levels (p > 0.05). Conclusion: Liraglutide acutely modulates selected hepatic and metabolic parameters in a dose-dependent manner. These results provide insight into short-term hepatic profile of liraglutide and inform its safety assessment under normal liver conditions.

Keywords

References

Drucker DJ, Nauck MA. The incretin system: glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-705. DOI: 10.1016/S0140-6736(06)69705-5.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med.2016;375(4):311-22. DOI:10.1056/NEJMoa1603827.
Davies MJ, Bergenstal R, Bode B, Kushner RF, Lewin A, Skjøth TV, et al. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA. 2015;314(7):687-99. DOI: 10.1001/jama.2015.9676.
Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, et al. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology. 2010;51(5):1584-92. DOI: 10.1002/hep.23569.
Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740-56. DOI: 10.1016/j.cmet.2018.03.001.
Svegliati-Baroni G, Saccomanno S, Rychlicki C, Agostinelli L, De Minicis S, Candelaresi C, et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011;31(9):1285-97. DOI: 10.1111/j.1478-3231.2011.02462.x.
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebocontrolled phase 2 study. Lancet. 2016;387(10019):679-90. DOI: 10.1016/S0140-6736(15)00803-X.
Metzner V, Herzog G, Heckel T, Bischler T, Hasinger J, Otto C, et al. Liraglutide + PYY(3-36) Combination Therapy Mimics Effects of Roux-en-Y Bypass on Early NAFLD Whilst Lacking-Behind in Metabolic Improvements. J Clin Med. 2022;11(3). DOI: 10.3390/jcm11030753.

Elsiad EA, Abd El Aal HA, Salem HA, El-Yamany MF, Rabie MA. Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 and Autophagy Pathways in Wistar Rats. Toxics. 2025;13(7). DOI: 10.3390/toxics13070594.
Atef MM, Abou Hashish NA, Hafez YM, Selim AF, Ibrahim HA, Eltabaa EF, et al. The potential protective effect of liraglutide on valproic acid induced liver injury in rats: Targeting HMGB1/RAGE axis and RIPK3/MLKL mediated necroptosis. Cell Biochem Funct. 2023;41(8):1209-19. DOI: 10.1002/cbf.3855.
Fan B, Meng L, Zheng X, Bai L, Du Y, Ding H, et al. Liraglutide inhibits the proliferation of rat hepatic stellate cells under high glucose conditions by suppressing the ERK signaling pathway. Sci Rep. 2025;15(1):13360. DOI: 10.1038/s41598-025-97872-w.
Bołdys A, Borówka M, Bułdak Ł, Okopień B. Impact of Short-Term Liraglutide Therapy on Non-Invasive Markers of Liver Fibrosis in Patients with MASLD. Metabolites. 2025;15(8). DOI: 10.3390/metabo15080510.
Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021;384(12):1113-24. DOI: 10.1056/NEJMoa2028395.
Hsu C-C, Cheng J-T, Hsu PH, Li Y, Cheng K-C. Bolus Injection of Liraglutide Raises Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1 Receptor in the Brain. Pharmaceuticals. 2022;15(7):904. DOI: 10.3390/ph15070904.
Model JFA, Lima MV, Ohlweiler R, Lopes Vogt É, Rocha DS, Souza SKd, et al. Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats. Molecular and Cellular Endocrinology. 2021;524:111158. DOI: 10.1016/j.mce.2021.111158.
Khoo J, Hsiang J, Taneja R, Law NM, Ang TL. Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial. Diabetes Obes Metab. 2017;19(12):1814-7. DOI: 10.1111/dom.13007.
Nagakubo D, Shirai M, Nakamura Y, Kaji N, Arisato C, Watanabe S, et al. Prophylactic effects of the glucagonlike Peptide-1 analog liraglutide on hyperglycemia in a rat model of type 2 diabetes mellitus associated with chronic pancreatitis and obesity. Comp Med. 2014;64(2):121-7.
Liberini CG, Lhamo R, Ghidewon M, Ling T, Juntereal N, Chen J, et al. Liraglutide pharmacotherapy reduces body weight and improves glycaemic control in juvenile obese/hyperglycaemic male and female rats. Diabetes Obes Metab. 2019;21(4):866-75. DOI:10.1111/dom.13591.
He Y, Ao N, Yang J, Wang X, Jin S, Du J. The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy. Ann Hepatol. 2020;19(1):44-52. DOI: 10.1016/j.aohep.2019.06.023.
Hayes MR, Kanoski SE, Alhadeff AL, Grill HJ. Comparative effects of the long-acting GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats. Obesity (Silver Spring). 2011;19(7):1342-9. DOI: 10.1038/oby.2011.50.
Zhang Q, Xiao X, Zheng J, Li M, Yu M, Ping F, et al. Liraglutide protects cardiac function in diabetic rats through the PPARα pathway. Biosci Rep. 2018;38(2). DOI: 10.1042/BSR20180059.
Healthineers S. Atellica® Solution Training Guide: Operator Manual and Instructions for Use. Version 1.0 ed. Erlangen, Germany: Siemens Healthcare Diagnostics Inc.; 2020 9 October 2025.
Crabtree T, Rowles S, Tarpey S, Kennedy A, Chalmers J, Nayar R, et al. Reductions in alanine aminotransferase levels with liraglutide treatment are greatest in those with raised baseline levels and are independent of weight loss: real-world outcome data from the ABCD Nationwide Liraglutide Audit. British Journal of Diabetes. 2019;19:118-23. DOI:10.15277/bjd.2019.227.
Armstrong MJ, Houlihan DD, Rowe IA, Clausen WH, Elbrønd B, Gough SC, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data metaanalysis of the LEAD program. Aliment Pharmacol Ther. 2013;37(2):234-42. DOI: 10.1111/apt.12149.
Arredouani A. GLP-1 receptor agonists, are we witnessing the emergence of a paradigm shift for neuro-cardio-metabolic disorders? Pharmacol Ther. 2025;269:108824. DOI:10.1016/j.pharmthera.2025.108824.
Tran KL, Park YI, Pandya S, Muliyil NJ, Jensen BD, Huynh K, et al. Overview of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Patients with Type 2 Diabetes. Am Health Drug Benefits. 2017;10(4):178-88.
Irie S, Matsumura Y, Zdravkovic M, Jacobsen LV, Kageyama S. Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP- 1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study. Int J Clin Pharmacol Ther. 2008;46(6):273-9. DOI: 10.5414/cpp46273.
Flint A, Nazzal K, Jagielski P, Hindsberger C, Zdravkovic M. Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide. Br J Clin Pharmacol. 2010;70(6):807-14. DOI: 10.1111/j.1365-2125.2010.03762.x.
Zhou R, Lin C, Cheng Y, Zhuo X, Li Q, Xu W, et al. Liraglutide Alleviates Hepatic Steatosis and Liver Injury in T2MD Rats via a GLP-1R Dependent AMPK Pathway. Front Pharmacol. 2020;11:600175. DOI: 10.3389/fphar.2020.600175.
Sharma S, Mells JE, Fu PP, Saxena NK, Anania FA. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS One. 2011;6(9):e25269. DOI: 10.1371/journal.pone.0025269.
Tomas E, Stanojevic V, Habener JF. GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept. 2011;167(2-3):177-84. DOI: 10.1016/j.regpep.2011.01.003.
Bajic Z, Sobot T, Smitran A, Uletilovic S, Mandić-Kovačević N, Cvjetkovic T, et al. Liraglutide Treatment Restores Cardiac Function After Isoprenaline-Induced Myocardial Injury and Prevents Heart Failure in Rats. Life. 2025;15(3):443. DOI: 10.3390/life15030443.
Pham VA, Tran HT, Mai TP, Nguyen LH, Nguyen VH, Nguyen TH, et al. Myocardial infarction model induced by isoproterenol in rats and potential cardiovascular protective effect of a nattokinase-containing hard capsule. Phytomedicine Plus. 2023;3(3):100472. DOI:10.1016/j.phyplu.2023.100472.
Meng J, Ma X, Wang N, Jia M, Bi L, Wang Y, et al. Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through ß-Catenin. Stem Cell Reports. 2016;6(4):579-91. DOI: 10.1016/j.stemcr.2016.02.002.
Milani L, Galindo CM, Turin de Oliveira NM, Corso CR, Adami ER, Stipp MC, et al. The GLP-1 analog liraglutide attenuates acute liver injury in mice. Ann Hepatol. 2019;18(6):918-28. DOI: 10.1016/j.aohep.2019.04.011.
Cuthbertson DJ, Irwin A, Gardner CJ, Daousi C, Purewal T, Furlong N, et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS One. 2012;7(12):e50117. DOI: 10.1371/journal.pone.0050117.
Rezaei S, Tabrizi R, Nowrouzi-Sohrabi P, Jalali M, Atkin SL, Al-Rasadi K, et al. GLP-1 Receptor Agonist Effects on Lipid and Liver Profiles in Patients with Nonalcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol. 2021;2021:8936865. DOI: 10.1155/2021/8936865.
Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225-45. DOI: 10.1038/s41580-019-0190-7.
Zobel EH, Ripa RS, von Scholten BJ, Rotbain Curovic V, Kjaer A, Hansen TW, et al. Effect of liraglutide on expression of inflammatory genes in type 2 diabetes. Sci Rep. 2021;11(1):18522. DOI: 10.1038/s41598-021-97967-0.
Carretta TR, Ree MJ. Correction for range restriction: Lessons from 20 research scenarios. Mil Psychol. 2022;34(5):551-69. DOI: 10.1080/08995605.2021.2022067.
Jones AK, Salem AH, Freise KJ. Power Determination During Drug Development: Is Optimizing the Sample Size Based on Exposure-Response Analyses Underutilized? CPT Pharmacometrics Syst Pharmacol. 2019;8(3):138-45. DOI: 10.1002/psp4.12380.
Mader JK, Jensen L, Ingwersen SH, Christiansen E, Heller S, Pieber TR. Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus. Clin Pharmacokinet. 2016;55(11):1457-63. DOI: 10.1007/s40262-016-0413-4.
Mantovani A, Targher G. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic steatohepatitis: new insights from subcutaneous semaglutide. Hepatobiliary Surg Nutr. 2021;10(4):518-21. DOI: 10.21037/hbsn-2021-13.
Abdelsameea AA, Abbas NA, Abdel Raouf SM. Liraglutide attenuates partial warm ischemia-reperfusion injury in rat livers. Naunyn Schmiedebergs Arch Pharmacol. 2017;390(3):311-9. DOI: 10.1007/s00210-016-1330-7.
Fontana J, Kučera O, Mezera V, Anděl M, Červinková Z. Glucagon-like peptide-1 analogues exenatide and liraglutide exert inhibitory effect on the early phase of liver regeneration after partial hepatectomy in rats. Physiol Res. 2017;66(5):833-44. DOI: 10.33549/physiolres.933464.
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. New England Journal of Medicine. 2015;373(1):11-22. DOI: 10.1056/NEJMoa1411892.
Soldin OP, Mattison DR. Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2009;48(3):143-57. DOI:10.2165/00003088-200948030-00001.
Matz-Soja M, Berg T, Kietzmann T. Sex-related variations in liver homeostasis and disease: From zonation dynamics to clinical implications. Journal of Hepatology. 2025. DOI: 10.1016/j.jhep.2025.08.007.
Park J, Kim J-W, Lim S. Impact of Liraglutide 3.0 mg on Metabolic Dysfunction-Associated Steatotic Liver Disease in Individuals with Obesity: A Real-World Study. Annals of Nutrition and Metabolism. 2025. DOI: 10.1159/000547347.
Somm E, Montandon SA, Loizides-Mangold U, Gaïa N, Lazarevic V, De Vito C, et al. The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Translational Research. 2021;227:75-88. DOI: 10.1016/j.trsl.2020.07.008.

Details

Primary Language

English

Subjects

Internal Diseases

Journal Section

Research Article

Authors

Aytaç Gül ^*
0009-0003-6353-9505
Türkiye

Hüseyin Özkan
0000-0001-5753-8985
Türkiye

Mehmet Güvenç
0000-0002-9716-0697
Türkiye

Tuğba Çalışır
0009-0004-3230-599X
Türkiye

Publication Date

December 16, 2025

Submission Date

September 12, 2025

Acceptance Date

November 3, 2025

Published in Issue

Year 2025 Volume: 16 Number: 56

DOI

https://doi.org/10.17944/interdiscip.1782720

IZ

https://izlik.org/JA65CB78DK

Cite

RIS / Bibtex

APA

Gül, A., Özkan, H., Güvenç, M., & Çalışır, T. (2025). Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats. Interdisciplinary Medical Journal, 16(56), 193-204. https://doi.org/10.17944/interdiscip.1782720

AMA

1.Gül A, Özkan H, Güvenç M, Çalışır T. Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats. Interdiscip Med J. 2025;16(56):193-204. doi:10.17944/interdiscip.1782720

Chicago

Gül, Aytaç, Hüseyin Özkan, Mehmet Güvenç, and Tuğba Çalışır. 2025. “Dose-Dependent Acute Effects of Liraglutide on Liver Function and Metabolic Parameters in Healthy Rats”. Interdisciplinary Medical Journal 16 (56): 193-204. https://doi.org/10.17944/interdiscip.1782720.

EndNote

Gül A, Özkan H, Güvenç M, Çalışır T (December 1, 2025) Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats. Interdisciplinary Medical Journal 16 56 193–204.

IEEE

[1]A. Gül, H. Özkan, M. Güvenç, and T. Çalışır, “Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats”, Interdiscip Med J, vol. 16, no. 56, pp. 193–204, Dec. 2025, doi: 10.17944/interdiscip.1782720.

ISNAD

Gül, Aytaç - Özkan, Hüseyin - Güvenç, Mehmet - Çalışır, Tuğba. “Dose-Dependent Acute Effects of Liraglutide on Liver Function and Metabolic Parameters in Healthy Rats”. Interdisciplinary Medical Journal 16/56 (December 1, 2025): 193-204. https://doi.org/10.17944/interdiscip.1782720.

JAMA

1.Gül A, Özkan H, Güvenç M, Çalışır T. Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats. Interdiscip Med J. 2025;16:193–204.

MLA

Gül, Aytaç, et al. “Dose-Dependent Acute Effects of Liraglutide on Liver Function and Metabolic Parameters in Healthy Rats”. Interdisciplinary Medical Journal, vol. 16, no. 56, Dec. 2025, pp. 193-04, doi:10.17944/interdiscip.1782720.

Vancouver

1.Aytaç Gül, Hüseyin Özkan, Mehmet Güvenç, Tuğba Çalışır. Dose-dependent acute effects of liraglutide on liver function and metabolic parameters in healthy rats. Interdiscip Med J. 2025 Dec. 1;16(56):193-204. doi:10.17944/interdiscip.1782720