Liraglutide ameliorates diabetic-induced testicular dysfunction in male rats: role of GLP-1/Kiss1/GnRH and TGF-β/Smad signaling pathways

Maha Abdelhamid Fathy; Amira Ebrahim Alsemeh; Marwa A Habib; Hanim M Abdel-Nour; Doaa M Hendawy; Asmaa Monir Eltaweel; Adel Abdelkhalek; Mona M Ahmed; Maha K Desouky; Jinlian Hua; Liana Mihaela Fericean; Ioan Banatean-Dunea; Ahmed Hamed Arisha; Tarek Khamis

doi:10.3389/fphar.2023.1224985

Liraglutide ameliorates diabetic-induced testicular dysfunction in male rats: role of GLP-1/Kiss1/GnRH and TGF-β/Smad signaling pathways

Front Pharmacol. 2023 Jul 11:14:1224985. doi: 10.3389/fphar.2023.1224985. eCollection 2023.

Authors

Maha Abdelhamid Fathy¹, Amira Ebrahim Alsemeh², Marwa A Habib¹, Hanim M Abdel-Nour³, Doaa M Hendawy³, Asmaa Monir Eltaweel^{4

2}, Adel Abdelkhalek⁵, Mona M Ahmed⁶, Maha K Desouky⁷, Jinlian Hua⁸, Liana Mihaela Fericean⁹, Ioan Banatean-Dunea⁹, Ahmed Hamed Arisha^{10

11}, Tarek Khamis¹²

Affiliations

¹ Medical Physiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
² Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
³ Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
⁴ Basic Medical Science Department of Anatomy and Embryology, College of Medicine-King Saud Abdulaziz, University for Health Sciences-Kingdom of Saudi Arabia, Jeddah, Saudi Arabia.
⁵ Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt.
⁶ Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
⁷ Department of Anatomy, Faculty of Medicine, Minia University, Minia, Egypt.
⁸ College of Veterinary Medicine/Shaanxi Centre of Stem Cells Engineering and Technology, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China.
⁹ Department of Biology, Faculty of Agriculture, University of Life Sciences, King Mihai I" from Timisoara [ULST], Timisoara, Romania.
¹⁰ Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt.
¹¹ Department of Physiology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.
¹² Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt.

Abstract

Introduction: Glucagon-like peptide -1 (GLP-1) is released by intestinal cells to stimulate glucose-dependent insulin release from the pancreas. GLP-1 has been linked to ameliorating obesity and/or diabetic complications as well as controlling reproductive function. Liraglutide is a GLP-1 receptor agonist (GLP-1RA) with 97% homology with GLP-1. The main objective of this study was to investigate the ameliorative role of liraglutide in diabetic-induced reproductive dysfunction in male rats. Methods: Rats were randomly allocated into 3 groups; a control group, a diabetic group, and a liraglutide-treated diabetic group. Results: In the diabetic group, a significant increase in BMI, FBG, HbA1c, HOMA-IR, TC, TAG, LDL, IL6, TNFα, and MDA, as well as decreased serum insulin, HDL, GSH, total testosterone, LH, and FSH, were shown compared to the control group. Furthermore, A significant downregulation in relative hypothalamic gene expression of GLP-1R, PPAR-α, PGC-1α, kiss, kiss1R, leptin, leptin R, GnRH GLP-1R, testicular PGC-1α, PPARα, kiss1, kiss1R, STAR, CYP17A1, HSD17B3, CYP19A, CYP11A1, and Smad7, as well as upregulation in hypothalamic GnIH and testicular TGF- β and Smad2 expression, were noticed compared to the control group. Liraglutide treatment significantly improved such functional and structural reproductive disturbance in diabetic rats. Conclusion: GLP-1RAs ameliorated the deleterious effects of diabetes on reproductive function by targeting GLP-1/leptin/kiss1/GnRH, steroidogenesis, and TGF- β/Smad pathways.

Keywords: GLP-1; HPG axis; TGF-β 1; antioxidant enzymes; kisspeptin; liraglutide; steroidogenesis.

Grants and funding

This research received no external funding, and the APC was funded by the project 6PFE of the University of Life Sciences “King Mihai I” from Timisoara and the Research Institute for Biosecurity and Bioengineering from Timisoara, Romania.