The impact of liraglutide treatment on erectile function of the diabetic rats

Year 2023, Volume: 9 Issue: 4, 759 - 769, 04.07.2023

Serkan Gönültaş , Murat Tüken , Mehmet Gökhan Çulha , Suhejb Sulejman , Hasan Hüseyin Tavukçu , Yavuz Bastug , Ege Can Serefoglu , Atilla Semerciöz

https://doi.org/10.18621/eurj.1140921

Abstract

Objectives: Glucagon like peptide-1 (GLP-1) is a hormone released from intestinal L-cells following nutrient consumption. It potentiates secretion of insulin from pancreatic beta-cells thus GLP-1 analogues are used for the treatment of type-2 diabetes mellitus( T2DM). This study aims to evaluate impact of GLP-1 receptor agonist liraglutide on erectile function of diabetic rats.

Methods: Male Sprague-Dawley rats (n = 30, 13-weeks old, 240-335 gr) were fed with fatty diet for 2-weeks and divided into 3 groups (n = 10 each). The rats in the first group served as controls (Group C) whereas the rats in the remaining two groups were injected with streptozocin and became T2DM for forming diabetic group (Group D) and treatment group (Group DT). Rats in group D received citrate buffer injections whereas rats in the group DT received liraglutide injections (0.3 mg/kg/12h) subcutaneously. Erectile functions of all rats were evaluated with intracavernosal pressure (ICP)/mean arterial pressure (MAP) measurements. Moreover, plasma sex hormone levels (Testosterone, FSH, LH) were measured and histological assessment of midpenile tissue were performed (Collagen-Type-IV, rat epithelial antigen-1, nNOS).

Results: Maximum ICP/MAP ratios were 0.790 ± 0.164, 0.263 ± 0.139 and 0.652 ± 0.131 in Group C, Group D and Group DT. Although mean ICP/MAP ratios were similar in Group C and Group DT (p = 0.076), mean ICP/MAP ratio was significantly lower in Group D (p < 0.001). Testosterone and FSH results were significantly lower in the Group D as well (p = 0.001). Histological analyses revealed that nNOS (p < 0.001), rat epithelial antigen-1 (p = 0.016) and muscle/collagen ratio (p = 0.015) were also lower in Group D, compared with the other groups.

Conclusions: GLP-1 receptor agonist liraglutide demonstrated protective effects on the erectile tissues of the diabetic rats. Clinical trials are required to confirm if liraglutide treatment has similar beneficial effects on men who have T2DM.

Keywords

Erectile dysfunction, GLP-1 agonist, intracavernosal pressure, liraglutide, nNOS, type 2 diabetic rat

References

• 1. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83-90.
• 2. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61.
• 3. Salonia A, Castagna G, Sacca A, Ferrari M, Capitanio U, Castiglione F, et al. Is erectile dysfunction a reliable proxy of general male health status? The case for the International Index of Erectile Function-Erectile Function domain. J Sex Med 2012;9:2708-15.
• 4. Besiroglu H, Otunctemur A, Ozbek E. The relationship between metabolic syndrome, its components, and erectile dysfunction: a systematic review and a meta-analysis of observational studies. J Sex Med 2015;12:1309-18.
• 5. McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF. The prevalence of diabetic impotence. Diabetologia 1980;18:279-83.
• 6. Giuliano FA, Leriche A, Jaudinot EO, de Gendre AS. Prevalence of erectile dysfunction among 7689 patients with diabetes or hypertension, or both. Urology 2004;64:1196-201.
• 7. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Eng J Med 1989;320:1025-30.
• 8. Costa C, Soares R, Castela A, Adaes S, Hastert V, Vendeira P, et al. Increased endothelial apoptotic cell density in human diabetic erectile tissue--comparison with clinical data. J Sex Med 2009;6:826-35.
• 9. Wingard C, Fulton D, Husain S. Altered penile vascular reactivity and erection in the Zucker obese-diabetic rat. J Sex Med 2007;4:348-62; discussion 62-3.
• 10. Vernet D, Cai L, Garban H, Babbitt ML, Murray FT, Rajfer J, et al. Reduction of penile nitric oxide synthase in diabetic BB/WORdp (type I) and BBZ/WORdp (type II) rats with erectile dysfunction. Endocrinology 1995;136:5709-17.
• 11. Jesmin S, Sakuma I, Salah-Eldin A, Nonomura K, Hattori Y, Kitabatake A. Diminished penile expression of vascular endothelial growth factor and its receptors at the insulin-resistant stage of a type II diabetic rat model: a possible cause for erectile dysfunction in diabetes. J Mol Endocrinol 2003;31:401-18.
• 12. Kizilay F, Gali HE, Serefoglu EC. Diabetes and sexuality. Sex Med Rev 2017;5:45-51.
• 13. Malavige LS, Levy JC. Erectile dysfunction in diabetes mellitus. J Sex Med 2009;6:1232-47.
• 14. Elbrond B, Jakobsen G, Larsen S, Agerso H, Jensen LB, Rolan P, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 2002;25:1398-404.
• 15. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012;8:728-42.
• 16. Korner M, Stockli M, Waser B, Reubi JC. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J Nucl Med 2007;48:736-43.
• 17. Zhou SJ, Bai L, Lv L, Chen R, Li CJ, Liu XY, et al. Liraglutide ameliorates renal injury in streptozotocininduced diabetic rats by activating endothelial nitric oxide synthase activity via the downregulation of the nuclear factorkappaB pathway. Mol Med Rep 2014;10:2587-94.
• 18. Aliperti LA, Lasker GF, Hagan SS, Hellstrom JA, Gokce A, Trost LW, et al. Efficacy of pioglitazone on erectile function recovery in a rat model of cavernous nerve injury. Urology 2014;84:1122-7.
• 19. Kovanecz I, Ferrini MG, Vernet D, Nolazco G, Rajfer J, Gonzalez-Cadavid NF. Pioglitazone prevents corporal veno-occlusive dysfunction in a rat model of type 2 diabetes mellitus. BJU Int 2006;98:116-24.
• 20. Heidenberg DJ, Haney NM, Rezk BM, Talwar S, Okpechi SC, Srivastav SK, et al. Pioglitazone's beneficial effects on erectile function preservation after cavernosal nerve injury in the rat are negated by inhibition of the insulin-like growth factor-1 receptor: a preclinical study. Int J Impot Res 2019;31:1-8.
• 21. Galli A, Errenger K, Niswender K, Robertson S, Saunders C, Matthies H, et al. WO2011162989A2. Glp-1 receptor modulation of addiction, neuropsychiatric disorders and erectile dysfunction. 2011.
• 22. Yue L, Xu JL, Dong J, Xjang GD, Xiang L, Zhao LS, et al. [Regulatory effect of liraglutide on the expression of eNOS in the corpus cavernosum of diabetic rats]. Zhonghua Nan Ke Xue 2016;22:212-8. [Article in Chinese]
• 23. Yuan P, Ma D, Gao X, Wang J, Li R, Liu Z, et al. Liraglutide ameliorates erectile dysfunction via regulating oxidative stress, the RhoA/ROCK pathway and autophagy in diabetes mellitus. Front Pharmacol 2020;11:1257.
• 24. Albersen M, Lin G, Fandel TM, Zhang H, Qiu X, Lin CS, et al. Functional, metabolic, and morphologic characteristics of a novel rat model of type 2 diabetes-associated erectile dysfunction. Urology 2011;78:476.e1-8.
• 25. Hendarto H, Inoguchi T, Maeda Y, Ikeda N, Zheng J, Takei R, et al. GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism 2012;61:1422-34.
• 26. Mullerad M, Donohue JF, Li PS, Scardino PT, Mulhall JP. Functional sequelae of cavernous nerve injury in the rat: is there model dependency. J Sex Med 2006;3:77-83.
• 27. Tamas V, Kempler P. Sexual dysfunction in diabetes. Handb Clin Neurol 2014;126:223-32.
• 28. Giagulli VA, Carbone MD, Ramunni MI, Licchelli B, De Pergola G, Sabba C, et al. Adding liraglutide to lifestyle changes, metformin and testosterone therapy boosts erectile function in diabetic obese men with overt hypogonadism. Andrology 2015;3:1094-103.
• 29. Gonzalez-Cadavid NF. Mechanisms of penile fibrosis. J Sex Med 2009;6 Suppl 3:353-62.
• 30. Ahn GJ, Sohn YS, Kang KK, Ahn BO, Kwon JW, Kang SK, et al. The effect of PDE5 inhibition on the erectile function in streptozotocin-induced diabetic rats. Int J Impot Res 2005;17:134-41.
• 31. Wei P, Lane PH, Lane JT, Padanilam BJ, Sansom SC. Glomerular structural and functional changes in a high-fat diet mouse model of early-stage Type 2 diabetes. Diabetologia 2004;47:1541-9.
• 32. Ha TS, Hong EJ, Ahn EM, Ahn HY. Regulation of type IV collagen alpha chains of glomerular epithelial cells in diabetic conditions. J Korean Med Sci 2009;24:837-43.
• 33. Howland BE, Zebrowski EJ. Some effects of experimentally-induced diabetes on pituitary testicular relationships in rats. Hor Metab Res 1976;8:465-9.