Could Increased Glp1r Expression via Sitagliptin in the GLP-1/GLP-1 Receptor Axis in the DietInduced Obesity Rat Model be Important in Liver Metabolism?

Abstract

Objective: The aim of this study was to evaluate the contribution of sitagliptin, which is used in the treatment of type 2 diabetes mellitus due to its insulinotropic effects, to the levels of glucagon-like peptide-1 (GLP-1) expressed in many systemic tissues in obesity, in liver, skeletal muscle, and fat tissue. Materials and Methods: Adult Wistar albino rats (n=32) were randomly divided into four groups for 16 weeks of intervention. These groups were control (C) (n=8), obese (Ob) (n=8), sitagliptin (C+Stg) (n=8), and obese (Ob+Stg) given sitagliptin (n=8). Glp1r expression in rat liver, muscle, and adipose tissue was confirmed by quantitative real-time PCR. Results: No significant change was detected in Glp1r expression levels in muscle and fat tissue in 4 groups. A 10.64-fold increase in Glp1r gene expression was observed in Ob compared to C (p=0.008). Additionally, a 4.03-fold increase in expression level was found in Ob+Stg compared to Ob (p=0.02) and a 12.52-fold increase in expression level was found in Ob+Stg compared to C (p=0.01). Conclusion: The increased Glp1r expression intensity in obese individuals using sitagliptin compared with controls and obese individuals not using sitagliptin may play a role in the reorganization of liver metabolism that is impaired due to obesity, such as the gluconeogenesis process.

Keywords

• Sitagliptin
• GLP-1
• obesity
• liver metabolism
• Glp1r
• GLP1R

References

1. 1. Burcelin R, Gourdy P. Harnessing glucagon-like peptide-1 receptor agonists for the pharmacological treatment of overweight and obesity. Obes Rev 2017; 18(1): 86-98. google scholar
2. 2. Scott LJ. Sitagliptin: A review in type 2 diabetes. Drugs 2017; 77(2): 209-24. google scholar
3. 3. Sheikh A. Direct cardiovascular effects of glucagon like peptide-1. Diabetol Metab Syndr 2013; 5(1): 47. google scholar
4. 4. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 2002; 87: 1239-46. google scholar
5. 5. McIntosh CH, Demuth HU, Pospisilik JA, Pederson R. Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents? Regul Pept 2005; 128(2): 159-65. google scholar
6. 6. Mannucci E, Pala L, Ciani S, Bardini G, Pezzatini A, Sposato I, et al. Hyperglycaemia increases dipeptidyl peptidase IV activity in diabetes mellitus. Diabetologia 2005; 48(6): 1168-72. google scholar
7. 7. Kosat E. Sitagliptin’in rat karaciğer ve böbrek dokusunda oksidatif stres metabolizmasi üzerine etkisi. Adnan Menderes Üniversitesi, Sağlık Bilimleri Enstitüsü, Yüksek Lisans Tezi. 2011. google scholar
8. 8. Dupre J, Behme MT, Hramiak IM, McFarlane P, Williamson MP, Zabel P, et al. Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM. Diabetes. 1995; 44(6): 626-30. google scholar

9. 9. Ahren B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab 2007; 21(4): 517-33. google scholar
10. 10. Roberge JN, Brubaker PL. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 1991; 128(6): 3169-74. google scholar
11. 11. Hewedy WA. Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice. Brazilian J Pharma Sci 2020; 56: e18482. google scholar
12. 12. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin 2008; 24(2): 489-96. google scholar
13. 13. Coskun ZM, Koyuturk M, Karabulut S, Bolkent S. CB-1R and GLP-1R gene expressions and oxidative stress in the liver of diabetic rats treated with sitagliptin. Pharmacol Rep 2017; 69(4): 822-9. google scholar
14. 14. O’Harte FP, Gray AM, Abdel-Wahab YH, Flatt PR. Effects of non-glycated and glycated glucagon-like peptide-1(7-36) amide on glucose metabolism in isolated mouse abdominal muscle. Peptides 1997; 18(9): 1327-33. google scholar
15. 15. Kato H, Nagai Y, Ohta A, Tenjin A, Nakamura Y, Tsukiyama H, et al. Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes. Diabetes Res Clin Pract 2015; 109(1): 199-205. google scholar
16. 16. Prakash S, Rai U, Kosuru R, Tiwari V, Singh S. Amelioration of diet-induced metabolic syndrome and fatty liver with sitagliptin via regulation of adipose tissue inflammation and hepatic Adiponectin/AMPK levels in mice. Biochimie 2020; 168: 198-209. google scholar
17. 17. Nahon KJ, Doornink F, Straat ME, Botani K, Martinez-Tellez B, Abreu-Vieira G, et al. Effect of sitagliptin on energy metabolism and brown adipose tissue in overweight individuals with prediabetes: a randomised placebo-controlled trial. Diabetologia. 2018; 61(11): 2386-97. google scholar
18. 18. Akaslan SB, Degertekin CK, Yilmaz G, Cakir N, Arslan M, Toruner FB. Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats. Metab Syndr Relat Disord 2013; 11(4): 243-50. google scholar
19. 19. Tahara A, Matsuyama-Yokono A, Shibasaki M. Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice. Eur J Pharmacol 2011; 655(1-3): 108-16. google scholar
20. 20. Yang F, Dang S, Lv H, Shi B. Combined treatment with a gastric inhibitory polypeptide receptor antagonist and a peptidyl peptidase-4 inhibitor improves metabolic abnormalities in diabetic mice. J Int Med Res 2021; 49(1): 300060520985664. google scholar
21. 21. Tremblay AJ, Lamarche B, Kelly I, Charest A, Lepine MC, Droit A, et al. Effect of sitagliptin therapy on triglyceride-rich lipoprotein kinetics in patients with type 2 diabetes. Diabetes Obes Metab 2014; 16(12): 1223-9. google scholar
22. 22. Hematyar J, Rashidi H, Zakerkish M, Payami SP, Ghaderian SB. Effect of sitagliptin versus glibenclamide on glycemic markers, lipid profile inflammatory and oxidative stress factors in type 2 diabetes patients: a double-blinded randomized controlled trial. Maedica (Bucur) 2022; 17(4): 762-70. google scholar
23. 23. Li S, Li H, Wang R, Zhang JP. The effect of sitagliptin on obese patients with insulin treatment-induced diabetes mellitus. Eur Rev Med Pharmacol Sci 2017; 21(15): 3490-5. google scholar
24. 24. Shams HA, Aziz HM, Al-Kuraishy HM. The potential effects of metformin and/or sitagliptin on leptin/adiponectin ratio in diabetic obese patients: a new therapeutic effect. J Pak Med Assoc 2024; 74(10 (Supple-8)): 241-5. google scholar
25. 25. Wang X, Weng W, Cui Y, Zou C. Sitagliptin alleviates obesity in immature mice by inhibiting oxidative stress and inflammation. Reprod Sci 2024; 31(11): 3549-59. google scholar
26. 26. Zong Y, Wang X, Zhang Y, Tan N, Zhang Y, Li L, Liu L. Sitagliptin ameliorates Creb5/lncRNA ENSMUST00000213271-mediated vascular endothelial dysfunction in obese mice. Cardiovasc Drugs Ther 2024; 38(4): 679-91. google scholar