Metabolic effects of GABA derivatives and their combined use with sitagliptin in experimental obesity

BACKGROUND: The increase in the number of people with obesity is associated with an increase in the prevalence of cardiovascular diseases, justifying the search for new drugs to correct metabolic disorders.

AIM: To assess the metabolic effects of GABA derivatives (FPS and MFBA compositions) when used separately and in combination with sitagliptin in a model of carbohydrate metabolism disorder induced by alimentary obesity.

MATERIALS AND METHODS: The study was conducted on male rats with alimentary obesity. Following a six-month high-fat, high-calorie diet, seven groups were formed (n=8), including a positive control group (intact rats without obesity) and a negative control group, as well as five groups with comparable obesity severity. These groups received the studied compositions separately for 30 days: MFBA (20 mg/kg) and FPS (50 mg/kg), the reference drug sitagliptin (10 mg/kg), and combinations of MFBA+sitagliptin (20+10 mg/kg), FPS+sitagliptin (50+10 mg/kg). Upon completion of the treatment course, changes in body weight, visceral fat mass, lipid profile, and severity of carbohydrate disorders based on the oral glucose tolerance test and the insulin tolerance test were assessed. Levels of glucagon, insulin, and glucagon-like peptide-1 (GLP-1) were determined by enzyme-linked immunosorbent assay. The degree of liver damage was evaluated based on levels of liver transaminases (ALT and AST) and through morphological examination of structural changes.

RESULTS: It was established that the MFBA and FPS compositions, separately and in combination with sitagliptin, significantly reduced body weight and visceral fat mass, and enhanced the hypoglycemic action of sitagliptin (especially in combination with FPS). The separate and combined administration of MFBA and FPS with sitagliptin increased the levels of GLP-1 and insulin, improved glucose utilization, and increased insulin sensitivity, as well as normalized the lipid profile and levels of ALT, AST. Morphological examination revealed fewer foci of lymphoid infiltration and less pronounced fatty degeneration of the liver during treatment. The combination of FPS+sitagliptin showed the highest effectiveness.

CONCLUSION: GABA derivatives - MFBA and FPS, in monotherapy and more pronouncedly in combination with sitagliptin, reduced the severity of metabolic disorders associated with obesity. The anorexigenic effect noted for the cyclic GABA derivative (FPS) and the ability to improve carbohydrate and lipid metabolism are of interest for further studies.

1. Koliaki C, Dalamaga M, Liatis S. Update on the Obesity Epidemic: After the Sudden Rise, Is the Upward Trajectory Beginning to Flatten? Curr Obes Rep. 2023;12(4):514-527. doi: https://doi.org/10.1007/s13679-023-00527-y

2. Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother. 2021;137:111315. doi: https://doi.org/10.1016/j.biopha.2021.111315

3. Mezouar S, Chantran Y, Michel J, et al. Microbiome and the immune system: from a healthy steady-state to allergy associated disruption. Hum. Microbiome J. 2018;10:11–20. doi: https://doi.org/10.1016/j.humic.2018.10.001

4. Santos-Marcos JA, Perez-Jimenez F, Camargo A. The role of diet and intestinal microbiota in the development of metabolic syndrome. J Nutr Biochem. 2019;70:1-27. doi: https://doi.org/10.1016/j.jnutbio.2019.03.017

5. Al-Kuraishy HM, Hussian NR, Al-Naimi MS, et al. The Potential Role of Pancreatic γ-Aminobutyric Acid (GABA) in Diabetes Mellitus: A Critical Reappraisal. Int J Prev Med. 2021;12:19. doi: https://doi.org/10.4103/ijpvm.IJPVM_278_19

6. Wang KL, Tao M, Wei TJ, Wei R. Pancreatic β cell regeneration induced by clinical and preclinical agents. World J Stem Cells. 2021;13(1):64-77. doi: https://doi.org/10.4252/wjsc.v13.i1.64

7. Hagan DW, Ferreira SM, Santos GJ, Phelps EA. The role of GABA in islet function [published correction appears in Front Endocrinol (Lausanne). 2023;14:1301830]. Front Endocrinol (Lausanne). 2022;13:972115. doi: https://doi.org/10.3389/fendo.2022.972115

8. Lee HY, Lee GH, Hoang TH, et al. GABA and Fermented Curcuma longa L. Extract Enriched with GABA Ameliorate Obesity through Nox4-IRE1α Sulfonation-RIDD-SIRT1 Decay Axis in High-Fat Diet-Induced Obese Mice. Nutrients. 2022;14(8):1680. doi: https://doi.org/10.3390/nu14081680

9. Rezazadeh H, Sharifi MR, Soltani N. Insulin resistance and the role of gamma-aminobutyric acid. J Res Med Sci. 2021;26:39. doi: https://doi.org/10.4103/jrms.JRMS_374_20

10. Hosseini Dastgerdi A, Sharifi M, Soltani N. GABA administration improves liver function and insulin resistance in offspring of type 2 diabetic rats. Sci Rep. 2021;11(1):23155. doi: https://doi.org/10.1038/s41598-021-02324-w

11. Purwana I, Zheng J, Li X, et al. GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes. 2014;63(12):4197-4205. doi: https://doi.org/10.2337/db14-0153

12. Fortin SM, Lipsky RK, Lhamo R, et al. GABA neurons in the nucleus tractus solitarius express GLP-1 receptors and mediate anorectic effects of liraglutide in rats. Sci Transl Med. 2020;12(533):eaay8071. doi: https://doi.org/10.1126/scitranslmed.aay8071

13. Goldsmith F, Keenan MJ, Raggio AM, et al. Induction of Energy Expenditure by Sitagliptin Is Dependent on GLP-1 Receptor. PLoS One. 2015;10(5):e0126177. doi: https://doi.org/10.1371/journal.pone.0126177

14. Janani L, Bamehr H, Tanha K, et al. Effects of Sitagliptin as Monotherapy and Add-On to Metformin on Weight Loss among Overweight and Obese Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis. Drug Res (Stuttg). 2021;71(9):477-488. doi: https://doi.org/10.1055/a-1555-2797

15. Tyurenkov IN, Faibisovich TI, Bakulin DA. Synergistic effects of GABA and hypoglycemic drugs. Problemy endokrinologii. 2023;69(4):61-69. (In Russ).

16. Tiurenkov IN, Kurkin DV, Bakulin DA, et al. The influence of novel GPR119 agonist on body weight, food intake and glucose metabolism in obesity rats provoked high-fat and -carbohydrate diet. Problemy endokrinologii. 2016;62(1):44-49. (In Russ).]

17. Tyurenkov IN, Bakulin DA, Velikorodnaya YuI, et al. Pancreatic β-cell protective effect of novel GABA derivatives in rats with type 2 diabetes. Research Results in Pharmacology. 2023;9(3):59-70. doi: https://doi.org/10.18413/rrpharmacology.9.10042

18. Tyurenkov IN, Bakulin DA, Andriashvili TM, et al. Screening in a range of structural analogs of GABA substances with pancreoprotective effect. Lekarstvenny` vestnik. 2023;24(3):36-42. (In Russ).

19. Prud’homme GJ, Glinka Y, Udovyk O, et al. GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity. Biochem Biophys Res Commun. 2014;452(3):649-654. doi: https://doi.org/10.1016/j.bbrc.2014.08.135

20. Quek J, Chan KE, Wong ZY, et al. Global prevalence of nonalcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2023;8(1):20-30. doi: https://doi.org/10.1016/S2468-1253(22)00317-X