Pancreatic β-cell protective effect of novel GABA derivatives in rats with type 2 diabetes

Authors

DOI:

https://doi.org/10.18413/rrpharmacology.9.10042

Abstract

Introduction: Gamma-aminobutyric acid (GABA) and GABAergic compounds emerged as potential therapeutic agents for diabetes mellitus and its complications. GABA acts as an inhibitory neurotransmitter in the central nervous system and as an extracellular signaling molecule in pancreatic islets, exerting beneficial effects on insulin secretion, glucagon production, apoptosis, beta-cell survival, and regeneration.

Aim: This study aimed to compare the efficacy of GABA and GABAergic compounds as pancreatic β-cell protective agents in aged rats (18 months) with prolonged hyperglycemia induced by streptozotocin-nicotinamide injection.

Materials and Methods: Male outbred albino rats aged 12 months were intraperitoneally injected with streptozotocin (65 mg/kg) and nicotinamide (230 mg/kg). Over the next 6 months, the level of glycemia was monitored every 4 weeks. Further, rats with postprandial glycemia levels between 11 and 18 mmol/L were selected. The experimental groups were treated with GABA and GABAergic compounds (compositions 2 and 3) for 1 month, while the control group received saline. An oral glucose tolerance test (OGTT) was performed after treatment. Blood and samples of the pancreatic tissue (splenic part) were collected for enzyme-linked immunosorbent assay (GLP-1, TNF-α serum level and NF-κB, Nrf2, Klotho tissue homogenate level), immunohistochemistry (islet NF-κB, Nrf2 and Klotho protein expression) and immunofluorescence assays (islet insulin and glucagon expression).

Results: The research findings demonstrate significant hypoglycemic effects of the studied GABA derivatives in aged rats with prolonged hyperglycemia. These GABA derivatives effects were accompanied with increased GLP-1 production and improved pancreatic β-cell function and mass. Furthermore, elevated levels of Klotho protein and Nrf2 transcription factor, along with the suppression of NF-κB transcription factor after treatment, may play a crucial role in the β-cellprotective effects of these GABA derivatives.

Conclusion: Novel GABA derivatives exhibit significant pancreatic β-cell protective effects that may be mediated by enhanced GLP-1, Klotho protein, and Nrf2 transcription factor, and suppressed NF-κB transcription factor. These results highlight the potential of GABA derivatives as promising therapeutic agents for managing diabetes mellitus and its associated complications.

Graphical Abstract

Keywords:

diabetes mellitus, GLP-1, insulin, Klotho protein, NF-κB, Nrf2, streptozotocin

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Author Contribution

Ivan N. Tyurenkov, Volgograd State Medical University

Doctor Habil of Medical Sciences, Professor, corresponding member of the Russian Academy of Sciences, Head of the Laboratory of Pharmacology of Cardiovascular Drugs, Scientific Center of Innovative Medicines with Pilot Production, Volgograd State Medical University, Volgograd, Russia; e-mail: fibfuv@mail.ru; ORCID ID http://orcid.org/0000-0001-7574-3923. The author was responsible for the idea and planning of the work structure.

Dmitry A. Bakulin, Volgograd State Medical University

Candidate of Sciences (Medicine), Senior Researcher, Laboratory of Pharmacology of Cardiovascular Drugs, Scientific Center of Innovative Medicines with Pilot Production, Volgograd State Medical University, Volgograd, Russia; e-mail: mbfdoc@gmail.com; ORCID ID http://orcid.org/0000-0003-4694-3066. The author was responsible for modeling and control of pathology, design of the final version of the manuscript.

Yulia I. Velikorodnaya, Volgograd Medical Research Center

Researcher of Laboratory of Pathomorphology, Volgograd Medical Research Center, Volgograd, Russia; e-mail: Alta-u@mail.ru; ORCID ID http://orcid.org/0000-0003-2976-6352. The author was responsible for histochemical staining and assessment of morphological changes, analysis and description of the results.

Alexander V. Borisov, Volgograd Medical Research Center

Candidate of Sciences (Medicine), researcher of Laboratory of Pathomorphology, Volgograd Medical Research Center, Volgograd, Russia; email: borissow1978@rambler.ru; ORCID ID http://orcid.org/0000-0003-0202-00082. The author was responsible for carrying out enzyme immunoassay and describing the results.

Elizaveta E. Abrosimova, Volgograd State Medical University

Graduate student, Department of Pharmacology and Pharmacy, Volgograd State Medical University, Volgograd, Russia; e-mail: Abrosimova.volgmed@gmail.com; ORCID ID http://orcid.org/0000-0002-6472-6906. The author was responsible for carrying out enzyme immunoassay and describing the results.

Alexey V. Smirnov, Volgograd State Medical University

Doctor Habil. of Medical Sciences, Professor, Head of the Department of Pathological Anatomy, Volgograd State Medical University of the Ministry of Health of the Russian Federation, Volgograd, Russia; e-mail: alexeysmirnov.volggmu@gmail.com; ORCID ID https://orcid.org/0000-0001-5351-6105. The author was responsible for studying the effect of the compositions on the functional state of the pancreas.

Grigoriy L. Snigur, Volgograd State Medical University

Doctor Habil. of Medical Sciences, Associate Professor, Head of the Department of Biology, Volgograd State Medical University of the Ministry of Health of the Russian Federation, Volgograd, Russia; e-mail: sgrigoryl@mail.ru; ORCID ID https://orcid.org/0000-0002-8612-6186. The author was responsible for studying the effect of the compositions on the functional state of the pancreas and performing immunofluorescence microscopy.

Svyatoslav S. Surin, Volgograd State Medical University

Senior Lecturer at the Department of Biology, Volgograd State Medical University of the Ministry of Health of the Russian Federation, Volgograd, Russia; e-mail: svyatoslavsurin@gmail.com; ORCID ID https://orcid.org/0000-0002-7770-5995. The author was responsible for studying the effect of the compositions on the functional state of the pancreas and performing immunofluorescence microscopy.

Daria A. Kavalerova, Volgograd State Medical University

Senior Lecturer at the Department of Biology, Volgograd State Medical University of the Ministry of Health of the Russian Federation, Volgograd, Russia;  e-mail: dareznikova@yandex.ru; ORCID ID https://orcid.org/0000-0003-4525-3688. The author was responsible for studying the effect of the compositions on the functional state of the pancreas and performing immunofluorescence microscopy.

Olga S. Vasilyeva, Herzen Russian State Pedagogical University

Candidate of Sciences (Chemistry), Senior Researcher, Laboratory of Nitro Compounds, Herzen Russian State Pedagogical University, St. Petersburg, Russia; e-mail: ovasja@gmail.com; ORCID ID https://orcid.org/0000-0002-0309-1580. The author was responsible for the development of the studied compounds.

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Published

30-09-2023

How to Cite

Tyurenkov IN, Bakulin DA, Velikorodnaya YI, Borisov AV, Abrosimova EE, Smirnov AV, Snigur GL, Surin SS, Kavalerova DA, Vasilyeva OS (2023) Pancreatic β-cell protective effect of novel GABA derivatives in rats with type 2 diabetes. Research Results in Pharmacology 9(3): 59–70. https://doi.org/10.18413/rrpharmacology.9.10042

Issue

Vol. 9 No. 3 (2023)

Section

Experimental Pharmacology

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Copyright (c) 2023 Иван Н. Тюренков, Дмитрий А. Бакулин, Юлия И. Великородная, Александр В. Борисов, Елизавета А. Абросимова, Алексей В. Смирнов, Григорий Л. Снигур, Святослав С. Сурин, Дарья А. Кавалерова, Ольга С. Васильева

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