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

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.

Keywords

• diabetes mellitus
• glp-1
• insulin
• klotho protein
• nf-κb
• nrf2
• streptozotocin