GABAA and GABAB Receptor Gene Expression and Functional Regulation During Pancreatic Regeneration and Insulin Secretion in Rats
Year: 2005
Type: dissertation
Abstract: The present study demonstrate the functional alterations of the GABAA and GABAB\nreceptors and the gene expression during the regeneration of pancreas following\npartial pancreatectomy. The role of these receptors in insulin secretion and\npancreatic DNA synthesis using the specific agonists and antagonists also are studied\nin vitro. The alterations of GABAA and GABAR receptor function and gene\nexpression in the brain stem, crebellum and hypothalamus play an important role in\nthe sympathetic regulation of insulin secretion during pancreatic regeneration.\nPrevious studies have given much information linking functional interaction between\nGABA and the peripheral nervous system. The involvement of specific receptor\nsubtypes functional regulation during pancreatic regeneration has not given emphasis\nand research in this area seems to be scarce. We have observed a decreased GABA\ncontent, down regulation of GABAA receptors and an up regulation of GABAB\nreceptors in the cerebral cortex, brain stem and hypothalamus. Real Time-PCR\nanalysis confirmed the receptor data in the brain regions. These alterations in the\nGABAA and GABAB receptors of the brain are suggested to govern the regenerative\nresponse and growth regulation of the pancreas through sympathetic innervation. In\naddition, receptor binding studies and Real Time-PCR analysis revealed that during\npancreatic regeneration GABAA receptors were down regulated and GABAB\nreceptors were up regulated in pancreatic islets. This suggests an inhibitory role for\nGABAA receptors in islet cell proliferation i.e., the down regulation of this receptor\nfacilitates proliferation. Insulin secretion study during 1 hour showed GABA has\ninhibited the insulin secretion in a dose dependent manner in normal and\nhyperglycaemic conditions. Bicuculline did not antagonize this effect. GABAA\nagonist, muscimol inhibited glucose stimulated insulin secretion from pancreatic\nislets except in the lowest concentration of 1O-9M in presence of 4mM glucose.Musclmol enhanced insulin secretion at 10-7 and 10-4M muscimol in presence of\n20mM glucose- 4mM glucose represents normal and 20mM represent\nhyperglycaemic conditions. GABAB agonist, baclofen also inhibited glucose induced\ninsulin secretion and enhanced at the concentration of 1O-5M at 4mM glucose and at\n10-9M baclofen in presence of 20mM glucose. This shows a differential control of\nthe GABAA and GABAB receptors over insulin release from the pancreatic islets.\nDuring 24 hours in vitro insulin secretion study it showed that low concentration of\nGABA has inhibited glucose stimulated insulin secretion from pancreatic islets.\nMuscimol, the GABAA agonist, inhibited the insulin secretion but, gave an enhanced\nsecretion of insulin in presence of 4mM glucose at 10-7\n, 10-5 and 1O-4M muscimol.\nBut in presence of 20mM glucose muscimol significantly inhibited the insulin\nsecretion. GABAB agonist, baclofen also inhibited glucose induced insulin secretion\nin presence of both 4mM and 20mM glucose. This shows the inhibitory role of\nGABA and its specific receptor subtypes over insulin synthesis from pancreatic bete-islets.\nIn vitro DNA synthesis studies showed that activation of GABAA receptor by\nadding muscimol, a specific agonist, inhibited islet DNA synthesis. Also, the\naddition of baclofen, a specific agonist of GABAB receptor resulted in the stimulation\nof DNA synthesis.Thus the brain and pancreatic GABAA and GABAB receptor\ngene expression differentially regulates pancreatic insulin secretion and islet cell\nproliferation during pancreatic regeneration. This will have immense clinical\nsignificance in therapeutic applications in the management of Diabetes mellitus.
Authors: S. Balarama Kaimal, C.S. Paulose
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2163891193