G-protein coupled receptors expressed by islet cells modulate glucagon as well as insulin secretion in type 2 diabetes

• Main Author: Gormley, Noella Marie
• Published: Ulster University 2016
• Subjects: 616.4
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706476

GPCRs have emerged as a major target for the development of novel pharmaceuticals due to their ability to regulate physiological responses to a variety of stimuli. A number of GPCRs have been implicated in the regulation of glucose and energy homeostasis and the development of GLP-1 mimetics has shown their efficacy in the treatment of type 2 diabetes. Until recently, hyperglucagonaemia associated with type 2 diabetes has been overlooked, mainly due to the lack of understanding of the complex workings of the pancreatic alpha cell. This thesis addresses the role of GPCRs in the regulation of islet function, focusing on the modulation of glucagon secretion, in an attempt to bridge the gap of knowledge surrounding the pancreatic a-cell. The insulin and glucagon secreting properties of selected endogenous and synthetic GPCR agonists for GPR120, GPR55, GPR119 and GPR39 were investigated in clonal BRIN-BD11 cells, clonal alpha-TC1.9 cells and isolated islets, in addition to their effects during antagonism of the receptors. Dose dependent effects were observed and stimulatory pathways were identified following investigation of alterations in intracellular Ca2+ and cAMP, in addition, agonists were found to affect GPCR and glucagon mRNA expression. Double immunofluorescent staining confirmed the expression of GPCRs in pancreatic beta- and alpha -cells, whilst relative intensity of mean fluorescence measurements in lean and high fat fed NIH Swiss mice highlighted the effect of metabolic abnormalities on receptor expression in pancreatic islets. Intraperitoneal administration of agonists to NIH Swiss mice demonstrated insulinotropic, glucose-lowering and anti-hyperglucagonaemic effects. These studies highlight the ability of synthetic GPCR agonists to enhance the paracrine effects of islet cells for the maintenance of glucose homeostasis, and show promise for the development of diabetes therapeutics in the future.