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Involvement of adenosine signalling in the release of gastric and pancreatic peptides

University of British Columbia

Adenosine is precursor and a metabolic intermediate of adenosine triphosphate in energy transfer, and cyclic adenosine monophosphate in signal transduction. Recent studies have demonstrated that the role of adenosine in the body is much more than just structural as it can also behave as an important regulator of homeostatic functions. Adenosine signalling relies on the activation of the A₁, A₂A, A₂B and A₃ adenosine receptors. Through the development of pharmacological tools and genetic knockout mouse models of specific receptor subtypes, the involvement of these receptors in various physiological systems is quickly being established. This thesis investigates the function of adenosine in the digestive system and specifically how adenosine regulates the release of gastric and pancreatic peptides. With the use of a novel vascularly perfused isolated mouse stomach model and specific A₁ and A₂A receptor knockout animals, the role of adenosine on the release of somatostatin and ghrelin was determined. Lower concentrations of adenosine can inhibit the release of somatostatin and ghrelin via the activation of A1 receptors, while higher concentrations can stimulate their release via activation of A₂A receptors. Given the importance of somatostatin in regulating gastric acid secretion and motility, and ghrelin in regulating systemic energy balance, better understanding of how the release of these two peptides is regulated may reveal potential therapies for eating disorders, gastrointestinal dysfunctions and metabolic diseases. In the pancreas, adenosine was shown to regulate both insulin and glucagon secretion from the pancreatic islets. Studies presented in this thesis demonstrate that adenosine signalling interacts with the effects of the incretin hormone GLP-1 in the pancreas such that concomitant administration of adenosine and GLP-1 in the perfused pancreas induced greater insulin release than GLP-1 administration alone. Furthermore, A₁ receptor knockout mice exhibited more frequent pulses of insulin secretion, which may have contributed to their superior glucose tolerance compared to wild type control mice. These findings on the role of adenosine signalling in the pancreas may have implications in the etiology of diabetes mellitus. The involvement of adenosine signalling in the digestive tract further illustrates the importance of adenosine as a metabolic regulator in homeostasis.

Text

2011-07-04

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/35862

Physiology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/