Role of somatostatin signalling on pancreatic islet function and energy homeostasis

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For over 90 years, the study of the endocrine pancreas has mainly been limited to insulin and glucagon. However, the intact pancreatic islet acts as a complete organ system with five different cell types (, , , , ) and a dedicated vasculature and neural supply. Within the islet, the delta () cell secretes the inhibitory hormone somatostatin (SST) that binds to various G-coupled protein SST receptors (SSTR1-5) found on the other cell types. SSTR1/2 are expressed in a number of other tissues that impact energy metabolism, including the adipose tissue, liver and skeletal muscle, but the role of these receptors on metabolism is unclear. We have discovered that SST release from pancreatic islets is impacted during low, normal and high blood glucose levels and that SST levels dramatically influences the release of glucagon during hypoglycemia. This suggests that SST plays a critical regulatory role in the regulatory defence against hypoglycemia. However, it is still unclear what impact SST signalling has in the release of various islet hormones including insulin, amylin, glucagon, pancreatic peptide and ghrelin under various conditions including exercise, mild hyperglycemia, mild hypoglycemia and euglycaemia. This Discovery Grant aims to elucidate the local cross-talk among islet cells, with an emphasis on SST signalling during so called normal' physiology. Using primarily in vivo approaches (rodent models) and a library of newly developed SSTR agonists and antagonists, we will elucidate the normal mechanisms for SST's tight regulation of islet function to maintain energy homeostasis. Using novel pharmacological agents and new in vivo approaches, this research will focus on the potential direct role of SST signalling in regulating islet hormone release and substrate metabolism in liver, skeletal muscle and adipose tissue. Aim 1 will focus on using various agonists and antagonists, chosen for their specificity for each of the five receptor subtypes, to determine how SST signalling impacts islet function and hormone release (insulin, glucagon, amylin, pancreatic polypeptide, ghrelin and SST) into the portal circulation using under basal conditions (fasting, rested state) and under various stimulated conditions (feeding, exercise). Aim 2 will examine the potential triggers of SST release in vivo