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