Role of somatostatin signalling on pancreatic islet function and energy homeostasis

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Forover 90 years, the study of the endocrine pancreas has mainly been limited to insulinand glucagon. However, the intactpancreatic 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 variousG-coupled protein SST receptors (SSTR1-5) found on the other cell types. SSTR1/2 are expressed in a numberof 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 releasefrom pancreatic islets is impacted during low, normal and high blood glucoselevels and that SST levels dramatically influences therelease of glucagon during hypoglycemia. This suggests that SST plays a criticalregulatory role in the regulatory defence against hypoglycemia. However, it isstill unclear what impact SST signalling has in the release of various islethormones including insulin, amylin, glucagon, pancreatic peptide and ghrelinunder various conditions including exercise, mild hyperglycemia, mild hypoglycemiaand 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 vivoapproaches (rodent models) and a library of newly developed SSTR agonists and antagonists,we will elucidate the normal mechanisms for SST's tight regulation of isletfunction to maintain energy homeostasis. Using novel pharmacological agents andnew in vivo approaches, this researchwill focus on the potential direct role of SST signalling in regulating islethormone release and substrate metabolism in liver, skeletal muscle and adiposetissue. Aim 1 will focus on using various agonists and antagonists, chosen fortheir 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 underbasal conditions (fasting, rested state) and under various stimulated conditions(feeding, exercise). Aim 2 will examine the potential triggers of SST release in vivo