Objectives: Somatostatin (SST) inhibits glucagon and insulin secretion. Five receptor subtypes for SST are known (SSTR1-SSTR5), all of which are expressed in the endocrine pancreas. SSTR2 inhibits glucagon secretion in vitro, however its role in vivo is not well understood. Here, we characterize the role of SSTR2 in regulating glucose homeostasis in mice with diet-induced obesity.
Methods: SSTR2-deficient (SSTR2−/−) and control mice (SSTR2+/+) were fed high-fat diet (HFD) for 14 weeks and the parameters of endocrine pancreas function were determined. Hepatic glycogen and lipid content was evaluated enzymatically and by histomorphology. Expression of enzymes regulating glycogen synthesis and breakdown were measured by a real-time PCR and Western blot. Insulin, somatostatin and glucose tolerance tests were performed. Glucagon secretion from isolated islets was measured by RIA, and glycogenolysis in isolated hepatocytes.
Results: Postprandial glucagon and glucose concentrations were increased in SSTR2-deficient mice. Glucose disappearance rate following administration of glucose, insulin or SST was delayed in SSTR2−/− mice. SSTR2-deficient mice had decreased hepatic glycogen content and decreased glucokinase mRNA. Glycogen synthase of SSTR2−/− mice was decreased while glycogen synthase kinase-3 was increased. Glycogen phosphorylase, phosphorylase-kinase, and CREB were increased. The hepatic lipid content of SSTR2-deficient mice was decreased. Glucose was unable to suppressglucagon secretion from pancreatic islets isolated from SSTR2-deficient mice. Hepatic glycogenolysis was inhibited by an SSTR2-selective agonist.
Conclusions: We demonstrate here that SSTR2 inhibits glucagon secretion in mice with diet-induced obesity. Deletion of SSTR2 accounts for the postprandial hyperglucagonemia. Increased glucose concentration may be due to decreased hepatic glucose utilization, lipid accumulation, and increased glycogen breakdown. SSTR2 may provide a valuable therapeutic target at improving hyperglycemia in patients with peripheral insulin resistance and obesity.
28 Apr - 02 May 2007
European Society of Endocrinology