Exp Clin Endocrinol Diabetes 2007; 115 - OR06_3
DOI: 10.1055/s-2007-972235

Deletion of somatostatin receptor subtype 2 leads to hyperglucagonemia and impaired glucose control in mice with diet-induced obesity

M Strowski 1, C Grötzinger 1, V Singh 1, E Göncz 1, S Zacharias 1, B Wiedenmann 1, U Plöckinger 1
  • 1Charité – Universitätsmedizin Berlin, Campus Virchow-Klinikum, Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie & Interdisziplinäres Stoffwechsel-Centrum/Endokrinologie und Diabetes mellitus, Berlin, Germany

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 function in vivo is not well understood. Here, we characterize the role of SSTR2 in regulating glucose homeostasis in mice with diet-induced obesity.

Methods: Male SSTR2-deficient (SSTR2-/-) and age matched control mice (SSTR2+/+) were fed high-fat diet (HFD) for 14 weeks and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid content was quantified enzymatically and visualized by histomorphology. RNA levels of enzymes regulating glycogen synthesis and breakdown were measured by a real time PCR and their activity by Western blot. Insulin, somatostatin and glucose tolerance tests were performed. Glucagon secretion from isolated islets was measured by RIA.

Results: Postprandial glucagon and glucose levels 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 less potently suppressed glucagon secretion from islets isolated from SSTR2-deficient mice.

Conclusions: We demonstrate for the first time 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.