title: Somatostatin receptor subtype 5 regulates insulin secretion and glucose homeostasis.
abstract: Somatostatin (SRIF) regulates pancreatic insulin and glucagon secretion. In the present study we describe the generation of SRIF receptor subtype 5 knockout (sst(5) KO) mice to examine the role of SRIF receptor subtypes (sst) in regulating insulin secretion and glucose homeostasis. Mice deficient in sst(5) were viable, fertile, appeared healthy, and displayed no obvious phenotypic abnormalities. Pancreatic islets isolated from sst(5) KO mice displayed increased total insulin content as compared with islets obtained from wild-type (WT) mice. Somatostatin-28 (SRIF-28) and the sst(5)/sst(1)-selective agonist compound 5/1 potently inhibited glucose-stimulated insulin secretion from WT islets. SRIF-28 inhibited insulin secretion from sst(5) KO islets with 16-fold less potency while the maximal effect of compound 5/1 was markedly diminished when compared with its effects in WT islets. sst(5) KO mice exhibited decreased blood glucose and plasma insulin levels and increased leptin and glucagon concentrations compared with WT mice. Furthermore, sst(5) KO mice displayed decreased susceptibility to high fat diet-induced insulin resistance. The results of these studies suggest sst(5) mediates SRIF inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity. Our findings suggest a potential beneficial role of sst(5) antagonists for alleviating metabolic abnormalities associated with obesity and insulin resistance.
authors.affiliation: Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. mathias.strowski@charite.de
authors.forename: Mathias Z
authors.initials: MZ
authors.lastname: Strowski
authors.forename: Martin
authors.initials: M
authors.lastname: Kohler
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chen
authors.forename: Myrna E
authors.initials: ME
authors.lastname: Trumbauer
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Deborah
authors.initials: D
authors.lastname: Szalkowski
authors.forename: Shobhna
authors.initials: S
authors.lastname: Gopal-Truter
authors.forename: Jill K
authors.initials: JK
authors.lastname: Fisher
authors.forename: James M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: Allan D
authors.initials: AD
authors.lastname: Blake
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular / Q000379:methods; D006224:Cricetinae; D005260:Female; D018390:Gene Targeting / Q000379:methods; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D017481:Receptors, Somatostatin / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013004:Somatostatin / Q000378:metabolism; D053561:Somatostatin-28; D014162:Transfection
chemical_list: D007328:Insulin; D017481:Receptors, Somatostatin; D013004:Somatostatin; D053561:Somatostatin-28; C094573:somatostatin receptor 5; D005947:Glucose