Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes: An in Vitro Study of Pancreatic Islets from Somatostatin Receptor 2 Knockout Mice*

Abstract

Somatostatin (SST) potently inhibits insulin and glucagon release from pancreatic islets. Five distinct membrane receptors (SSTR1-5) for SST are known, and at least two (SSTR2 and SSTR5) have been proposed to regulate pancreatic endocrine function. Our current understanding of SST physiology is limited by the receptor subtype selectivity of peptidyl SST analogs, making it difficult to assign a physiological function to an identified SST receptor subtype. To better understand the physiology of SSTRs we studied the in vitro effects of potent subtype-selective nonpeptidyl SST analogs on the regulation of pancreatic glucagon and insulin secretion in wild-type (WT) and in somatostatin receptor 2 knockout (SSTR2KO) mice. There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets. In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.

Somatostatin Receptor Subtypes 2 and 5 Inhibit Corticotropin-Releasing Hormone-Stimulated Adrenocorticotropin Secretion from AtT-20 Cells

“…Recently, potent, subtype-selective, nonpeptidyl SRIH agonists have been developed and these ligands now provide a means to associate an individual receptor subtype with a biological response [17, 18]. Defining the receptor subtypes involved in ACTH secretion is of particular interest, since SRIH’s effects on growth hormone and insulin release are well documented [19, 20, 21, 22]. …”

Interactions with PDZ Domain Proteins PIST/GOPC and PDZK1 Regulate Intracellular Sorting of the Somatostatin Receptor Subtype 5

“…Thus, SSTR1 was detected on the axon terminals of hypothalamic neurons extending to the median eminence (13), SSTR4 was found on dendrites in hippocampal neurons (14), and SSTR3 is localized to neuronal cilia in the rodent brain (15). The SSTR5 is of particular pharmacological relevance as this receptor subtype regulates growth hormone secretion from the pituitary as well as insulin secretion from pancreatic ␤-cells (16,17). In the AtT20 cell line, a widely used model for the regulation of hormone release by somatostatin, SSTR2 is present at the cell surface whereas SSTR5 is largely confined to the trans-Golgi-network (TGN, Ref.…”

Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

“…The effect of SST is mediated through binding to SST receptors of which five different isoforms have been identified (reviewed by Moller et al (2003)). In pancreatic islets, receptors have been identified on both a-and b-cells (Strowski et al 2000, Cejvan et al 2003 and exogenously administered SST inhibits both insulin and glucagon secretion (Schuit et al 1989, Strowski et al 2000, Cejvan et al 2003, findings consistent with a negative regulatory role for SST in islet secretory function. In rodents, this effect is primarily mediated via receptors 5 and 2, respectively, although all five receptors are expressed in the islets (Ludvigsen et al 2004).…”

“…In rodents, this effect is primarily mediated via receptors 5 and 2, respectively, although all five receptors are expressed in the islets (Ludvigsen et al 2004). Results from studies using SSTR-deficient mice (SSTR1, SSTR2 or SSTR5) revealed changes in both basal and stimulated insulin secretion (Strowski et al 2000, Wang et al 2005, which is consistent with a role for SST in regulating hormone release. We have recently used islets from SST-deficient mice to demonstrate that SST released from the d-cell exerts a tonic inhibitory input on hormone secretion from both a-and b-cells (Hauge-Evans et al 2009) and it has further been shown that the release of islet SST, like insulin, is stimulated by glucose (Vieira et al 2007, Hauge-Evans et al 2012.…”

“…Thus, whereas the results of some studies indicate that SST inhibits stimulus-dependent hormone release from isolated rodent and human islets as well as the perfused pancreas (e.g. Casad & Adelman 1992, Zambre et al 1999, Strowski et al 2000, others have found that exogenous SST was ineffective in suppressing insulin or glucagon secretion from isolated mouse islets (Cejvan et al 2003, Hauge-Evans et al 2009). An analogous system has been reported in the exocrine pancreas, where exogenous SST did not inhibit enzyme secretion from isolated, arterially perfused pancreas, nor from acinar cells in vitro, but suppressed pancreatic enzyme release indirectly via binding to SSTR2 in the dorsal vagal complex (Liao et al 2007).…”