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.

Function and expression of somatostatin receptors of the endocrine pancreas

“…This study also demonstrated that the deletion of A c c e p t e d M a n u s c r i p t 14 SSTR2 leads to the loss of moderate insulinostatic activity of the SSTR2-agonist, suggesting that at higher concentrations an SSTR2-agonist could interfere with other SSTRs (at 100 nM). The SSTR-multireceptor theory as regulators of murine insulin secretion was confirmed using islets lacking the SSTR5 gene (Strowski et al, 2003). In these SSTR5-deficient islets the insulinostatic activities of both SST-28 and a SSTR5-selective agonist were markedly attenuated, but not completely lost.…”

“…The results of these studies indicate that SSTR1, SSTR2 and SSTR5 regulate murine insulin secretion. While the residual activity of the SSTR5-selective agonist (Berk et al, 1999;Rohrer et al, 1998;Rohrer and Schaeffer 2000) on insulin secretion from SSTR5-deficient islets (Strowski et al, 2003) could be explained by an interaction with the SSTR1 (only 10-fold selectivity). Collectively, there are several important findings originating from the studies mentioned above that could be possibly explained by the ability of SSTRs to interact with each other.…”

“…Specifically they reported that SSTR5-deficient mice with age display an increase in basal and stimulated insulin secretion and decreased glucose levels (Wang et al, 2005). High-fat diet induced obesity in younger mice with the deletion of the SSTR5-gene resulted in less prominent glucose intolerance and lower basal insulin concentration, as compared to control mice (Strowski et al, 2003). While the results of the study on lean animals fit very well with the inhibitory function of SSTR5 on insulin secretion, the metabolic changes in SSTR5-/-mice with diet-induced obesity are unexpected.…”

Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion

“…Indeed, dopamine receptors are able to homodimerize (47,48) and heterodimerize (49) with members of the same family or with another type of receptors. For instance, somatostatin type 5 receptors, which contribute to the regulation of glucose homeostasis and insulin sensitivity (50), can heterodimerize with D2 receptors, thereby enhancing functional activity (51). Therefore, in the context of insulin secretion, dopamine receptors could interact with somatostatin receptors known to be present in beta cells.…”

Novel signals mediating the functions of somatostatin: The emerging role of NO/cGMP

“…The cloning of the receptors promoted the development of specific SRIF ligands, agonists and antagonists (Rohrer et al, 1998;Bass et al, 1996;Reubi et al, 2000;Hoyer et al, 2004;Tulipano et al, 2002), specific antibodies and genetically modified mice (Kreienkamp et al, 1999;Viollet et al, 2000;Allen et al, 2003;Strowski et al, 2003) An extensive number of studies and a number of reviews Patel 1999;Tannenbaum and Epelbaum, 2000;Csaba and Dournaud, 2001;Olias et al, 2004) have addressed the intracellular signalling pathways responsible for SRIF's diverse actions. The results obtained were mostly from studies performed in cell lines transfected with the recombinant receptors, but also in native systems.…”