Intra-Islet Somatostatin Regulates Glucagon Release via Type 2 Somatostatin Receptors in Rats

Abstract

Exogenously administered somatostatin (SST) inhibits secretion of insulin and glucagon. Furthermore, it is hypothesized that islet SST regulates glucagon secretion by a local action. A number of studies utilizing SST antibodies have been performed to test this hypothesis, and their results have been conflicting. Five subtypes of SST receptor (SSTR1-5) mediate the effect of SST on target cells. In rodents, SST inhibits the release of glucagon, but not that of insulin, via SSTR2. A novel SSTR2-selective antagonist, DC-41-33, was synthesized recently. We have investigated the effects of this antagonist on arginine-stimulated glucagon and insulin release in batch incubations of isolated rat islets, perifused isolated rat islets, and isolated perfused rat pancreas. In batch incubations at 3.3 mmol/l glucose, DC-41-33 increased glucagon release in a dose-dependent manner. At the maximum dose tested (2 mol/l), DC-41-33 enhanced the glucagon response by 4.3-to 5-fold. Similarly, this compound increased arginine-induced glucagon release in perifused islets at 3.3 mmol/l glucose (2.8-fold) and perfused pancreas at 3.3 and 5.5 mmol/l glucose (2.5-and 2.3-fold, respectively). In the two latter experimental systems, DC-41-33 had no significant effect on insulin release. In conclusion, our results strongly support the hypothesis that islet SST inhibits glucagon secretion via a local action. Diabetes 52:1176 -1181, 2003 I t is well established that exogenously administered somatostatin (SST) inhibits the release of insulin (1,2) and glucagon (3,4) from the endocrine pancreas. In addition, it has been hypothesized that SST released from islet D-cells regulates the secretion of insulin and glucagon by a local "paracrine" action (5,6). This hypothesis was supported by experiments demonstrating that immunoneutralization of endogenous SST in batch incubations of isolated pancreatic islets enhances glucagon and insulin secretion (7,8). However, the results of these studies do not necessarily depict physiological events, since released hormones accumulate in the medium and islet interstitium during the 30-to 90-min incubation period, reaching concentrations that most probably exceed those that are physiologically relevant. Additionally, isolated islets retain neither their normal interstitial structure nor their microcirculation. Further support for the involvement of local effects of SST came from an in vivo study in dogs, in which low and medium doses of a nonimmunoreactive SST analog suppressed the release of endogenous SST and markedly enhanced glucagon release, while insulin release was enhanced moderately (9). The possibility remains, however, that this analog had systemic effects that influenced hormone release.For the reasons stated above, studies with isolated perfused pancreas are of special relevance when considering paracrine interactions between islet cells. In the perfused isolated canine pancreas, exogenous SST inhibited arginine-stimulated insulin and glucagon secretion at concentrations as low as 20% of those measure...

The alpha cell expresses glucagon-like peptide-2 receptors and glucagon-like peptide-2 stimulates glucagon secretion from the rat pancreas

“…Also in line with these studies, no effect of GLP-2 on insulin secretion was observed. It is well established that somatostatin inhibits glucagon secretion in the endocrine pancreas, and we have recently shown that GLP-1 mediates its inhibitory effect on the pancreatic alpha cell through somatostatin acting on somatostatin receptor subtype 2 (J. de Heer, D. H. Coy, J. J. Holst, unpublished results) [19][20][21]. However, in the present study the release of somatostatin was unaltered in response to GLP-2.…”

“…The influence of GLP-2 alone and in combination with GLP-1 on glucagon secretion was examined in the isolated perfused rat pancreas. In addition, we evaluated the effect of GLP-2 on the secretion of other islet hormones, as both insulin and somatostatin have been implicated in the regulation of glucagon release [19][20][21].…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…A study with an SSTR2 antagonist DC-41-33 potentiated the rise of arginine-stimulated glucagon secretion at low glucose and antagonized SST-dependent inhibition of glucagon secretion in rat pancreatic islets confirmed the role of SSTR2 as an inhibitor of glucagon secretion (Cejvan et al, 2003). The effects of DC-41-33 on insulin secretion were much less potent.…”

“…DC-41-33 is an SSTR2-specific antagonist having 9-21 times lower affinity for SSTR3 and SSTR5 (Hocart et al, 1999;Rossowski et al, 1998). In perifused islets DC-41-33 more potently enhanced the maximal and the arginine-stimulated second phase of glucagon secretion, as compared to its effects on insulin secretion (Cejvan et al, 2003). While the effects on glucagon are clearly SSTR2-dependent, the moderate stimulation of insulin secretion suggests that SSTR2 may be involved in regulating insulin secretion.…”

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

“…There is evidence that substances including Zn 2+ [5], γ-aminobutyric acid (GABA) [6][7][8] released from beta cells and somatostatin secreted from neighbouring delta cells [9] have important roles in the modulation of glucagon secretion. Thus, it has been proposed that glucose may induce suppression of glucagon release by indirect actions via a paracrine mechanism.…”