Pancreastatin and islet hormone release.

Abstract

The effect of pancreastatin on the release of insulin, glucagon, and somatostatin was studied in the isolated perfused rat pancreas. After an initial equilibration period (-20 to 0 min) with a basal glucose concentration (3.3 mM), the pancreata were perfused with either 16.7 mM glucose (040 min) or with 20 mM arginine (0-20 min). Pancreastatin was introduced 10 min prior to and throughout the administration of the high glucose and arginine and continued during their perfusion. As expected, the glucose and the arginine augmented insulin and somatostatin release. Pancreastatin (1 and 10 nM) markedly suppressed the first phase of insulin release with both insulinogogues used, while the early somatostatin secretion was not significantly decreased. However, the peak incremental somatostatin response to arginine was reduced by 50% (P < 0.05). Conversely, the peptide (10 nM) tended to augment arginine-induced glucagon release. Pancreastatin (100 nM) also suppressed glucose-stimulated insulin release from isolated rat islets. These pancreastatin-mediated alterations in islet hormone release are reminiscent of those known to characterize non-insulin-dependent diabetes. Therefore, the significance of pancreastatin in islet physiology and pathophysiology deserves special consideration.Pancreastatin, a 49-residue peptide with a C-terminal glycine amide, was isolated from porcine pancreatic extracts by using the amide structure as a marker during the isolation procedure (1). It has been shown that pancreastatin inhibited the early phase of glucose-induced insulin release from the isolated perfused rat pancreas (1). This study confirms and extends this finding by demonstrating that pancreastatin significantly suppresses arginine as well as glucose-stimulated insulin release. Furthermore, the peak somatostatin response to arginine decreased while the peptide seemed to augment arginine-induced glucagon release. MATERIALS AND METHODSChemical Synthesis of Pancreastatin. The chemical synthesis of pancreastatin was performed manually by using the stepwise solid-phase synthetic approach as described by Merrifield (2). The 49-residue peptide amide was prepared by using p-methylbenzhydrylamine resin (3) and amino acid derivatives with conventional protection groups. Side-chain protecting groups used were aspartic acid [p- CH2Cl2, and (viii) coupling of the amino acid derivative with dicyclohexylcarbodiimide for 90 min. Each coupling step was monitored by a ninhydrin test (4). In some steps, a double coupling was carried out to improve the yields. The peptide was deprotected and cleaved from the resin by hydrofluoric acid, and the lyophilized crude peptide material obtained was purified by anion-exchange chromatography on a DEAESephadex A-25 column (AB Pharmacia, Uppsala, Sweden) and by preparative HPLC on a uBondapak C18 column (Waters Associates). The synthetic pancreastatin thus obtained was found to be homogenous and to coelute in HPLC with the native peptide. In the experiments described below on the biological effects...

Isolation and characterization of a tumor‐derived human protein related to chromogranin A and its in vitro conversion to human pancreastatin‐48

“…The potent effect of the C-terminal fragment of pancreastatin on pancreatic secretion suggested that this portion of the molecule is important for the biological activity [3] and that the Cterminal active fragments of pancreastatin may be generated in vivo at the site where it exhibits its physiological functions.…”

“…This peptide has been shown to inhibit glucose-induced insulin release from the isolated perfused pancreas [3]. Porcine pancreastatin shows striking sequence similarity to a part of bovine chromogranin A [4 -81, a protein normally present in the secretory granules of endocrine and neuronal cells [9].…”

The importance of the C‐terminal amide structure of rat pancreastatin to inhibit pancreatic exocrine secretion

“…Pancreastatin has been shown to inhibit endocrine and exocrine pancreatic secretions [2,3]. We recently found that rat pancreastatin inhibited pancreatic exocrine secretions produced by central vagal nerve stimulation [4], and suggested that pancreastatin acted by means of inhibiting vagal efferent nerve excitation.…”

Pancreastatin receptor is coupled to a guanosine triphosphate-binding protein of the Gg/11α family in rat liver membranes

“…[11][12][13][14] The role of PST as a regulatory enteropancreatic peptide has been established in the light of a variety of biologic effects in a number of tissues, which could be assigned to the carboxyl-terminal part of the molecule (see Sánchez-Margalet et al 15 for review). These effects are exerted on endocrine and exocrine pancreatic secretion, [16][17][18][19][20][21] gastric secretion, 22,23 parathormone release, 24 plasma catecholamine levels, 25 and memory retention. 26 Synthetic rat pancreastatin has also been shown to have biologic activity in various tissues.…”