Biological Activity of Somatostatin and Somatostatin Analogs on Inhibition of Arginine-Induced Insulin and Glucagon Release in the Rat

Abstract

Somatostatin and dihydrosomatostatin (H2somatostatin) are equipotent in inhibiting insulin and glucagon release induced by arginine in the rat. The ID50 of H2somatostatin on insulin and glucagon secretion induced by arginine are 14 +/- 6 and 6 +/- 10 mug/100 g BW respectively, similar to the ID50 of H2somatostatin (18 +/- 10 mug/100 g BW) on inhibition of insulin release induced by glucose. Thyrotropin releasing factor, luteinizing hormone releasing factor, alpha-MSH, and the N-terminus decapeptide of the beta-chain of porcine hemoglobin did not alter the secretion of insulin and glucagon induced by arginine. With the exception of [Ala2[-somatostatin and [Ala5]-somatostatin, alanine substituted analogs of somatostatin were less potent than somatostatin. [D-Trp8]-somatostatin is 6-8 times as potent as somatostatin in inhibiting insulin and glucagon release induced by arginine. The relative potencies of these analogs to inhibit the secretion of the pancreatic hormones are in good agreement with our previously reported values based on the inhibition of GH secretion in vitro.

Structure‐activity relationships of eighteen somatostatin analogues on gastric secretion.

“…This is in agreement with the observation that both Ala2 and D-Ala2-somatostatin are more potent with respect to inhibition of GH, insulin and glucagon secretion than is cyclic-somatostatin Brown et al 1976a).…”

“…It therefore seems probable that the indole ring is important to position 8 (Rivier et al 1976). The increased activity of D-Trp8-somatostatin against the secretion of GH, insulin and glucagon is not due to increased duration of action (Brown et al 1976a). However, it has been reported that D-Trp8-somatostatin is less susceptible to in vitro enzymic degradation by rat and human plasma (Benuck & Marks, 1976).…”

“…The role of Trp8 is interesting since GH, insulin and glucagon inhibiting activity is lost upon substitution by tyrosine (Rivier et al 1976) or alanine Brown et al 1976a) whilst formyl-blocked-Trp8-somatostatin is reported to be equipotent with cycic-somatostatin in blocking glucose-induced insulin release from the perfused rat pancreas (Curry & Bennett, 1976). We have shown 5-F-Trp8-somatostatin to have the same potency as cyclic-somatostatin (Tables 2 and 3).…”

“…Ala5-somatostatin has similar activity when tested against glucagon, insulin and GH release Brown et al 1976a) but removal of Asn5 without substitution results in a compound which inhibits insulin but not glucagon release (Sarantakis, McKinley, Jaunakais, Clark & Grant, 1976;Effendic, Luft & Sievertsson, 1975;Brown, Rivier & Vale, 1976b). It is possible, therefore, that the Asn5 acts as a spacer in the somatostatin molecule which is important in the inhibition of glucagon release, but not GH or insulin.…”

Structure-Activity Relationships of Somatostatin Analogs in the Rabbit Ileum and the Rat Colon

“…Finally, in the D-amino acid substitution series, each amino acid was replaced with its D-isomer, thus changing the backbone conformation of the molecule. This series was of particular interest because of the dissociation of biologic activities that certain analogs exhibited in other systems (13)(14)(15)(16)(17)(18).…”