Effects of xenin-25 on insulin and glucagon secretions in healthy conscious sheep.

The aim of present study was to determine effect of an intravenous injection of xenin-25 on insulin and glucagon secretion in healthy conscious sheep. After feeding once at 17:00, the experiment was started from 9:00 on the next day. Xenin-25 was intravenously (i.v.) injected at a dose of 100 to 1000 pmol/kg with and without the simultaneous injection of glucose at a dose of 200 μmol/kg, and blood was withdrawn before and after the injections. A single xenin-25 injection at 100 and 300 pmol/kg significantly increased the plasma insulin concentration, whereas the 1000 pmol/kg dose did not elicit significantly enhanced insulin response. Plasma glucose and glucagon concentrations did not significantly change after a single xenin-25 injection. Xenin-25 injection significantly and dose-dependently augmented the glucose-induced insulin secretion. However, the changes in the plasma glucose and glucagon level after the glucose injection were not altered by xenin injection. A prior intravenous injection of the neurotensin receptor subtype-1 (NTR-1) antagonist SR 48692 at 100 nmol/kg did not modify the glucose-induced change in plasma insulin caused by xenin-25 at 300 pmol/kg, and intravenous injection of the NTR-2 agonist levocabastine at 1000 pmol/kg did not augment the insulin response to the glucose injection. On the other hand, no xenin-25 immunopositive cells were detected in the ovine pancreas. The mRNAs of the three NTR subtypes were highly expressed in the ovine pancreas in comparison with the expression in the abomasum. These results suggest that xenin-25 released from the upper gastrointestinal tract plays a role of an insulinotropic factor in sheep, possibly through NTRs in the pancreatic islets, but not via NTR-2.