Urotensin-II is present in pancreatic extracts and inhibits insulin release in the perfused rat pancreas.
OBJECTIVE
Previous work from our laboratory has demonstrated that frog urotensin-II (UII), at a high concentration, inhibits glucose-induced insulin release in the rat pancreas. We have investigated the effect of rat UII and two structural analogs on insulin secretion and searched for the presence of UII-immunoreactivity in rat pancreatic extracts.


METHODS
The study was performed in the perfused rat pancreas. UII as well as its analogs were synthesized by solid phase methodology. Pancreatic extracts were analyzed for UII by reversed-phase HPLC combined with a sensitive UII RIA.


RESULTS
Infusion of synthetic rat UII inhibited glucose-induced insulin release in a dose-dependent manner (IC(50): 0.12 nmol/l). UII (1 nmol/l) also inhibited the insulin responses induced by carbachol, glucagon-like peptide-1, and a calcium channel agonist (BAY K 8644). The inhibitory effect of UII was mimicked by the potent G protein-coupled receptor (GPR14) agonist [3-iodo-Tyr(6)]UII(4-11). In contrast, [Ala(8)]UII(4-11), a UII analog devoid of contractile activity on rat aortic rings, did not affect glucose-induced insulin secretion. Analysis of rat pancreatic extracts revealed the presence of an immunoreactive peptide exhibiting the same retention time as synthetic rat UII.


CONCLUSIONS
Our results demonstrate that UII is a potent insulinostatic peptide. The observation that UII is actually present in the pancreas suggests that this peptide may play a physiological role in the control of insulin secretion. Concerning the two UII analogs tested, only [3-iodo-Tyr(6)]UII(4-11), reportedly possessing GPR14-mediated contractile activity, mimics the insulinostatic effect of UII. This finding would support the view that UII acts on the pancreatic beta cell through the GPR14 receptor.
Silvestre
Ramona A
RA
Hospital Universitario Puerta de Hierro and Department of Physiology, Universidad Autónoma de Madrid, Madrid, Spain.
Egido
Eva M
EM
Hernández
Raquel
R
Leprince
Jérome
J
Chatenet
David
D
Tollemer
Hélène
H
Chartrel
Nicolas
N
Vaudry
Hubert
H
Marco
José
J
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003864:Depression, Chemical; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D010184:Pancreatic Extracts / Q000737:chemistry*; D010277:Parasympathomimetics / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014579:Urotensins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
D001786:Blood Glucose; D002120:Calcium Channel Agonists; D007328:Insulin; D010184:Pancreatic Extracts; D010277:Parasympathomimetics; D014579:Urotensins; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002217:Carbachol; C029677:urotensin II