Dose-response for inhibition by amylin of cholecystokinin-stimulated secretion of amylase and lipase in rats.
OBJECTIVE
The neuroendocrine hormone amylin, cosecreted with insulin from pancreatic beta-cells in response to nutrient ingestion, has several physiologic actions to limit the rate of nutrient uptake, including the slowing of gastric emptying.


METHODS
To investigate whether amylin might modulate digestive enzyme secretion from the exocrine pancreas, anesthetized Sprague Dawley rats were cannulated via the pancreatic duct and the secretory response (flow, amylase and lipase) to cholecystokinin (1 microg s.c.) was measured in the absence and in the presence of 0.1, 0.3 and 1 microg s.c. doses of amylin.


RESULTS
Amylin alone did not affect pancreatic secretion, but it dose-dependently inhibited cholecystokinin-stimulated amylase secretion by up to 58% and lipase secretion by up to 67%. The ED50's for these responses were 0.21 microg+/-0.18 log and 0.11 microg+/-0.05 log, respectively, doses that result in excursions of plasma amylin concentration that are within the reported physiological range. Amylin did not evoke cell signalling in the Ar42j model of pancreatic acinar cells, and responses to amylin were not observed in either Ar42j cells or isolated pancreatic acini in a microphysiometer indicating that the effect of amylin was indirect.


CONCLUSIONS
Inhibition of stimulated pancreatic enzyme secretion is likely to be a physiological, extrapancreatic, action of amylin. Amylinergic mechanisms modulating both gastric emptying and pancreatic enzyme secretion may thus match, respectively, the appearance of substrate and enzymes in the gut lumen.
Amylin Pharmaceuticals Inc, 9360 Towne Centre Drive, San Diego, CA 92121, USA. ayoung@amylin.com
Andrew A
AA
Young
Carolyn
C
Jodka
Richard
R
Pittner
David
D
Parkes
Bronislava R
BR
Gedulin
D000681:Amylases / Q000378:metabolism*; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005746:Gastric Emptying; D007328:Insulin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D008049:Lipase / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000166:cytology / Q000201:enzymology; D010195:Pancreatitis / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D002766:Cholecystokinin; D008049:Lipase; D000681:Amylases