Our long term objectives are to investigate the mechanisms of secretion and actions of secretin and cholecystokinin (CCK) to better understand physiology and pathophysiology of the two gut hormones. This proposal is to test two major hypotheses: 1) the release of secretin and cholecystokinin are luminally mediated by releasing factors secreted from the upper small intestinal mucosa and actions of the two hormones on pancreatic exocrine secretion are controlled by pancreatic islet hormones including insulin, pancreatic polypeptide, somatostatin and glucagon. Pancreatic juice or proteases in the upper small intestine suppress the release of both CCK and/or secretin and pancreatic exocrine secretion in interdigestive and/or intestinal phase. Feedback regulation of exocrine pancreas observed in rats, dogs and humans are found to be hormonally mediated. These observations,suggested the presence of trypsin-sensitive releasing factors for the two hormones. The releasing factors are found in rat upper intestinal secretion as trypsin-sensitive peptides. The presence of these factors will be confirmed further in the rat and dog. First, secretin releasing factor (S-RF) will be isolated from the intestinal acid perfusate or extract of rats and dogs and purified to homogeneity. Their primary structure will be determined. Subsequently, CCK-releasing factors (CCK-RF) will be isolated and purified, and their structure will be determined. Both factors will be custom synthesized and their specific radioimmunoassay will be developed. The mechanism of releases of S-RF or CCK-RF and their actions in vivo and in vitro will then be investigated. In conscious rats, immunoneutralization of circulating insulin with a rabbit anti-insulin serum completely suppresses pancreatic exocrine secretion stimulated by a liquid meal or exogenous secretin and CCK-8. It also suppresses the release of secretin and CCK. The effect of insulin on the actions of secretin and CCK will be investigated in rats, dogs and humans as well as animals and patients with diabetes mellitus. The study will be extended to isolated perfused pancreas models of normal and diabetic rats and dogs to elucidate the mechanism of insulin action and the roles of 3 pancreatic inhibitory hormones on the exocrine pancreas. The proposed study will enrich the fundamental knowledge of physiology and pathophysiology of secretin and CCK and the pancreatic exocrine function, and also help us to better manage patients with impaired digestive and absorptive function as well as diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Genesee Hospital
United States
Zip Code
Chey, William Y; Chang, Ta-Min (2014) Secretin: historical perspective and current status. Pancreas 43:162-82
Chey, William Y; Chang, Cecilia H; Pan, Huei-Ju et al. (2003) Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa. Regul Pept 111:183-90
Li, J P; Chang, T M; Chey, W Y (2001) Roles of 5-HT receptors in the release and action of secretin on pancreatic secretion in rats. Am J Physiol Gastrointest Liver Physiol 280:G595-602
Li, J P; Lee, K Y; Chang, T M et al. (2001) MEK inhibits secretin release and pancreatic secretion: roles of secretin-releasing peptide and somatostatin. Am J Physiol Gastrointest Liver Physiol 280:G890-6
Li, J P; Chang, T M; Wagner, D et al. (2001) Pancreatic phospholipase A2 from the small intestine is a secretin-releasing factor in rats. Am J Physiol Gastrointest Liver Physiol 281:G526-32
Li, P; Song, Y; Lee, K Y et al. (2000) A secretin releasing peptide exists in dog pancreatic juice. Life Sci 66:1307-16
Chang, T M; Thagesen, H; Lee, K Y et al. (2000) Canine vagus nerve stores cholecystokinin-58 and -8 but releases only cholecystokinin-8 upon electrical vagal stimulation. Regul Pept 87:7-Jan
Li, P; Chang, T M; Coy, D et al. (2000) Inhibition of gastric acid secretion in rat stomach by PACAP is mediated by secretin, somatostatin, and PGE(2). Am J Physiol Gastrointest Liver Physiol 278:G121-7
Jyotheeswaran, S; Li, P; Chang, T M et al. (2000) Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats. Pancreas 20:401-7
Song, Y; Li, P; Lee, K Y et al. (1999) Canine pancreatic juice stimulates the release of secretin and pancreatic secretion in the dog. Am J Physiol 277:G731-5

Showing the most recent 10 out of 29 publications