Secretin is not necessary for exocrine pancreatic development and growth in mice

Abstract

Adaptive exocrine pancreatic growth is mediated primarily by dietary protein and the gastrointestinal hormone cholecystokinin (CCK). Feeding trypsin inhibitors such as camostat (FOY-305) is known to induce CCK release and stimulate pancreatic growth. However, camostat has also been reported to stimulate secretin release and, because secretin often potentiates the action of CCK, it could participate in the growth response. Our aim was to test the role of secretin in pancreatic development and adaptive growth through the use of C57BL/6 mice with genetic deletion of secretin or secretin receptor. The lack of secretin in the intestine or the secretin receptor in the pancreas was confirmed by RT-PCR. Other related components, such as vasoactive intestinal polypeptide (VIP) receptors (VPAC(1) and VPAC(2)), were not affected. Secretin increased cAMP levels in acini from wild-type (WT) mice but had no effect on acini from secretin receptor-deleted mice, whereas VIP and forskolin still induced a normal response. Secretin in vivo failed to induce fluid secretion in receptor-deficient mice. The pancreas of secretin or secretin receptor-deficient mice was of normal size and histology, indicating that secretin is not necessary for normal pancreatic differentiation or maintenance. When WT mice were fed 0.1% camostat in powdered chow, the pancreas doubled in size in 1 wk, accompanied by parallel increases in protein and DNA. Camostat-fed littermate secretin and secretin receptor-deficient mice had similar pancreatic mass to WT mice. These results indicate that secretin is not required for normal pancreatic development or adaptive growth mediated by CCK.

Genetic deletion of Rab27B in pancreatic acinar cells affects granules size and has inhibitory effects on amylase secretion

“…Immunofluorescence was performed as described previously [19]. Briefly, pancreatic tissues were fixed for 30 min in 4% formaldehyde (freshly prepared from paraformaldehyde) in PBS, cryoprotected as described [19], embedded in a 1:1 mixture of OCT and 20% sucrose and then 6 μm sections were cut with a CM 1950 Leica Cryostat.…”

“…Briefly, pancreatic tissues were fixed for 30 min in 4% formaldehyde (freshly prepared from paraformaldehyde) in PBS, cryoprotected as described [19], embedded in a 1:1 mixture of OCT and 20% sucrose and then 6 μm sections were cut with a CM 1950 Leica Cryostat. The primary polyclonal anti-amylase antibody, and Oregon Green 488 Phalloidin which stains F-actin were diluted 1:1,000, and 1:50, respectively.…”

Regulation of Normal and Adaptive Pancreatic Growth

“…Until recently the most common technique was dissecting and weighing the pancreas. This yields values for young adults, usually males, fed a control diet, of 8-12 mg pancreatic weight/g body weight for mice (22,64,120,125,143), 22.5 mg PW/gBW for Syrian Hamster (124), 2.5-4 mg PW/g BW for rats (25,34,40,57,123,158), and 0.5-1.1 g PW/kg BW for adult humans (13,127). Note that the relative pancreas size gets smaller as the animal gets larger.…”

“…In both rats and mice the adaptive growth is reversible and when the TI is removed the pancreas returns to its original size (21, 105,106). No dependence on secretin was seen in mice as TI had similar effects in mice where secretin signaling was genetically deleted (120). The evidence as to whether such a feedback loop involving CCK occurs in humans is mixed and may involve proteases other than trypsin (36,72,73).…”

Secretin

“…Secretin also increased the content of polyamines in the pancreas which accompanies and is required for growth (28). However, studies in mice with genetically deleted secretin or secretin receptor showed a normal sized pancreas which grew normally in response to elevated endogenous CCK (87). Another proposed action of secretin not fully evaluated is to stimulate the synthesis of pancreatic lipase.…”