
autonomic nervous system, illustrating the complex
interaction between endocrine, neurocrine, and para-
crine systems. Gastrin release is stimulated directly by
the ingestion of food, especially protein, and by the
neuropeptide GRP, which is itself released by choli-
nergic stimulation. Gastrin secretion is inhibited by
acid, and by somatostatin, acting in a paracrine
manner. The ingestion of fat, once the fat has passed
though the stomach and into the small intestine, in-
hibits gastric acid secretion via the stimulation of GI
hormones GIP, glucagon-like polypeptide-1 (GLP-1),
and CCK. It seems likely that their modes of action
vary and include both direct inhibitory effects on
parietal cells, as in the case of CCK, and indirect
effects on acid secretion via gastrin and somatostatin.
0010 Pancreatic exocrine secretion contains two major
components. The first is an aqueous solution contain-
ing a high concentration of bicarbonate whose
function is to neutralize acid entering the duodenum
from the stomach. The second is a solution of
enzymes which aid the absorption and digestion of
carbohydrate, fat, and protein. Secretin and cholecys-
tokinin are traditionally thought to be responsible for
pancreatic exocrine secretion, but other gut peptides,
notably vasoactive intestinal peptide (VIP), neuroten-
sin, and pancreatic polypeptide, may also influence
secretion. Secretin is responsible for most of the water
and bicarbonate secretion. CCK acts synergistically
with secretin to augment pancreatic bicarbonate
output, and interactions between neurotensin and
secretin also appear to be important. During diges-
tion, pancreatic exocrine secretion is partly controlled
by efferent vagal fibers, mediated by VIP. Pancreatic
polypeptide inhibits pancreatic secretion and may
be involved with the damping-down of pancreatic
exocrine secretion following a meal.
0011 CCK has been considered a major hormone con-
trolling gallbladder emptying, and release of pancre-
atic enzymes. However, the lack of reliable assays
to measure circulating levels of CCK has caused dif-
ficulty in ascribing a physiological, as opposed to
pharmacological, role for the hormone. Recent stud-
ies using CCK-A (the predominant CCK receptor
found in the pancreas and gallbladder) receptor
antagonists have confirmed the role of CCK as
the primary stimulator of gallbladder contraction,
although the effects of CCK receptor antagonists on
pancreatic secretion are less clear, probably reflecting
multiple pathways of control for pancreatic exocrine
secretion.
Gastric Emptying and Gut Motility
0012 Between the striated muscles of the esophagus and the
external anal sphincter, which are dependent upon
efferent nerves for proper functioning, lie the smooth
muscles which form the bulk of the GI tract. They are
capable of executing their function without extrinsic
innervation, and sympathetic and parasympathetic
nerves act only in a modulatory capacity. The intrin-
sic nerves of the gut form two major networks or
plexi: the myenteric plexus which lies between the
longditudinal and circular muscles of the gut, and the
submucous plexus, which lies between the mucosa
and circular muscle layer. Control of gut motility
involves many neuronally located gut peptides. Re-
ceptors for many peptides have been located on gut
smooth muscle cells, including motilin, the opioid
peptides, the tachykinins, VIP, and neuropeptide Y.
0013Regulation of the rate of gastric emptying depends
on many factors, including the physical state and size
of the meal and its macronutrient content. Three
endocrine gut hormones have been implicated in the
control of gastric emptying. Secretion of CCK is
responsible for the delay in gastric emptying when
fat is added to a meal; the presence of fat in the
duodenum is a powerful stimulus for CCK release.
GLP-1, secreted in response to the presence of all
three macronutrients in the upper small intestine,
also delays gastric emptying and regulates the influx
of nutrients into the upper part of the gut. Peptide YY,
which is colocalized and often cosecreted with GLP-
1, inhibits gastric emptying and also small intestinal
motility. It has been termed the ‘ileal brake’ and
its actions following a meal are thought to enable
sufficient time to occur for the meal’s absorption.
Following the ingestion of food, waves of alternate
contraction and relaxation descend from the gut, fa-
cilitating the passage of food and aiding its absorp-
tion. VIP causes smooth muscle relaxation and its
distribution is consistent with the role of a transmitter
in the descending inhibitory nerves. Opioid peptides
increase the contractile activity of the gut and their
net effect is to slow the transit of food. The tachyki-
nins also have potent exitatory and spasmogenic
effects on smooth muscle and appear to be involved
in regulation of the peristaltic reflex.
0014When fasting is prolonged, interdigestive myoelec-
tric complexes occur. These are waves of contraction
beginning in the stomach which move slowly down
the small intestine, whose function is to clear out the
intestine between feeds and keep the intraluminal
bacterial population low. Motilin is primarily in-
volved in the regulation of this interdigestive activity.
Potentiation of Insulin Secretion and other
Metabolic Effects
0015One of the more important metabolic actions of gut
hormones is their ability to modulate insulin secre-
tion. Orally administered glucose leads to far higher
circulating insulin levels than the same amount of
3148 HORMONES/Gut Hormones