ENDOCRINE SYSTEM
DR.AMJAD H. ABID LECTURE (3)GIT HORMONES
GIT is regarded as the largest endocrine organ in the body. Collectively, GIT hormones influence motility, secretion, digestion, and absorption in the gut. In addition, they regulate bile flow, secretion of pancreatic hormones; affect tonicity of vascular walls, blood pressure and cardiac output. The principle GIT hormones include:- Gastrin
- Secretin- Cholecystokinin- pancreozymin (cck- pz)
- Vocative intestinal polypeptide (VIP)
- Gastric inhibitory polypeptide (GIP)
- Others
Gastrin
There are 3 molecular forms of gastrin that are present in the blood circulation and tissues and these are:1. Big Gastrin; which is a linear polypeptide of 34 amino acids called as (G- 34).
2. Little gastrin; which is a linear polypeptide of 17amino acids called as (G- 17).
3. Minigastrin; which is a linear polypeptide of 14 amino acids called as (G- 14).
However, they all exert the same biological effects on the target cells. Gastrin is secreted and stored by endocrine cells called as (G cells) mainly in the antral mucosa of the stomach, and to a lesser extent by G cells of the proximal part of the duodenum, and by (D- cells) of the pancreas. Following secretion to the blood stream, the main circulating form is (G- 34). Gastrin has the following main functions:
1. Stimulates the fundal parietal cells to secrete the gastric acid.
2. Stimulates gastric mucosal cells to secrete pepsinogen and intrinsic factor.3. Stimulates small intestinal mucosal cells to secrete a hormone called (secretin).
4. Stimulates the secretion of pancreatic enzymes and bicarbonate (HCO3-).
5. Provokes gastric and intestinal motility.
6. Enhances gastric mucosal growth.
7. Stimulates hepatic bile flow.
The main stimulus for the release of gastrin is antral dilatation due to presence of food in the stomach mainly protein digestion products (polypeptides, peptides, and amino acids). In addition, other stimuli may include:
- alcohol
- caffeine
- insulin induced hypoglycemia
- vagal stimulation (sight, smell, taste, thinking of food)
Maximum secretion of gastrin occurs at an antral pH of 5-7. However, when pH gets lower; a negative feedback mechanism will inhibit further secretion of gastrin.
Cholecystokinin- Pancreozymin
It is a (33) a.a. polypeptide hormone released from the upper small intestinal mucosal cells (I cells) mainly in the duodenum in response to:Presence of partially digested protein products in the lumen of the intestine.
Entry of gastric acid to the intestine.
Presence of fatty acids mainly in the form of micells.
As the name implies, it stimulates the gall bladder contraction, and meanwhile the secretion of pancreatic enzymes. It is present in multiple molecular forms; the most active form is the one containing the sulfated tyrosyl residue. The five a.a. sequence at the C- terminal are identical to those of gastrin. The structural similarity with gastrin makes CCK- PZ exert some gastric action mainly in stimulating intestinal motility and increasing release of pancreatic enzymes. It competes with gastrin for its intestinal receptors and this may help in terminating gastrin action following meals.
Secretin
It is a polypeptide with structural similarity with VIP, GIP and Glucagon. It is released from the granular mucosal cells (S- cells) that are mainly present in the duodenum, but however are distributed throughout the small intestine. It is called as such because it permits a good flow of pancreatic juice following meals. Secretin release is stimulated by contact of S- cells with gastric acid. However, its only inhibitor is somatostatin. The principle function of secretin is increasing pancreatic juice release with increased concentration of bicarbonate. So, it is used for testing pancreatic function. It inhibits gastrin release and thus gastric acid secretion.Vasoactive Intestinal Polypeptide (VIP)
It is a linear polypeptide of 28 a.a., has some structural similarities with secretin, GIP, and Glucagon. It is present in almost all body tissues, but mainly concentrated in the GIT and the nervous system. It is present in the nerve fibers along all of the gut from the esophagus to the colon, but mainly in the jejunum, ileum, and the colon. VIP has a large no. of ill defined non- specific physiological effects, among which are:1. Acts as a neurotransmitter in the CNS and in the autonomic nervous system of the gut.
2. Relaxation of the smooth muscle fibers in vessels walls, gut, and genito- urinary system.3. Increases pancreatic secretion.
4. Increases water and electrolytes secretion from the gut.
5. Inhibition of gastrin release and thus gastric acid secretion.
6. Increases hormonal release from the pancreas, gut, and hypothalamus.
7. Stimulation of lipolysis, glycogenolysis, and bile flow.
Gastric Inhibitory Polypeptide (GIP)
It is consisted of 42 a.a. released from [K- cells] which are located in the jeujenal and duodenal mucosa. Its main functions include:1. In the presence of hyperglycemia, like following meals, it stimulates the secretion of insulin. This is the most important action of GIP, and that is why it is called {Glucose dependant insulinotropic peptide}.
2. Decreases intestinal motility despite increased intestinal secretion of water and electrolyte.
3. In supraphysiological concentrations, it acts to inhibit gastric acid, pepsin, and gastric secretion.
Glucagon like Peptide-1 (GLP-1)
It is a linear polypeptide chain that is released from the small intestinal mucosal cells “L- cells” mainly in response to elevated blood glucose levels soon after meals. It has some structural similarities with glucagon, however their actions are totally different.It acts to lower blood glucose levels by mechanisms similar to those of GIP, i.e. reducing GIT motility and gastric acid- pepsin secretion, in addition to affecting the satiety center in the brain to decrease food intake. However, its main action is stimulating pancreatic B-cells to release further insulin in response to high blood glucose to an extent that may even result in B-cells mass hypertrophy.
GIP and GLP-1 roles in treatment of diabetes
Both incretins (GIP & GLP-1) are of optimal benefit to control blood sugar. However, their major problem is that their half-life in the circulation is very short as they are soon degraded by the enzyme “Dipeptidyl- peptidase-4 or DPP-4” which is present in almost every body tissue. For this reason, DPP-4 inhibitors have been synthesized as potent drugs for T2DM (like Sitagliptin or Januvia 100mg tab.) to prolong the t1/2 of the incretins enabling them to stimulate insulin secretion efficiently. These drugs have been used as additive therapies to control T2DM successfully.Moreover, synthetic analogues of GLP-1 have been used (in injection forms) for the control of hyperglycemia in T2DM, eg. Exenatide and others.
Other Hormones of the Gut
Somatostatin: It is one of the most potent well- known inhibitory hormones for a lot of endocrine secretion. It inhibits the release (as well as the action on the target cells) of a lot of hormones including gastrin, secretin, GIP, insulin, glucagon, VIP, pancreatic polypeptide, and others.
Motilin: It acts to increase the contraction of the smooth muscle fibers in the upper GIT namely the lower esophageal sphincter, gastric fundus, antrum, and duodenum. Its unique feature is that its actions are restricted to fasting state only.
Pancreatic Polypeptide (PP): It is mainly secreted from the pancreas. It acts to increase and then decrease (i.e. biphasic action) the pancreatic secretion of water, electrolytes, and enzymes. Its high blood levels can be used as a landmark of pancreatic endocrine tumors.
Enteroglucagon: Is a group of substances that are released from the gut but have biological effects similar to pancreatic glucagon (i.e. catabolic hyperglycemic) although are chemically different.