hormones of gastrointestinal tract
DESCRIPTION
hormonesTRANSCRIPT
M.Prasad NaiduMSc Medical
Biochemistry,Ph.D.Research Scholar
The acinar portion of pancreas has exocrine function .
Endocrine portion consists of islets of langerhans.
Insulin is hetero dimeric polypeptide . Insulin gene is located on short arm of
chromosome 11 . Insulin is synthesized as a preproinsulin ( 86
AA) .
The location of 3 disulfide bonds is invarient & the A & B chains have 21 & 30 amino acids respectively in most species .
Substitutions occur commonly at 8 , 9 , 10 positions of the A chain thus this region is not crucial for bioactivity .
Zinc is present in high concentrations in B cell & forms complexes with insulin & proinsulin .
The proinsulin molecule undergoes a series of site specific peptide cleavages that results in formation of equimolar amounts of mature insulin & C – peptide .
Mature insulin & C peptide are present together in the secretory granule .
C – peptide is less susceptible than insulin to hepatic degrdation , & it is a distinct molecule from an antigenic stand point .
Glucose level more than 70mg/dl stimulates insulin synthesis , primarily by enhancing protein translation & processing .
Glucose is the key regulator of insulin secretion .
Elevated plasma arginine is a potent stimulus for insulin synthesis & secretion .
The intestinal peptides cholecystokinin & gastric inhibitory polypeptide increase insulin secretion in response to oral glucose & so are referred to as incretins .
Chronic exposure to excessive levels of GH , cortisol, placental lactogen , estrogen & progestins increase insulin secretion .
The synthesis & release of insulin are decreased when there is scarcity of dietary fuels & also during periods of stress .
Alpha adrenergic agonist principally epinephrine , inhibits insulin release even when this process was stimulated by glucose .
Beta adrenergic agonists stimulate insulin release , probably by increasing the intracellular c AMP .
Plasma half life of insulin is 3 – 5 minutes under normal conditions .
The major organs involved in insulin metabolism are liver , kidney & the placenta .
Insulin specific protease & hepatic glutathione transhydrogenase are involved in degradation of insulin .
Effect on membrane transport : insulin promotes glucose entry into muscle & adipose tissue .
The transporter translocation is temperature & energy dependent & is protein synthesis independent .
Insulin promotes amino acid entry into cells particularly in muscle & enhances the movement of K+ , Ca ++ , nucleotides , & inorganic phosphate . These effects are independent of action of glucose entry .
Insulin increases hepatic glycolysis by increasing the activity & amount of glucokinase , phosphofructokinase , & pyruvate kinase .
Insulin decreases the activity of glucose 6 phosphatse , an enzyme found in liver not in muscle.
In skeletal muscle insulin stimulates glucose entry through transporters & also increases hexokinase II
Insulin stimulates lipogenesis in adipose tissue .
1. By providing acetyl CoA & NADPH required for fatty acid synthesis .
2. By maintaining normal level of enzyme acetyl CoA carboxylase &
3. By providing glycerol involved in the TAG synthesis .
Lipogenesis is decreased in insulin deficiency .
Increased fatty acids in circulation due to several hormones unopposed action by insulin .
Free fatty acids feed back inhibit their own synthesis by inhibiting acetyl CoA carboxylase .
Free fatty acids inhibit glycolysis at several steps & stimulates gluconeogenesis .
In liver & muscle insulin stimulates conversion of glucose to glucose 6 phosphate ( by the actions of glucokinase & hexokinase II resepectively .
Glucose 6 phosphate is isomerized to glucose 1 phosphate & is incorporated into glycogen .
Glycogen synthase is stimulated by insulin . Insulin inhibits the enzyme phosphorylase . The net effect of insulin on glycogen metabolism
is anabolic .
Effect on glucose production : insulin decreases the key gluconeogenic enzyme phospho enol pyruvate carboxy kinase ( PEPCK ) by selectively inhibiting transcription of gene that codes for mRNA for PEPCK .
Effects on lipid metabolism : insulin is a potent inhibitor of lipolysis in liver & adipose tissue .
The above action is due to its ability to decrease cAMP levels by activating phosphodiesterases .
Insulin inhibits hormone sensitive lipase by the action of phosphatase .
Insulin affects the formation or clearance of VLDL & LDL .
Effects on protein metabolism : insulin promote protein synthesis & retards protein degradation .
The effect of insulin on protein synthesis in skeletal & cardiac muscle & in liver are thought to be exerted at the level of mRNA translation .
Insulin shown to influence the synthesis of specific proteins by effecting changes in corresponding mRNAs.
Insulin activates a protein kinase path way that results in activation of eIF – 4E , a factor essential for the rate limiting step in protein synthesis .
The regulation of mRNA synthesis is a major action of insulin
Insulin decrease transcription of PEPCK gene leading to decreased amount of primary transcript & of mature mRNA .
More than 100 specifc mRNA by insulin.
• Effects on cell replication : insulin stimulates the proliferation of number of cells in culture & it may also be involved in the regulation of growth invivo .
• Insulin potentiats the ability of1.Fibroblast growth factor ,2.PDFG 3.EGF4.Tumor promoting phorbol esters5.PGF2 alpha6.Vasopressin & cAMP analougues
Insulin receptor along with PDGF & EGF has tyrosine kinase activity .
oncogene products involved in stimulating malignant cell replication are also tyrosine kinases.
Mammalian cells contain analogs of these oncogenes ( protooncogenes ) which may be involved in the replication of normal cells .
Expression of two protooncogene products , c – fos , c – myc increases following addition of insulin & PDGF to growth arrested cells .
Glucagon is synthesized as precursor molecule. Half life of glucagon is 5 minutes . Glucagon is inactivated by liver an enzyme
removes 1st 2 aminoacids from the amino terminal end by cleaving Ser 2 & Gln 3 .
Secretion of glucagon is inhibited by glucose . Glucagon binds to specific receptors &
activates adenylyl cyclase through G protein linked mechanism .
The cAMP activates phosphorylase , which enhances glycogenolysis while inhibiting glycogen synthase enzyme .
Glucagon through cAMP , increase the rate of transcription of mRNA from PEPCK gene & stimulates synthesis of more PEPCK .
PEPCK is the rate limiting enzyme gluconeogenic pathway .
Glucagon is a potent lipolytic agent , it increases adipose cell cAMP & this activates hormone sensitive lipase .
D cells of islets synthesize large somatostatin prohormone .
The rate of transcription of prosomatostatin is gene is markedly increased by enhanced cAMP .
Somatostatin inhbits the release other islet cell hormones through a paracrine action .
In CNS it acts as neurotransmitter , in GIT it decreases the delivery of nutrients into the circulation .
Two families of GI horomones gastrin family & secretin family .
Gastrin family consists of gastrin & cholecystokinin .
Secretin family includes secretin , glucagon , gastric inhibitory polypeptide (GIP ) , Vasoactive intestinal peptides .