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Hormones of the Pancreas & Gastrointestinal tract M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
Hormones of the Pancreas • The acinar portion of pancreas has exocrine function . • Endocrine portion consists of islets of langerhans.
Insulin • Insulin is hetero dimeric polypeptide . • Insulin gene is located on short arm of chromosome 11 . • Insulin is synthesized as a preproinsulin ( 86 AA) .
contd • The location of 3 disulfide bonds is invarient & the A & B chains have 21 & 30 amino acids respectively in most species .
contd • Substitutions occur commonly at 8 , 9 , 10 positions of the A chain thus this region is not crucial for bioactivity .
contd • Zinc is present in high concentrations in B cell & forms complexes with insulin & proinsulin .
contd • 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 .
contd • C – peptide is less susceptible than insulin to hepatic degrdation , & it is a distinct molecule from an antigenic stand point .
Synthesis of insulin • Glucose level more than 70mg/dl stimulates insulin synthesis , primarily by enhancing protein translation & processing .
Insulin secretion is precisely regulated • Glucose is the key regulator of insulin secretion .
contd • 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 .
contd • 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 .
Insulin is rapidly metabolized • 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 .
Metabolic effects 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 .
contd • 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 .
Effect on glucose utilization • 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
contd • Insulin stimulates lipogenesis in adipose tissue . • By providing acetyl CoA & NADPH required for fatty acid synthesis . • By maintaining normal level of enzyme acetyl CoA carboxylase & • By providing glycerol involved in the TAG synthesis .
contd • 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 .
contd • 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 .
contd • 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 .
contd • 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 .
contd • 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.
contd • 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 .
Insulin affects gene expression • 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.
contd • 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 of • Fibroblast growth factor , • PDFG • EGF • Tumor promoting phorbol esters • PGF2 alpha • Vasopressin & cAMPanalougues
contd • 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 an insulin antagonist • 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 .
contd • 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 .
Somatostatin inhibits growth hormone secretion • 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 .
Gastrointestinal hormones • 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 .
