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 .