structure& function of insulin,glucagon by dr. ashok kumar jeppu
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Structure& function of Insulin, glucagon
Dr. Ashok Kumar Jeppu
Management and Science University
Malaysia
Historical Aspects
Insulin - Latin word insula = islets
1922 Banting and Best extracted insulin from pancreas
First hormone to be isolated in pure form
First protein to be sequenced ( by Sanger)
First protein produced by recombinant technology
Structure of Insulin
• Protein hormone
• Has two polypeptide chain• A chain (21 amino acids)
• B chain (30 amino acids)
• A and B chain joined by two inter-chain disulfide links • A7 and B7
• A20 and B19
• There is a intra-chain disulfide bond in A chain between • A6 and A 11
Structure of Insulin
Synthesized as a large precursor Pre-proinsulin
(109 amino acids)
• Rough endoplasmic reticulum
23 amino acids from the amino terminal
( leader or signal sequence)
is removed in endoplasmic reticulum – Proinsulin
(86 amino acids)
• Endoplasmic reticulum
Proinsulin is cleaved by a protease to form Insulin
(33 amino acids removed)
• Golgi apparatus
Insulin packed into granules
Insulin takes the shape of hexamer
with 2 zinc ions and one calcium ion
About 50 units of insulin secreted per
day
Normal insulin level in blood 5 to 15 micro units/ml
Insulin and C peptide secreted
in equimolarconcentration
Glucose Transporters
Insulin secretion
Insulin secretion
Glucose enters beta cells Via GLUT 2
Metabolized to form ATP
ATP binding cassette (ABC) protein
stimulated
Potassium channels are closed and
calcium channels are opened
Increased intracellular
calcium
Secretion of insulin
Tyrosine kinase activity of β subunits
“autophosphorylation”
Biologic effects
Insulin receptor substrates (IRS)
Facilitates uptake of glucose by muscle adipose tissue etc.
Increase the rate of
Glycolysis
Increases Utilization of glucose
Fatty Acid Cholesterol
Activation of
• Glucokinase
• Phosphofructokinase – 1
• Pyruvate kinase
GLUCOSE
Activation of
• Pyruvate dehydrogenase
Activation of
• Acetyl CoA carboxylase; fatty acid synthase complex
• Increased activity of glucose 6 phosphate dehydrogenase
(Increased Lipogenesis)
Activation of
• HMG CoA reductase
Increases Utilization of glucose conti…..
GLUCOSE
Activation of
• Glycogen synthase
inactivation of
• Glycogen phosphorylase
GLUCOSE
Non carbohydrate substances
Repressing the enzyme (Decreasing the synthesis of)
• Pyruvate carboxylase
• Phosphoenol pyruvate carboxykinase (PEPCK)
• Fructose 1,6 bisphosphate
• Glucose-6- phosphatase
Decreases the rate of Gluconeogensis
Fatty Acid Glycerol
Inhibiton of
• Hormone Sensitive Lipase (HSL)
Anti-lipolytic effect
• Anti-ketogenic effect• Decreases HMG CoA synthase activity
• Protein synthesis is promoted
• Protein break down is retarded
• Movement of Potassium and phosphorous into the cells is facilitated
• At the transcriptional level regulates the synthesis of various proteins
• Insulin activates phosphodiesterase and which helps to activate or inactivate the enzyme proteins
LipogenesisGo
Glucagon
• Polypeptide hormone
• 29 amino acids
• Secreted by alpha cells of the pancreas
• Amino acid sequence of glucagon is the same in all mammalian species
• Synthesized as a large precursor – preproglucagon
• Converted to glucagon through series of proteolytic cleavages
• Half life is about 5 minute in the liver
• Inactivated in the liver
Stimulation of glucagon secretion
• Low blood glucose
• Amino acids ( arginine)
• Catecholamines ( epinephrine and norepinephrine)
Inhibition of glucagon secretion
• Elevated blood glucose and by insulin
Mechanism of action of Glucagon
Physiologic actions of Glucagon
Hyperglycemic hormone
Increases the rate of
• Glycogen breakdown (glycogenolysis)
( Activates glycogen phosphorylase and inhibits Glycogen synthase)
• Gluconeogenesis
(Increasing the synthesis of key enzymes of gluconeogenesis)
Effect on lipid metabolism• Inhibits lipogenesis
• By inhibiting the enzyme Acetyl CoA carboxylase
• Has a role in lipolysis in adipose tissue• Activating the enzymes hormone sensitive lipase
Effect on protein metabolism
• Increases the uptake of amino acids by the liver – increasing the availability of the amino acids for gluconeogenesis
Thank you
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