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