Insulin By Dr. Beenish Zaki

Senior Instructor Department of Biochemistry

Objectives

Insulin structure, synthesis, secretion.

Insulin receptor.

GLUT transporters.

Mechanism of insulin action. Degradation. Regulation.

Clinical manifestations of DKA

Insulin structure

Insulin is protein in nature.

It has Two polypeptide chains.

A Chain has 21 amino acid

B chain has 30 amino acid

Held together by disulphide bonds.

Difference between various Insulin

The Insulin can be derived from animal sources such as cow, pig.

The difference is in the B chain at 30th Amino acid.

Human being has Threonine

Bovine and pig have Alanine

Insulin

Produced by the Beta Cell of Islet cell of Langerhans in Pancreas

Synthesis of Insulin

Insulin is made as Pre Pro Insulin in the ribosomes. The leader stand is cleaved by proteases in the cell leading to stable ProInsulin.

ProInsulin is stored in the beta cells of Pancreas. ProInsulin is a single polypeptide chain with 86 amino acids.

Active Insulin has missing connecting peptide also know as C-peptide which is released in circulation.

How do we sense high blood sugar and release Insulin?

The beta cells are permeable to glucose.

The glucose is phosphorylated through Glucokinase.

Increasing blood glucose causes increase in glycolysis, TCA and generation of ATP.

Increased ATP generation inhibits ATP-sensitive K+ Channel causing membrane depolarization of cell membrane.

This causes Increase of Calcium stimulating exocytosis of Insulin.

Insulin Release

Glucose Transport from Lumen to Intestinal Cell

SGLuT-1 Transporters

Glucose has specific transporters which are trans membrane proteins.

Glucose Transport from Lumen to Intestinal cells happens because of SGLuT-1 by secondary active transport

Release of Glucose from Intestine to Blood

SGLuT

The same intestinal cells have a different transport mechanism facing capillaries.

They release glucose to blood stream by mechanism called Glucose transporter type (GluT 2)

This transporter is not dependent on sodium.

It is a uniport facilitated diffusion system.

GLUT 2 In Kidney

Glucose Transporter 4

Major transporter in skeletal muscles and adipose tissues.

Called GLUT 4

Under control of Insulin

Insulin induces the movement of GLUT4 molecules to the cell surface and Increases Glucose uptake.

GLuT 4 Mechanism

Glucose Transporters

Tissue Location Function

Facilitative bidirectional transporters

GLUT 1 Brain, Kidney, Colon, erythrocytes

Glucose uptake

GLUT 2 Liver, pancreatic beta cell, small intestine and kidney

Rapid uptake or release of Glucose

GLUT 3 Brain and Kidney Glucose uptake

GLUT 4 Heart and skeletal muscle, adipose tissue

Insulin-stimulated glucose uptake

GLUT 5 Small intestine Absorption of gluocse

Glucagon

Produced by the Alpha Cell of Islet cell of Langerhans in Pancreas

Tissue response to Insulin and Glucagon

Liver Adipose TissueGlu

Muscle

Increased by Insulin

Fatty acid synthesisGlycogen synthesisProtein synthesis

Glucose uptakeFatty acid synthesis

Glucose uptake

Decreased by Insulin

Ketogenesis Gluconeogenesis

Lipolysis

Increased by Glucagon

GlycogenolysisGluconeogenesisKetogenesis

Lipolysis

Glucagon opposes the action of Insulin

Secretion is stimulated by hypoglycemia

Effects only the liver.

Has no effect on muscle phosphorylase.

Acts by causing hyperglycemia through glycogenolysis and gluconeogenesis.

DKA