Metabolic Effects of Insulin

Metabolic Effects of Insulin on

Cellular Uptake of Glucose

Supachai A. Basit, RMT, PhD

Overview

• Four major organs

play a dominant role

in fuel metabolism

• Integration of energy

metabolism is

controlled primarily

by the actions of

insulin and glucagon

Insulin

• Polypeptide hormone

produce by the beta cells

of the islet of Langerhans

of the pancreas

• Most important hormone

coordinating the use of

fuels by tissues

• Metabolic effects

anabolic

– Favoring the synthesis of

glycogen, triacylglycerols

and protein

Structure of Insulin

• 51 amino acids

• Polypeptide A and B, linked together by a

disulfide bridges

• Intramolecular disulfide bridge between

amino acid residues of the A chain

Synthesis of Insulin

• Two inactive precursors cleaved to form

the active hormone plus the C-peptide

• C-peptide essential for proper insulin

folding

Stimulation of Insulin Secretion

• Insulin and glucagon

secretion is closely

coordinated at the

islet of Langerhans

• Secretion is

regulated so that the

rate of hepatic

glucose production

is kept equal to the

use of glucose by

peripheral tissues

Stimulation of Insulin Secretion is

Increased by: Glucose

• ß cells contain Glut-2

transporters and have

glucokinase activity and thus

can phosphorylate glucose in

amounts proportional to its

actual concentration in blood

• Ingestion of CHO rich meal

leads to a rise in blood

glucose, which is a signal for

insulin secretion and

decrease glucagon synthesis

and release

Stimulation of Insulin Secretion is

Increased by: Amino Acids

• Ingestion of protein

causes a transient

rise in plasma amino

acids level, which in

turn induces the

secretion of insulin

• Elevated plasma

arginine stimulates

insulin secretion

Stimulation of Insulin Secretion is

Increased by: Gastrointestinal Hormones

• Cholecytoskinin and gastric-

inhibitory peptide increased

insulin secretion

• Incretins

• Released from SI in response

to oral glucose and cause

anticipatory rise in insulin levels

• This may account for the fact

that the same amount of

glucose given orally induces a

much greater secretion of

insulin that is given

intravenously

Inhibition of Insulin Secretion: Epinephrine

• Scarcity of dietary fuels and during

the period of stress

• Direct effect on energy metabolism

causing glycogenolysis and

gluconeogenesis

• Can override the normal glucose-

stimulated release of insulin

• In emergency situation, the

sympathetic nervous system

largely replaces the plasma

glucose concentration as the

controlling influence over ß cells

secretion

Metabolic Effects of Insulin:

Carbohydrates Metabolism

• Promotes storage in 3

tissues

• In liver & muscle, increase

glycogen synthesis

• In muscle and adipose,

increase glucose uptake

by more GLUT-4

• Insulin decreased the

production of glucose by

inhibiting glycogenolysis

and gluconeogenesis

GLUT-4 Transport Protein

Metabolic Effects of Insulin:

Lipid Metabolism Decrease TAG

Degradation

• Insulin inhibits

hormone-sensitive

lipase

• Insulin acts by

promoting the

dephosphorylation and

hence inactivation of

enzymes

Increase TAG Synthesis

• Insulin increases the

transport and metabolism

of glucose into adipocytes

providing substrate for

glycerol-3-phosphate for

TAG synthesis

• Increases the lipoprotein

lipase, thus providing

fatty acids for

esterification

Metabolic Effects of Insulin:

Protein Synthesis

• Insulin stimulates

the entry of amino

acids into cells, and

protein synthesis

through activation of

factors required for

translation

Insulin binds to specific, high

affinity receptors in the cell

membrane of most tissues

including liver, muscle and

adipose tissue. The following

should be considered

1. Insulin receptor

2. Signal transduction

3. Membrane effects of

insulin

4. Receptor regulation

Mech

an

ism

of

Insu

lin

Acti

on

Membrane Effects of Insulin

• Glucose transport increases in the presence of insulin as this

promotes the recruitment of insulin-sensitive glucose transporter

(GLUT-4) from a pool located in intracellular vesicles

Characteristics of Glucose Transport in

Various Tissues

Receptor Regulation

• Binding of insulin is

followed by internalization

of the hormone-receptor

complex

• Once inside the cell, the

insulin is degraded in the

lysosomes

• The receptors may be

degraded but most are

recycled to the cell

surface