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Metabolic effects of insulin & glucagon. ENDO412. Introduction. Fuels are biomolecules (as carbohydrates, lipids & proteins) that can yield energy in the form of ATP on (catabolism or degradation). This energy (ATP) that can be used for all biological processes of the cells.

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introduction
Introduction

Fuels are biomolecules (as carbohydrates, lipids & proteins) that can yield

energy in the form of ATP on (catabolism or degradation). This energy (ATP) that can

be used for all biological processes of the cells.

Fuels can be also stored in certain sites of the body in the form of larger molecules

(anabolism or building) to be released in case of demand.

These procedures (catabolism & anabolism) are called energy metabolism.

Energy metabolism occurs mainly in 4 organs; liver, adipose, muscles & brain, in

which energy is stored, produced & released according to needs of the body.

These 4 organs communicate in a way that one of them produces substrates for another.

Among these 4 organs, energy metabolism is integrated & regulated primarily by the action of insulin & glucagon

(with catecholamines plays a supporting role).

introduction cont
Introduction(cont.)
  • In conclusion:

In case of well-fed state (directly after ingestion of a meal):

There is a abundance of energy yielding fuels (glucose etc..) more than actual body needs for energy.

Excess of fuels (energy) is stored by help of INSULIN hormone.

(anabolic pathways)

In case of stress or prolonged fasting (post absorptive):

These is a lack in energy-yielding fuels to give sufficient energy to all body.

Stored fuels are released to be available for used by cells of the body by the help

of GLUCAGON hormone.

Also, epinephrine plays a role in this status.

(catabolic pathways)

insulin
Insulin

Generally, insulin hormone is:

  • a polypeptide hormone
  • produced by b-cells of islets of Langerhands (1-2% of cells of the pancreas).
  • the most important hormone coordinating the use of fuels by tissues.
  • of anabolic metabolic effects favoring synthesis of glycogen, triacylglycerol (storing of energy) & proteins
structure of insulin
Structure of insulin
  • Insulin is protein composed of 51 amino acids,
  • which are arranged in 2 polypeptide chains A & B linked together by 2 disulfide bridges (in addition to intrmolecular disulfide bridges between amino acids of the A chain)
synthesis secretion of insulin
Synthesis & secretion of insulin

Preproinsulin(inactive precursor)

in ER

Proinsulin(inactive precursor)

Golgi apparatus

Insulin + C-peptide

Insulin & C-peptide are stored in cytosol as granules

To be released by certain stimulus by exocytosis to blood

C-peptide has a longer half-life in the plasma more than insulin.

& hence is a good indicator of insulin production & secretion in early cases of DM

regulation of secretion of insulin
Regulation of secretion of insulin
  • Insulin secretion by b-cells is coordinated with the release of glucagon by a-cells.
  • Relative amounts of insulin & glucagon released from the pancreas are regulated so that the rate of liver glucose production is equal to use of glucose by peripheral tissues.
  • In short:

Insulin is required for storing of glucose in liver.

Glucagon is required for releasing glucose from its stores in liver.

So, both hormones secretion from pancreas has to be regulated according to needs of the body.

regulation of secretion of insulin cont
Regulation of secretion of insulin (cont.)

1-Factors stimulating of insulin secretion:

- Glucoseingestion (or carbohydrate rich meals)

- Amino Acids

- Gastrointestinal hormones (as cystokinines & gastric-inhibitory polypeptides) increase

insulin secretion in response to oral glucose

2-Factors inhibiting insulin secretion:

Decrease of synthesis of insulin occurs when there is a scarcity of diet fuel & during periods of stress.

These effects are mediated by epinephrine, which causes rapid mobilization of energy-yielding fuels (including glucose from liver & fatty acids from adipose tissue).

Epinephrine binds to a-adrenergic receptors on b-cells resulting in decrease of insulin secretion.

metabolic effects of insulin
Metabolic effects of insulin

Carbohydrates Metabolism

Promotes storage of glucose

LiverMusclesadipose

Glycogen Glycogen uptake of

Synthesis Synthesis glucose

Gluconeogenesis Intake of

glucose

Glycogenlysis

Lipids Metabolism

TAG TAG

Degrad. Synth

Protein Synthesis

Entry of AA into cells

Protein Synth.

mechanism of action of insulin
Mechanism of action of insulin

Binding

Of Insulin on a-cells

Phosphorylationof

b-subunits

Phosphorylation

of IRS

CHANGES

IN

Gene Metabolism Growth

Expression

mechanism of action of insulin membrane effects of insulin
Mechanism of action of insulin(Membrane effects of insulin)

Glucose transport in some

tissues as skeletal muscles

& adipocytes increase in

the presence of insulin

Insulin promotes the

recruitment of insulin-sensitive

glucose transporters (GLUT-4)

from a pool located in

intracellular vesicles

N.B. Some tissues do not depend on insulin for glucose transport

As Liver cells, RBCs, neurons, intestinal mucosa, renal tubules & cornea

time course of action of insulin
Time course of action of insulin

Binding of insulin to its receptors on various cells provoke a

wide range of actions that varies in time course.

Some may occur immediately within few seconds, while others need

days

Immediate(within seconds): increased glucose transport into adipose tissue & sk. ms.

(membrane effect)

Within minutes to hours: changes in activity of enzymes.

(phosphorylation of proteins i.e. enzymes)

Within hours to days: increase amounts of many enzymes

(increase in gene expression with increase in mRNA & enzyme synth.)

down regulation of action of insulin receptor regulation
Down regulation of action of insulin(Receptor Regulation)

Binding of insulin to its receptors is followed by internalization of hormone-

receptor complex.

Once inside cells, insulin is degraded in lysosomes.

Receptors are either degraded or recycled to cell surface.

Elevated levels of insulin promote the degradation of receptors, with a decrease in

the number of surface receptors (a type of down regulation)

glucagon
Glucagon
  • Glucagon is a single polypeptide chain hormone secreted by a-cells of islets of Langerhands of the pancreas.
  • It is one of a group of hormones (glucagon, epinephrine, cortisol & growth hormone) that oppose many actions of insulin (anti-insulin hormones or diabetogenic hormones).
  • Glucagon mainly acts by maintaining blood glucose level by increasing glycogenlysis & gluconeogenesis in liver cells.
stimulation of glucagon actions
Stimulation of glucagon actions

a-cells are responsive to a variety of stimuli that signal hypoglycemia (actual or about to occur)

Glucagon secretion is increased by:

1- Low blood glucose in blood:

During an overnight or prolonged fasting, elevated glucagon levels prevent hypoglycemia.

2- Amino acids:

Amino acids released from meals containing protein stimulate both glucagon & insulin.

In this case, glucagon prevents the hypoglycemia that would occur as a result of increased insulin

secretion after a protein meal.

3- Epinephrine:

Epinephrine is released either by adrenal medulla or by sympathetic innervations of pancreas or both)

in cases of stress, trauma or severe exercise.

In these cases, glucagon levels are elevated to be ready for the possibility of increased glucose use.

inhibition of glucagon actions
Inhibition of glucagon actions

Glucagon secretion is significantly decreased by :

- Elevated blood glucose

- Insulin

Both substances are increased following ingestion of glucose or

carbohydrate-rich meal

metabolic effects of glucagon
Metabolic effects of glucagon

Carbohydrates Metabolism

Increases blood glucose

Liver

Glycogenlysis

Gluconeogenesis

Lipids Metabolism

TAG

Degrad.

in adipose tissue

fatty acids

in liver

ketone bodies

(ketpgenesis)

Protein Metabolism

Uptake of AA by liver

Carbon skeleton for gluconeogenesis