Metabolic effects of Metabolic effects of insulin & glucagoninsulin & glucagon

ENDO412

IntroductionIntroduction

Fuels are biomolecules (as carbohydrates, lipids & proteins) that can yield 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 storedstored 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 metabolismenergy metabolism.

Energy metabolism occurs mainly in 4 organs; liver, adipose, muscles & brain, in Energy metabolism occurs mainly in 4 organs; liver, adipose, muscles & brain, in which energy is stored, produced & released according to needs of the body.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 These 4 organs communicate in a way that one of them produces substrates for another.another.

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

(with catecholamines play a supporting role).(with catecholamines play a supporting role).

• In conclusion:In conclusion:

In case of well-fed state (directly after ingestion of a meal):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 storedstored by help of INSULININSULIN hormone. (anabolic pathways)anabolic pathways)

In case of stress or prolonged fasting (post absorptive):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 releasedreleased to be available for usedused by cells of the body by the help of GLUCAGONGLUCAGON hormone. Also, epinephrineepinephrine plays a role in this status. (catabolic pathwayscatabolic pathways)

IntroductionIntroduction (cont.)

InsulinInsulin

Generally, insulin hormone is:Generally, insulin hormone is: • a polypeptidepolypeptide hormone

• produced by -cells-cells of islets of Langerhans (1-2% of cells of the

pancreas).

• the most important hormone coordinating the use of fuels use of fuels by tissues.

• of anabolicanabolic metabolic effects favoring synthesis of glycogen, triacylglycerol (storing of energy) & proteins

Structure of insulinStructure 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)

Preproinsulin (inactive precursor)

in ER

Proinsulin (inactive precursor)

Golgi apparatus

Insulin + C-peptideInsulin & 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

Synthesis & secretion of insulinSynthesis & secretion of insulin

Synthesis & secretion of insulinSynthesis & secretion of insulin

Regulation of secretion of insulinRegulation of secretion of insulin

• Insulin secretion by -cells is coordinated with the release of glucagon by -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 storingstoring of glucose in liver.

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

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

1- Factors stimulating of insulin secretion:Factors stimulating of insulin secretion: - GlucoseGlucose ingestion (or carbohydrate rich meals) - Amino AcidsAmino Acids - Gastrointestinal hormones Gastrointestinal hormones (as secretin & gastric-inhibitory polypeptides) increase insulin secretion in response to oral glucose

2-2- Factors inhibiting insulin secretionFactors 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,epinephrine, which causes rapid mobilization of energy-yielding fuels (including glucose from liver & fatty acids from adipose tissue).

EpinephrineEpinephrine binds to -adrenergic receptors on -cells resulting in decrease of insulin secretion.

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

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

Metabolic effects of insulinMetabolic effects of insulin

Carbohydrates MetabolismCarbohydrates Metabolism

Promotes storage of glucose

Liver Muscles adipose

Glycogen Glycogen uptake of Synthesis Synthesis glucose

Gluconeogenesis Intake of glucose

Glycogenlysis

Lipids MetabolismLipids Metabolism

TAG TAG Degrad. Synth

Protein SynthesisProtein Synthesis

Entry of AA into cells

Protein Synth..

Mechanism of action of insulinMechanism of action of insulin

Binding Of Insulin on -cells

Phosphorylationof -cells

Phosphorylationof IRS

CHANGESIN

Gene Metabolism GrowthExpression

Mechanism of action of insulinMechanism of action of insulin((Membrane effects of insulinMembrane 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 transportAs Liver cells, RBCs, neurons, intestinal mucosa, renal tubules & cornea

Binding of insulin to its receptors on various cells provoke a Binding of insulin to its receptors on various cells provoke a wide range of actions that varies in time course. wide range of actions that varies in time course.

Some may occur immediately within few seconds, while others need Some may occur immediately within few seconds, while others need daysdays

ImmediateImmediate (within seconds): (within seconds): increased glucose transport into adipose tissue & sk. ms. (membrane effect)

Within minutes to hoursWithin minutes to hours: changes in activity of enzymes. (phosphorylation of proteins i.e. enzymes)

Within hours to daysWithin hours to days: increase amounts of many enzymes (increase in gene expression with increase in mRNA & enzyme synth.)

Time course of action of insulinTime course of action of insulin

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)

Down regulation of action of insulinDown regulation of action of insulin(Receptor Regulation)(Receptor Regulation)

GlucagonGlucagon

• Glucagon is a single polypeptide chain hormone secreted by -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 actionsStimulation of glucagon actions

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

Glucagon secretion is increased by:Glucagon secretion is increased by:

1- Low blood glucose in bloodLow blood glucose in blood:

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

2- Amino acidsAmino 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- EpinephrineEpinephrine:

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.

Glucagon secretion is significantly decreased by :Glucagon secretion is significantly decreased by :

- Elevated blood glucose

- Insulin

Both substances are increased following ingestion of glucose or

carbohydrate-rich meal

Inhibition of glucagon actionsInhibition of glucagon actions

Stimulation & Inhibition of Stimulation & Inhibition of glucagon releaseglucagon release

Metabolic effects of glucagonMetabolic effects of glucagon

Carbohydrates MetabolismCarbohydrates Metabolism

Increases blood glucose

Liver

Glycogenlysis

Gluconeogenesis

Lipids MetabolismLipids Metabolism

TAG Degrad.

in adipose tissue

fatty acids in liver

ketone bodies( ketpgenesis )

Protein MetabolismProtein Metabolism

Uptake of AA by liver

Carbon skeleton for gluco neogenesis

Mechanism of action of glucagonMechanism of action of glucagon