Integration of Metabolism(Chapter 23)

-         Overview

-         Insulin :

o Structure of insulin

o Synthesis of insulin

o Regulation of insulin secretion

Metabolic effects of insulin and glucagon

1st Lecture: Pages : 305 - 308

Overview:

The human body functions as one community.

Communication between tissues is mediated by the nervous system (by the circulating substrates and plasma hormones). (Figure 23.1)

The integration of energy metabolism is controlled primarily by the action of 2 hormones, (insulin & glucagon) and role of catecholamines (epinephrine and norepinephrine).

The four major organs playing important role in fuel metabolism are liver, adipose tissue, muscles and brain.

Insulin• Insulin is a polypeptide hormone produced

by the -cells of the islets of Langerhans of the pancreas. (Figure 23.2)

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

• Its metabolic effects are anabolic .

• stimulating the synthesis of : - glycogen (glycogensis) - triacylglycerol (lipogenesis) - protein.

A- Structure of insulin:

• Insulin is composed of 51 A.A. arranged in 2 polypeptide chains A & B , linked together by 2 disulfide bridges. (Figure 23.3 A)

• Insulin molecule also contains an intramolecular disulfide bridge in A chain.

• Beef insulin differs from human insulin at 3 A.A. positions.

• pork insulin differs from human insulin at only one A.A. position.

Figure 23.3 A : structure of Insulin

B- Biosynthesis of Insulin:

Insulin is first synthesized as preproinsulin which is changed to proinsulin then to insulin as follows:

  (Figure 23.3 B) Endoplasmic reticulum Golgi apparatus

peptide- C + Insulin Proinsulin Preproinsulin  Signal peptide

Biosynthesis of Insulin

Figure 23.3 B : Formation of human insulin from preproinsulin

• Preproinsulin and proinsulin are inactive.

• Insulin is stored in the cytosol in granules that are released by exocytosis. (Figure 23.4)

• Insulin is degraded by the enzyme insulinase present in the liver and to a lesser extent in the kidneys.

• Insulin has a plasma half-life of about 6 minutes.

• This short duration of action permits rapid changes in circulating levels of the hormone.

C- Regulation of Insulin Secretion:

1-Stimulation of insulin secretion:

• Insulin secretion by the -cells is closely coordinated with glucagon release by -cells of pancreas

• The relative amounts of insulin and glucagon secreted by the pancreas are regulated so that :

the rate of hepatic glucose production = use of glucose by peripheral tissues.

• The -cells respond to a variety of stimuli

Insulin synthesis and secretion are stimulated by:

a) Glucose: ingestion of glucose or a carbohydrate rich meal blood glucose stimulates insulin secretion.

b) Amino Acids: ingestion of protein plasma A.A. stimulate insulin secretion. ( plasma arginine stimulation for insulin secretion).

c) Gastrointestinal hormones: The intestinal peptide Secretin & GIT hormones stimulate insulin secretion after ingestion of the food. They cause an anticipatory in insulin level in portal vein before the actual in blood glucose. (Figure 23.5)

(The same amount of glucose given orally stimulates more insulin secretion than if given IV. ).

2. Inhibition of insulin secretion:

• The synthesis and release of insulin are during starvation and stress.

• These effects are mediated by epinephrine, trauma or extreme exercise.

• Under these conditions, secretion of epinephrine is controlled by the nervous system.

• Epinephrine stimulates glycogenolysis, gluconeogenesis and lipolysis and inhibits insulin secretion.

• In emergency, the sympathetic nervous system largely replaces the plasma glucose concentration as the controlling influence over β –cell secretion. (Figure 23.6)

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Metabolic effects of insulin and glucagon o  Metabolic effects of insulin

o  Mechanism of insulin action

        Glucagon :

o  Stimulation of glucagon secretion

o  Inhibition of glucagon secretion

2nd Lecture: Pages : 308 - 311

D- Metabolic effects of Insulin:

 1-Effects on carbohydrate metabolism:

• The effects of insulin on glucose metabolism are most prominent in the liver, muscles and adipose tissue.

• In muscles and adipose tissue : insulin glucose uptake by increasing the number of glucose transporters in the cell membrane.

• In muscles and liver, insulin glycogensis.

• In the liver, insulin the production of glucose by inhibiting both glycogenolysis and gluconeogenesis.

• Insulin is the only hypoglycemic hormone.

• Insulin glucose oxidation and utilization by tissues.

2-Effects on Lipid Metabolism:

Insulin the release of fatty acids from adipose tissue by:

) in triacylglycerol degradation:

Insulin inhibition of the activity of hormone- sensitive lipase in adipose tissue.

b) triacylglycerol synthesis:

- Insulin the transport and metabolism of glucose into adipocytes, providing glycerol 3 - phosphate for triacylglycerol synthesis.

- Insulin lipoprotein lipase activity of adipose tissue by the enzyme synthesis, providing fatty acids for esterification.

3-Effects on protein synthesis:

Insulin stimulation the entry of A.A. into cells and protein synthesis in most tissues.

E- Mechanism of Insulin Action:

- Insulin binds to specific, high-affinity receptors in the cell membrane of most tissues, including liver, muscle and adipose tissue.

- This is the first step in a cascade of reactions leading to many biological actions.

1- Insulin receptor (IR):

• It is synthesized as a single polypeptide that is glycosylated and cleaved into - and - subunits which is assembled into a tetramer linked by disulfide bonds. (Figure 23.7)

• The extracellular -subunit contains the insulin binding site.

• The cytosolic domain of the -subunit is a tyrosine kinase, which is activated by insulin.

2- Signal transduction :

• Binding of insulin to - subunits of insulin receptor conformational changes to the - subunits rapid auto-phosphorylation of a specific Tyrosine Residue on each - subunits . (Figure 23.7)

• Auto-phosphorylation cascade of cell signaling responses (Phosphorylation of Insulin Receptor Substrate (IRS) proteins ).

• At least 4 IRSs show similar structures but different tissue distributions.

• The actions of insulin are terminated by dephosphorylation of the receptors.

3-Membrane effects of Insulin:

• Glucose transport in many tissues (skeletal muscle and adipocytes) in the presence of insulin. (Figure 23.8)

• Insulin the recruitment of insulin-sensitive glucose transporters (GLUT-4) from a pool present in intracellular vesicles.

• Some tissues have insulin independent systems for glucose transport e.g. - hepatocytes - erythrocytes - cells of the nervous system - intestinal mucosa

- renal tubules - cornea (Figure 23.9).

4- Receptor regulation:

• Binding of insulin intracellular hormone-receptor complex insulin degradation in the lysosomes.

• The receptors may be degraded but most are recycled to the cell surface.

levels of insulin the degradation of receptors, the number of surface receptors.

• This is one type of “ down regulation “.

5-Time course of insulin actions:

- After insulin binding to the receptors, there will be:

 a) glucose transport into adipocytes & skeletal muscles (seconds).

 b) Change in enzyme activity (phosphorylation states)

(minutes to hours) .

c) in the amount of enzymes (e.g. glucokinase,

phosphofructokinase, and pyruvate kinase) (hours to

days).

- These changes gene transcription & enzyme synthesis

Glucagon  Glucagon is a polypeptide hormone secreted by the

α-cells of islets of Langerhans of the pancreas.

Glucagon is composed of 29 amino acids arranged in a single polypeptide chain.

Unlike insulin, the A.A. sequence of glucagon is the same in all mammalian species.

Glucagon maintains blood glucose levels by hepatic glycogenolysis & gluconeogenesis.

Epinephrine, glucagon, cortisol, and growth hormone are anti-insulin (Counterregulatory hormones).

A-Regulation of Glucagon Secretion:

 1-Stimulation of glucagon secretion:

a- Low blood glucose: hypoglycemia is the primary stimulus for glucagon secretion. (Figure 23 .10)

b- Amino acids: the secretion of both glucagon and insulin (Glucagon prevents hypoglycemia caused by insulin)

c- Epinephrine and nor epinephrine (during stress, trauma or severe exercise) glucagon secretion. In contrast insulin levels are

2-Inhibition of glucagon secretion : (Figure 23 .11)

Glucagon secretion is markedly by blood sugar and by insulin following carbohydrate-rich meal.

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Metabolic effects of insulin and glucagon

o   Metabolic effects of glucagon

  o Mechanism of action of glucagon

    Hypoglycemia :

o   Symptoms of hypoglycemia

o Glucoregulatory systems

3rd Lecture: Pages : 311 - 314

B- Metabolic Effects of Glucagon:

1-Effects on carbohydrate metabolism:

I.V. administration of glucagon blood glucose levels by hepatic glycogenolysis and gluconeogenesis.

2 -Effects on lipid metabolism:

- Glucagon hepatic oxidation of fatty acids formation of ketone bodies from acetyl CoA.

- Glucagon minimal lipolytic effect in adipose tissue in humans.

3- Effects on protein metabolism:

Glucagon A.A. uptake by the liver for gluconeogenesis plasma A.A

C-Mechanism of action of glucagon :

• Glucagon binds to high-affinity receptors on the cell membrane of the hepatocyte activation of the adenylate cyclase in the plasma membrane cAMP (second messenger). (Figure 23.12)

• cAMP activation of cAMP–dependent protein kinase phosphorylation of specific enzymes or other proteins.

• Phosphorylation activation or inhibition of the key regulatory enzymes of carbohydrate and lipid metabolism.

Hypoglycemia Hypoglycemia is a medical emergency

characterized by:

1)  Central nervous system symptoms, including confusion, aberrant behavior, or coma.

2)  Simultaneous blood glucose level equal to or less than 40 mg/dl.

3) Symptoms being corrected within minutes following the administration of glucose.

• CNS has an absolute need for a continuous supply of blood glucose as a fuel for energy metabolism.

• Transient hypoglycemia cerebral dysfunction, Severe, prolonged hypoglycemia brain death.

• The most important hormonal changes to correct hypoglycemia are:

glucagon and epinephrine combined with insulin secretion.

A. Symptoms of hypoglycemia:

1) Adrenergic symptoms:

•Anxiety, palpitation, tremor, and sweating.

•These symptoms are due to epinephrine secretion regulated by the hypothalamus due to hypoglycemia.

•These symptoms occur when the blood glucose levels fall rapidly.

2) Neuroglycopenic Symptoms:

glucose supply to the brain brain dysfunction headache, confusion, slurred speech, seizures, coma and death. -- It results from a gradual in blood glucose(<40mgdl)

B. Glucoregulatory Systems:

Humans have two overlapping glucose-regulating systems that are activated by hypoglycemia:

1) The islets of Langerhans (- cells), glucagon.

2) The glucoreceptors in the hypothalamus secretion of both epinephrine (through the autonomic nervous system) and ACTH and growth hormone (GH) by the anterior pituitary gland. (Figure 23.13)

- Glucagon, epinephrine, cortisol and GH are called the counter-regulatory hormones because they antagonize the action of insulin on glucose utilization.

1. Glucagon and Epinephrine:

Hypoglycemia is corrected by insulin secretion and secretion of glucagon, epinephrine, cortisol, and growth hormone.

Glucagon and epinephrine are most important in the acute, short- term regulation of blood glucose levels.

Glucagon : hepatic glycogenolysis and gluconeogenesis.

Epinephrine: glycogenolysis and lipolysis, insulin secretion, and insulin dependent uptake of glucose by tissues.

2.Cortisol and Growth hormone:

These hormones are less important in the short term regulation of blood glucose levels, but they are important in the long term regulation of glucose metabolism.

They gluconeogenesis.

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