‫بسم هللا الرحمن الرحيم‬
‫﴿و ما أوتيتم من العلم إال قليال﴾‬
‫صدق هللا العظيم‬
‫االسراء اية ‪58‬‬
Blood Glucose
Regulation
By
Dr. Abdel Aziz M. Hussein
Lecturer of Physiology
Member of American Society of Physiology
• The normal blood glucose level ranges ( ) 80-120
mg %.
• The total amount of glucose in circulating blood is
about 3.3 to 7gm
• 5 grams of glucose is about equivalent to a
commercial sugar packet (as provided in many
restaurants with coffee or tea).
• Failure to maintain blood glucose in the normal
range leads to conditions of persistently high
(hyperglycemia) or low (hypoglycemia) blood
sugar.
•
Normal Blood glucose is regulated by 2 mechanisms:
A. Hormones
Pancreatic hormones
e.g. insulin, glucagon, and
somatostatin
Other hormones e.g.
adrenaline, thyroxin,
glucocorticoids, and
Growth hormone
B. Tissues
Liver acts as
glucostat
• Endocrine cells of the pancreas are present in groups
called ‘islets of Langerhan’s’
• Are more numerous in the tail than in the body
• Islets are 1-2% of its pancreatic weight
Alpha cells
25 %
Secretes
Glucagon
Beta cells
60%
Secretes
Insulin
Delta cells
10%
Secretes
somatostatin
F cells
5%
Secretes
pancreatic
polypeptide
Chemistry :
• Insulin is one of the most important peptide hormones.
• Plays a central role in the rapid modulation of all energy
reactions in the body.
• Was first isolated from pancreas in 1922 by Banting and
Best
• It consists of 2 straight chains linked by 2 disulfide bridges.
1. A chain → contains 21 amino acids and an intra-chain
disulfide ring.
2. B chain → contains 30 amino acids.
Synthesis and Release:
• mRNA → by Ribosomes → preproinsulin → split of 23
amino acids from preproinsulin → proinsulin (insulin + C or
connecting peptide) → by trypsin-like and
carboxypeptidase-like enzymes during transport from
endoplasmic reticulum and package by Golgi apparatus →
split into insulin and C peptide
• Both insulin and C peptides are secreted by exocytosis in
equimolar amounts
• C peptide has 10% of insulin activity
Mechanism of action:
• Insulin acts on insulin receptor (2 subunits, alpha and beta
subunits).
• It is a tyrosine kinase i.e. functions as an enzyme that
transfers phosphate groups from ATP to tyrosine residues on
intracellular target proteins.
• Binding of insulin to the alpha subunits causes the beta
subunits to phosphorylate themselves
(autophosphorylation), thus activating the catalytic activity
of the receptor.
• The activated receptor then phosphorylates a number of
intracellular proteins called insulin-receptor substrates
(IRS1-4).
• These substrates are coupled to several additional protein
kinase signal systems
Functions of insulin:
1.
2.
3.
4.
CHO metabolism: it is hypoglycemic hormone
Fat metabolism: stimulate lipogenesis
Protein synthesis: anabolic hormone
Electrolyte metabolism: K, Ca, Mg and PO4
Insulin and CHO metabolism
Insulin tends to lower blood glucose level by:
1. Stimulate glycogenesis in Liver and SK. Ms by activating
the glycogen synthetase enzyme.
2. Inhibition of glycogenolysis by decreasing glycogen
phosphorylase activity.
3. Increase glucose uptake by the tissues (liver, ms, and fat
tissues) by activating glucokinase enzyme and insertion
of GLUT4 into cell membrane
4. Inhibition of gluconeogenesis by decreasing the hepatic
uptake of amino acids.
5. Stimulate lipogenesis in adipose tissue, by activating
lipoprotein lipase enzyme.
Insulin Action in Muscle and Fat Cells
Mobilization of GLUT4 to the Cell Surface
Plasma membrane
Insulin
receptor
Intracellular
signaling
cascades
Intracellular
GLUT4 vesicles
Insulin
GLUT4 vesicle mobilization
to plasma membrane
GLUT4 vesicle
integration into
plasma membrane
GLUT4=glucose transporter 4
Glucose
Glucose entry into cell
via GLUT4 vesicle
Insulin and Protein Metabolism
Insulin is powerful anabolic hormone and stimulate tissue
growth by :
1. Stimulates the uptake of certain amino acids by Sk. Ms
2. Stimulates the rate of protein synthesis (enhance
activity of ribosomes)
3. Anticatabolic effects i.e. inhibits proteolysis.
4. Certain peptides called insulin-like growth factors, have
similar amino acid sequences, and cross react modestly
with insulin receptors.
Insulin and Electrolyte Metabolism
1. Insulin increases cellular uptake of potassium,
phosphate and magnesium.
2. It increases the reabsorption of potassium,
phosphate and sodium by renal tubules.
N.B.
• Insulin stimulate glucose entry in all tissues except
brain cells, RBCs, intestinal cells and renal tubule
cells
Stimuli of Insulin Secretion
1. Blood glucose:
• Virtually, no insulin is secreted below a plasma glucose level of
50 mg%.
• A half maximum insulin secretory response occurs at a plasma
glucose level of about 150 mg%
• A maximum response at 300 to 500 mg%.
Stimuli of Insulin Secretion
2. GIT hormones:
a. Gastric inhibitory polypeptide (GIP):
• The most important of insulinogogue i.e. stimulate insulin
secretion
• Released from specific intestinal cells in response to oral
glucose and drop in pH
• So, oral glucose stimulate insulin secretion than IV insulin
b. High concentrations gastrin, secretin, cholecystokinin,
pancreatic glucagons and enteroglucagon stimulate insulin
secretion
• This mechanism inhibit the rise of blood glucose after ingestion
and absorption of CHO meals
3. ↑ Blood free fatty acids, ketoacids and triglycerides
have little effect
4. ↑ blood amino acids e.g. arginine, leucine, lysine and
alanine
Stimuli of Insulin Secretion
5. Other hormones e.g. Glucagon, GH, cortisol
• Glucagon stimulate insulin secretion by direct paracrine
action on beta cells and indirect action through increase of
blood glucose level
6. Minerals e.g. K and Ca ions (are essential for the response of
insulin secretion to glucose)
6. Parasympathetic (Ach) and Beta adrenergic stimulation.
7. Obesity
8. Sulfonylurea drugs
Inhibitors of Insulin Secretion
1.
2.
3.
4.
5.
6.
Fasting
Exercise
Somatostatin
-Adrenergic stimuli
Prostaglandins
Drugs e.g. Diazoxide and Phenytoin
Chemistry :
• Polypeptide hormone (29 amino acid) synthesized from
a precursor called proglucagon.
• Secreted by  cells of the pancreatic islets
• Glucagon-like peptides, including glicentin, are
synthesized and secreted by the small intestinal cells
in humans and other species.
Functions :
1. On CHO metabolism:
• It increases blood glucose i.e. hyperglycemic factor by:
a) Glucagon promotes and sustains hepatic glucose output.
• It stimulate glycogenolysis by activation of glycogen
phosphorylase.
• Released G-6-P is prevented from forming glycogen by
inhibition of glycogen synthetase.
Functions :
1. On CHO metabolism:
b) It stimulates gluconeogenesis by:
• Increasing hepatic uptake of amino acids, especially
alanine.
• Activating the necessary enzymes.
N.B.: Glucagon has little or no influence on glucose utilization
by peripheral tissues.
Functions :
2. Glucagon activates adipose tissue lipase→ lipolysis→
delivery of free fatty acids from adipose tissue to the liver
and ketogenesis.
3. It decreases hepatic cholesterol synthesis.
4. Natriuresis, by inhibition of renal tubular Na reabsorption.
5. Activation of myocardial adenyl cyclase, causing a
moderate increase of cardiac output.
6. May act as a local CNS hormone for the regulation of
appetite.
Mechanism of action :
1. Hypoglycaemia causes 2-4 fold increase in
glucagon level.
2. Protein meal and, most powerfully, by amino acids
such as arginine and alanine. However, the -cell
response to protein is greatly reduced if glucose is
administered concurrently.
3. Reduction in plasma free fatty acids.
4. Exercise of sufficient intensity and duration.
5. Vagal stimulation or administration of acetylcholine.
6. Stress, including infection, toxaemia, burns and major
surgery.
7. Growth hormone.
1. Hyperglycaemia. It lowers glucagon level by about
50%.
2. Increase in plasma free fatty acids.
3. The neurohormone somatostatin inhibits
glucagons release.
1. Adrenaline: glycogenolytic acting on both liver and
muscles.
2. Glucocorticoids: Stimulate gluconeogenesis and
depress glucose uptake by the tissues.
3. Growth hormone: Stimulates the release of
glucagon hormone and also inhibits glucose uptake
by tissues.
4. Thyroxin: It increases glucose absorption from the
intestine, glycogenolysis and glucose uptake by cells.
The net result is a rise in blood glucose level.
Def.,
• This is one of the oldest known endocrine disorders,
the sweetness of urine, having been described in
Egypt in 1500 B.C.
Manifestations:
• It results from deficiency of insulin which leads to:
1. Hyperglycaemia, due to absence of the above
mentioned effects of insulin.
2. Glucosuria i.e. loss of glucose in urine.
• This occurs when the blood glucose level becomes
higher than the renal threshold (180 mg%).
Manifestations:
• 3. Polyuria due to:
• a) Excretion of glucose in urine→ osmotic diuresis.
• b) ↑ed osmotic pressure of the blood drags water out
of the cells towards the blood→ dehydration of the
tissue cells.
• 4. Polydepsia: intense thirst due to dehydration.
• 5. Acidosis: due to inhibition of CHO metabolism.
• The body depends on the fat metabolism which
supplies most of the energy needed→ accumulation of
the intermediary products of fat metabolism as
acetoacetic acid and beta hydroxybuteric acid.
Manifestations:
• 6. Loss of weight and asthenia:
• Due to mobilization of fat and proteins for the supply of
energy.
• 7. Increased cholesterol and triglycerides level in the
blood which leads to early development of
arteriosclerosis.
• Secreted form;
1. Hypothalamus:
• Somatostatin reaches the anterior pituitary via its
portal circulation
• Inhibits the secretion of GH and TSH
2. Delta cells of the pancreas:
• Inhibits the release of all other islet hormones: insulin,
glucagon and pancreatic polypeptide.
Secreted form;
3. Gastrointestinal tract
a) Inhibits secretion of gut hormones: Gastrin, secretin,
cholecystokinin and VIP.
b) Reduces the secretion of gastric acid and pepsin.
c) Decreases blood flow, motility and carbohydrate
absorption.
d) Increases water and electrolyte absorption.
THANKS