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Blood Glucose Regulation
Glucose is the most common respiratory
substrate utilised by cells, and is the sole
energy source for the brain and red blood cells
In normal circumstances,
blood glucose levels remain
remarkably stable as they are
under the homeostatic control of
two pancreatic hormones –
insulin and glucagon
In 1923, Banting and Macleod were
awarded the Noble Prize for the
discovery and isolation of the
hormone insulin, a breakthrough
that was to have a profound effect
on the lives of sufferers of diabetes
Many body tissues can use fatty acids
as a source of metabolic energy in
addition to, or instead of, glucose
In contrast, the brain and red blood
cells require glucose as their sole
energy source; brain disturbance
rapidly occurs if this nervous tissue is
deprived of glucose
Red blood cells lack mitochondria and can only obtain
their energy by anaerobic glycolysis
Sources of Blood Glucose
The glucose that circulates in the bloodstream
is derived from three main sources:
• Dietary intake and digestion of carbohydrates
• Glycogenolysis; the breakdown of stored
glycogen into glucose
• Gluconeogenesis; the conversion of
non-carbohydrate sources, such as amino
acids, into glucose
Dietary carbohydrates
include sugars, starch
and cellulose; during
digestion, disaccharide
sugars (e.g. maltose) and
starch are hydrolysed
to yield glucose
The conversion of noncarbohydrates (e.g. amino
acids and glycerol) into
glucose by liver cells is
called gluconeogenesis
Glycogenolysis is the
conversion of glycogen
(storage carbohydrate
found in liver and muscle
tissue) into glucose; the
released glucose enters
the bloodstream
Blood Glucose Regulation
Blood glucose levels are controlled by two principal
hormones, insulin and glucagon, secreted by the
endocrine portion of the pancreas
The pancreas is predominantly an exocrine gland
(secreting many digestive enzymes into the gut); the
pancreas also contains clusters of endocrine cells, called
the Islets of Langerhans, which secrete the hormones
insulin and glucagon into the bloodstream
The concentration of glucose in the blood normally lies in
the range of 90 – 100 mg/100 cm3 ( 5 – 5.6 mmol/l)
A rise in blood glucose level to above the norm, for
example after a meal, is detected by the beta cells of the
Islets of Langerhans, which respond by secreting insulin
If the blood sugar level drops below the norm, for
example between meals, or after fasting, then the alpha
cells of the Islets of Langerhans detect this change and
respond by secreting glucagon
Negative feedback
mechanisms operate to
achieve glucose homeostasis
Blood Glucose Regulation
Insulin decreases levels of blood glucose by:
• Increasing the permeability of body cells to
glucose by stimulating the incorporation of
additional glucose carriers into cell
membranes
• Glycogenesis; activation of the liver enzymes
that convert glucose into glycogen
(also occurs in muscle cells)
• Lipogenesis; stimulates the conversion of
glucose into fatty acids in adipose tissue
(fat cells)
A diabetic person and a non
diabetic person ate the same
amount of glucose. One hour
later, the glucose concentration in
the blood of the diabetic person
was higher than that of the non
diabetic person. Explain why
3 marks
answer
• In a diabetic person:
• Lack of insulin produced/reduce sensitivity
of cells to insulin because lack of receptors.
• Reduced uptake of glucose by
body/liver/muscles cells
• Reduced conversion of glucose to glycogen
Blood Glucose Regulation
Glucagon increases levels of blood glucose by:
• Glycogenolysis; activation of the liver
enzymes that convert glycogen into glucose
• Gluconeogenesis; activation of the liver
enzymes that convert non-carbohydrates into
glucose
• Lipolysis; stimulates the breakdown of
triglycerides into fatty acids and glycerol in
adipose tissue
detected by the
alpha cells
glucagon secretion
detected by the
beta cells
Dual Hormonal
Control achieves
Glucose Homeostasis
glycogen  glucose
non-carbohydrates  glucose
increased
permeability of body
cells to glucose
release of fatty
acids from
adipose tissue
uptake of
glucose for
fatty acid
synthesis
insulin secretion
glucose  glycogen
detected by the
beta cells of the
Islets of Langerhans
in the pancreas
rise in
blood glucose
insulin
secretion
restoration of the norm
(negative feedback)
restoration of the norm
(negative feedback)
fall in
blood glucose
detected by the
alpha cells of the
Islets of Langerhans
in the pancreas
• activation of enzymes that
promote the conversion of
glucose into glycogen in
liver and muscle tissue
• increase in the permeability
of body cells to glucose
• activation of enzymes that
promote fat synthesis
glucagon
secretion
• activation of enzymes that
promote the conversion of
glycogen into glucose in
liver tissue and fatty acid
release in adipose tissue
• activation of enzymes that
promote the conversion of
non-carbohydrates, such as
amino acids, into glucose
(gluconeogenesis)
Insulin binds to
receptors on cell
surface membranes
Effect of insulin on the
glucose permeability of cells
glucose carrier for
facilitated diffusion
intracellular
chemical
signal
plasma
membrane
signal triggers the
fusion of carriercontaining vesicles
with the surface
membrane
The additional
carriers increase
glucose
permeability
Hormone Action
Protein hormones, like insulin and glucagon, are polar,
lipid-insoluble molecules that are unable to diffuse
through the lipid bilayer of plasma membranes
These hormones bind to receptor proteins in the plasma
membranes of their target cells, and trigger a chain of
events that activate or inhibit the enzymes required for
specific biochemical reactions
The hormone itself is the ‘first messenger’; on binding to a
receptor at the surface of a target cell, the hormone
activates specific molecules at the membrane that lead to the
release of a ‘second messenger’, which enters the cytoplasm
and triggers a response
The glucagon second messenger is a small molecule called
cyclic AMP; the involvement of two messengers – the hormone
and cyclic AMP – amplifies the original signal; cyclic AMP is a
widely studied second messenger molecule although other
molecules perform this function for certain hormones
Hormone binds to Binding induces a change in the
The G-protein
surface receptor
shape of the receptor, which
activates the enzyme
activates a G-protein located on
adenyl cyclase
the inner surface of the membrane
Cyclic AMP
(second messenger)
Hormone induced change
Adenyl cyclase
converts ATP
into cyclic AMP
inactive enzyme
active enzyme
cAMP activates enzymes required
for specific biochemical reactions
Activated enzymes
produce specific
changes in the cell
Hormone Action and Amplification
When a protein hormone binds to its cell-surface
receptor, a cascade of events is triggered with one
event leading inevitably to another
Each molecule within the cascade system activates
many molecules of the next stage, such that there
is an amplification of the original message
triggered by the hormone
A single molecule of hormone promotes the synthesis
of thousands of the molecules of the final product
Each activated receptor
protein activates many
molecules of adenyl cyclase
Each activated adenyl
cyclase molecule converts
many molecules of ATP
into cyclic AMP
Each cyclic AMP molecule
activates many copies of
the desired enzyme
Each enzyme molecule
catalyses the formation of
many molecules of product
The binding of one hormone
molecule at the cell surface promotes
the synthesis of thousands of cyclic
AMP molecules (amplification); a
small concentration of hormone in
the blood produces a massive
response within the target cell
G-protein
Adenyl cyclase
Glucagon binds to
surface receptor
Many molecules of adenyl cyclase are activated, each of
which converts many molecules of ATP into cyclic AMP
Glucose enters the bloodstream
Many molecules of
Cyclic AMP
inactive enzyme
active enzyme
cAMP activates many copies of the
enzyme that splits glycogen into glucose
A phosphorylase
enzyme catalyses the
conversion of
glycogen into glucose
Diabetes mellitus
A breakdown in the homeostatic control of blood
glucose concentration may lead to a condition
called diabetes mellitus
Diabetes mellitus is characterised by an inability of cells to take
up glucose from the blood which, in untreated cases, forces the
cells to draw on other sources of energy, such as fat and protein
reserves; blood glucose concentrations
exceed the renal threshold and glucose is excreted in the urine
Diabetes mellitus may arise when the pancreatic beta cells fail
to produce insulin (or produce insufficient amounts), or when
the insulin receptors at cell membranes become abnormal
Diabetes mellitus
There are two principal types of diabetes mellitus:
• Type I or Juvenile-onset Diabetes appears suddenly
during childhood as a result of the destruction of the
insulin-producing cells of the pancreas; this is thought to
arise from either a viral infection or an attack by the
individual’s own antibodies (autoimmune reaction);
sufferers of Type I diabetes are insulin-dependent
• Type II or Maturity-onset Diabetes is generally a less
severe form of the condition, in which insulin levels may
be normal or reduced, but the target cells fail to respond
to the hormone due to receptor abnormalities
The Glucose Tolerance Test
When an individual is suspected of having diabetes,
a glucose tolerance test is usually performed
The test is used to determine the capacity of the body
to tolerate ingested glucose
The glucose tolerance test involves the following steps:
• Fasting for eight hours
• A blood test to determine fasting, blood glucose
concentration (time 0 minutes)
• Ingestion of a glucose load (usually 50 grams)
• Blood tests for monitoring blood glucose concentrations at
regular intervals over a period of 2½ hours
• Results are graphed to give a glucose tolerance curve
Blood Glucose
Concentration (mmol/l)
Time after
ingesting
glucose
(mins)
normal
mild
diabetes
severe
diabetes
0
4.4
4.4
11.8
30
6.3
7.9
14.3
60
4.4
11.8
17.6
90
4.0
10.0
17.3
120
4.2
7.8
17.1
150
4.3
6.4
16.9
Present these results in graphical form
Describe and explain
the differences
between the three
curves
Effects of Diabetes mellitus
Undersecretion of insulin, and the subsequent
inability of cells to utilise glucose as a respiratory
substrate, leads to a variety of metabolic effects in
untreated diabetics - these include:
• Hyperglycaemia; an increase in blood glucose concentration and
the excretion of glucose by the kidneys
• Protein Catabolism; the breakdown of muscle protein to amino
acids in response to the inability to use glucose as a principal
respiratory substrate; excess amino acids are converted into both
glucose and urea in the liver, increasing the excretion of nitrogen
and raising blood glucose levels (an unwanted effect)
• Fat Catabolism; stored fats are hydrolysed to fatty acids and
utilised by cells for respiration; excessive fatty acid oxidation
produces an excess of acetyl CoA molecules that are converted to
ketones by the liver; the release of ketones into the blood lowers
the pH (acidosis)
• Osmotic Diuresis; the high concentration of glucose in the urine
creates a hypertonic urine that reduces water reabsorption from
the collecting ducts; a large volume of urine is excreted
Stored fats are converted to fatty
acids and used by body cells for
respiration; large quantities of
acetyl CoA are a by-product of
fatty acid oxidation and these are
converted to ketones in the liver;
ketones make the blood acidic
Muscle protein is broken down
into amino acids producing a
surplus that is converted into
both urea and glucose in the liver;
increased excretion of urea leads
to a loss of nitrogen from the body
If the glomerular filtrate of a
diabetic person contains a high
concentration of glucose, he
produces a larger volume of
urine. Explain why?
The high concentrations of
glucose in the blood are such
that they exceed the renal
threshold and are excreted in
the urine; this produces a
hypertonic urine that enters
the collecting ducts of the
kidney tubules
The hypertonic urine reduces the
water potential gradient between
the urine and the hypertonic
tissue of the kidney medulla
As the urine flows through the
collecting ducts, less water is
reabsorbed and a large volume
of urine is produced (diuresis)
This loss of water can lead to
dehydration, and extreme thirst
may be experienced
Large volume
of urine
Treatment of Type I diabetes is
by subcutaneous injection of
insulin; insulin cannot be taken
orally as the protein nature of
this hormone would result in its
digestion within the gut
The insulin dose needs to be
adjusted carefully; an excessive
dose of insulin together with
a low carbohydrate intake
results in hypoglycaemia
(low blood sugar level)
Blood glucose levels are
regularly monitored to
determine the need for insulin;
biosensors are used by
individuals to keep track of
their sugar levels
Treatment of Type II diabetes
largely involves dietary control
Nutritionists work with sufferers to
devise a healthy eating plan that
limits sugar intake and is balanced
by an appropriate level of exercise
Modern methods of treatment
enable individuals, with either
Type I or Type II diabetes, to
lead normal lives
A test for glucose in urine uses
immobilised enzymes on a plastic
test strip. One of these enzymes
is glucose oxidase. Explain why
the test strip detect glucose and
no other substance.
2 marks
Enzyme has an specific shape to
active site/active site has an
specific tertiary structure.
Only glucose fits/has
complementary structure/can
form ES complex