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Regulation of blood glucose

Research study in Biochemistry


BY
Islam Ahmady Mohamed Ismail
Student in the second year
Faculty of medicine/ Zagazig University

Metabolic importance of glucose

Glucose is the single most important source of energy for almost all tissues
being utilised for both glycolysis and the tricarboxylic acid (TCA) cycle. Most
tissues can also utilise fatty acids via the b-oxidation pathway. However, the
brain is unusual in that it can only utilise glucose and ketone bodies
(acetoacetate and b-hydroxybutyrate). Hence, the maintenance of an
adequate plasma glucose concentration is especially important for the
.functioning of the central nervous system
Under normal circumstances the blood glucose level is maintained within a
narrow range. However, under some circumstances it may fall outside that
range and remain consistently low or high. When this occurs, the situation
.becomes potentially dangerous
Hypoglycemia: blood glucose concentration below the fasting range
Hyperglycemia: blood glucose above the normal range. Elevation of fasting
plasma glucose
levels over 7.8mM on more than one occasion is diagnostic of diabetes
.mellitus

Regulation of blood glucose

Following its absorption from the gut into the bloodstream any glucose that is
not immediately required for energy production is transformed and stored
either as glycogen or triglyceride via insulin-mediated processes. In the
fasting state the plasma glucose level is maintained by glycogenolysis
(glycogen breakdown) and gluconeogenesis (synthesis of glucose from nonsugar sources). The main regulators of these processes and, ultimately, of the
plasma glucose level are four hormones - insulin, glucagon, adrenalin and
cortisol.
There are a number of metabolic processes involved in the maintenance of
blood glucose levels, and their interplay can be complex, depending greatly
on the hormonal state. The various processes can be seen in the integrated
metabolic map above. They are:

Glycolysis
the oxidation of glucose to pyruvate via glucose-6-phosphate with the
formation of ATP. Pyruvate is further metabolised by conversion to acetyl-CoA
and entry into the TCA cycle with the production of more ATP. Insulin
stimulates this pathway by increasing cellular glucose uptake and through the
induction of some key enzymes.

Glycogenesis
formation of glycogen from glucose, stimulated by insulin

Glycogenolysis
breakdown of glycogen to glucose-1-phosphate and thence to glucose-6phosphate; stimulated by glucagon and adrenalin and inhibited by insulin.
Liver contains the enzyme glucose-6-phosphatase which allows glucose to be
formed. Muscle tissues do not contain this enzyme and therefore cannot
produce glucose from endogenous glycogen stores.

Gluconeogenesis
formation of glucose from amino acids, lactate and triglyceride-derived
glycerol. The conversion of amino acids to glucose is stimulated by cortisol
and inhibited by insulin.

Lipogenesis
formation of triglycerides from glucose, stimulated by insulin.

Lipolysis
liberation of glycerol and fatty acids from triglycerides, and conversion of
glycerol to glucose; lipolysis is suppressed by insulin, and stimulated by
insulin deficiency, glucagon and adrenalin.

Glucose storage

After a carbohydrate meal, the favoured metabolic pathways are glycogenesis


and lipogenesis, leading to a increase in the storage of energy as glycogen
and triglycerides. This is shown in the diagram above.
In the fasting state, glycolysis and lipolysis are favoured, making use of the
stored fuels to provide energy for the tissues.

Hormonal effects

The hormonal effects are summarised in the above table. Where the effect is indicated in
parentheses it is either indirect or dependent on other factors.

Ketone bodies
During fasting, when exogenous glucose is unavailable, endogenous adipose
tissue triglyceride is reconverted to free fatty acids (FFA) and glycerol by lipolysis.
Both are transported to the liver where glycerol enters the gluconeogenic pathway
at the triose phosphate stage. Glucose formed from glycerol in this way can be
released into the bloodstream at a time when the plasma glucose concentration
would otherwise tend to fall. Most tissues other than the brain use FFA as an
energy source by converting them to acetyl CoA which can enter the tricarboxylic
acid cycle.
However, when the rate of lipolysis is high, the liver receives more fatty acids than
are needed to maintain its own activity. In this situation, the liver converts the
excess acetyl-CoA into three other important metabolites which together are known
as the ketone bodies. These are shown above

Ketogenesis

The ketone bodies are formed by a process known as ketogenesis and they become
important sources of fuel and energy for peripheral tissues, including brain, heart
and skeletal muscle. Although the brain normally uses glucose as its source of
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metabolic fuel it is capable of using ketone bodies as its major source of energy
during periods of starvation.
Just as hormones regulate other pathways involved in glucose homeostasis, they
also influence ketogenesis both directly and indirectly. In normal ketogenesis the
transfer of acetyl-CoA into the mitochondria is controlled by the enzyme carnitine
acyl transferase (CAT). The activity of CAT is dependent upon:
Carnitine
increased levels of carnitine promote CAT activity
Malonyl-CoA
a low malonyl-CoA level stimulates CAT activity
Liver glycogen stores
high levels decrease CAT activity
The hormones which are involved in regulating ketogenesis are:
Glucagon
mobilises carnitine, thereby increasing CAT activity and stimulating ketogenesis
Insulin
increases malonyl-CoA (thus increasing fatty acid synthesis) and increases the
glycogen stores; both actions reduce CAT activity and inhibit ketogenesis

Insulin

Insulin is a hormone of the fed state and it is released in response to rising blood
glucose. Insulin stimulates the uptake of glucose into cells, the synthesis of
glycogen and lipogenesis, and several additional anabolic processes. Glucagon, on
the other hand, is a hormone of the fasted state and stimulaste the breakdown of
glycogen, while inhibiting several anabolic pathways.

Epinephrine is a hormone of the fasted state and of stress. Epinephrine secreted by


the adrenal medulla stimulates glycogenolysis and gluconeogenesis. It also inhibits
insulin release while stimulating glucagon secretion. Cortisol, a steroid hormone, is a
fed state hormone. Glucocorticoids increase gluconeogenesis, glycogen synthesis
and protein degradation.

Tyrosine kinase activity.

The intracellular second messages stimulated by insulin binding to its receptor


cause multiple anabolic effects while slowing degradative or catabolic metabolism.
Insulin both an anabolic hormone and growth factor which affects carbohydrate, lipid
and protein metabolism.

Insulin and leptin

Diabetes
In diabetes, where insulin is deficient or where the cells are unresponsive to insulin,
the uptake of glucose into muscle, liver and adipose tissue is significantly reduced,
and, despite abundant glucose in the blood, the cells are metabolically starved.
Hence, they respond by increasing gluconeogenesis and catabolising fat and
protein. In type I diabetes, increased gluconeogenesis consumes most of the
available oxaloacetate, but breakdown of fat and, to a lesser extent, protein
produces large amounts of acetyl-CoA. This increased acetyl CoA would normally
be directed into the tricarboxylic acid cycle but, with oxaloacetate in short supply, it
is used instead for production of unusually large amounts of ketone bodies. Acetone
can often be detected on the breath of Type I diabetics, an indication of high plasma
levels of ketone bodies.
In uncontrolled severe diabetes, particularly insulin-dependent diabetes mellitus
(IDDM), there can be excessive formation of ketone bodies leading particular form of
metabolic acidosis known as ketoacidosis. Patients in this condition may become
comatose. They have a smell of acetone on their breath and hyperventilate as a
physiological response to compensate for the acidosis.
As would be evident from the preceding discussion, the biochemical bases for the
symptoms of ketoacidosis are:
1.1. Low insulin levels
increased lipolysis and release of fatty acids
decreased fatty acid synthesis and lower concentration of malonyl-CoA
decreased liver glycogen content
2.2. High glucagon levels increased release of carnitine
A table containing basic information on the various hormones involved in
glucose homeostasis

Insulin structure and function

Insulin is a polypeptide hormone comprising two chains held together by two


disulphide bridges. The longer chain consists of 30 amino acids and the shorter has
21 amino acids. The shorter chain also has an internal disulphide bridge.
Insulin is synthesised in the b-cells of the pancreatic Islets of Langerhans and is
released from there into the bloodstream. As shown in earlier sections within this
Module, it is an anabolic hormone that:
stimulates the uptake of glucose into fat and muscle cells
promotes the conversion of glucose to glycogen or fat for storage
inhibits glucose production by the liver
stimulates protein synthesis and inhibits protein breakdown

Insulin biosynthesis
The precursor of insulin, preproinsulin, is synthesised by the ribosomes of the rough
endoplasmic reticulum of the pancreatic b-cells. Preproinsulin comprises a single
polypeptide chain of about 100 amino acids but it is not detectable in the circulation
under normal conditions because it is rapidly converted by cleaving enzymes to
proinsulin, an 84-amino acid polypeptide.
Proinsulin is stored in the secretory granules of the Golgi complex of the b-cells,
where proteolytic cleavage to insulin occurs. This cleavage involves the removal of
an internal 33-amino acid section of the proinsulin. This section is released as the
connecting peptide, more commonly known as C-peptide.

Release of insulin
At the plasma membrane of the b-cells, insulin and C-peptide are released into the
portal circulation in equimolar amounts. C-peptide has no known biological activity
but appears necessary to ensure the correct structure of insulin. After its release the
insulin is transported in the blood to specific receptor sites in insulin-sensitive
tissues such as muscle, adipose tissue and liver. Insulin and its receptors then
generate messenger molecules which initiate the metabolic responses.
The stimuli that direct the b-cells to release packaged insulin and to synthesise new
insulin are:
Glucose
Amino acids (especially leucine and arginine)
Pancreatic and gastrointestinal hormones (eg. glucagon, gastrin, secretin)
Some medications (eg. sulphonylureas, b-adrenergic agonists)
Conversely, insulin release is inhibited by:
Hypoglycaemia
Somatostatin - a hormone produced by the gamma cells of the pancreas
Various drugs (eg. a-adrenergic agonists, b-adrenergic agonists, phenytonin and
nicotinic acid)

Metabolic consequences of Diabetes

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The basic defect in diabetes mellitus is insulin deficiency (absolute or relative) which
affects glucose, lipid, protein, potassium and phosphate metabolism. The principal
manifestation is hyperglycaemia due to increased hepatic production of glucose and
decreased peripheral glucose utilisation. Increased hepatic production is caused by:
decreased glycogenesis (insulin lack)
increased glycogenolysis (insulin lack and unopposed action of glucagon and
adrenalin
increased gluconeogenesis (insulin lack and unopposed action of cortisol and
glucagon)
Decreased peripheral utilisation of glucose is due to:
decreased cellular uptake of glucose (insulin lack)
The consequences of hyperglycaemia are:
1.Increased glucose in the urine and osmotic diuresis with loss of water, sodium,
potassium and phosphate ions
2.Increased tonicity of the extracellular fluid which shifts water from the intracellular
space (cell dehydration) to the extracellular space causing extracellular dilution
Lack of insulin and the unopposed action of glucagon and adrenalin stimulate
lipolysis and the release of free fatty acids into the circulation. These are taken up
by the liver and converted to ketone bodies and triglycerides which are released in
the form of very low density lipoproteins.
Severe untreated diabetes involves a pattern of metabolic fuel supply and
consumption that is quite different from what occurs in healthy people or in
controlled diabetics. The diagram below illustrates the situation in diabetes. The
figures are for a 24 hour period under basal conditions, assuming a total energy
output of 2400 kcal ( 10.0 MJoules). It should be noted that there is a heavy drain on
muscle proteins for gluconeogenesis and that fatty acids and ketone bodies are
used as the principal energy source for all tissues except the brain and blood cells. It
should also be noted that a large fraction of the glucose formed from muscle
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proteins is lost in the urine together with up to one-third of the ketone bodies forme
from fatty acids in the liver. Hence, a large portion of the available energy goes to
waste.

Diabetic hyperlipidaemia

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Ketone bodies (diabetic)

Clinical complications of Diabetes


The main acute complications of diabetes are:
Ketoacidosis
Hyperosmolar non-ketotic coma
Lactic acidosis
Hypoglycaemia
Ketoacidosis is due to the presence of large quantities of ketone bodies in the blood. The
acidosis causes the patient to hyperventilate and may ld to loss of consciousness
(ketoacidotic coma).

Hyperosmolar non-ketotic coma usually occurs in the elderly and in patients with
NIDDM. It is associated with impaired consciousness due to severe hyperglycaemia
(>50 mM) and high plasma osmolarity- (>400 mmol/kg). Water loss is usually
greater than sodium loss. As the patient becomes less conscious, water intake is
reduced and the sodium level rises. The dehydration leads to high plasma creatinine
and urea levels. However, ketosis and acidosis are absent.
Lactic acidosis (plasma lactate in excess of 4.0 mM compared with normal <2.0
mM) occurs in about 50% of patients with ketoacidosis. This develops when the
activity of the tricarboxylic acid cycle decreases with a consequent fall in ATP
production. This leads to the stimulation of glycolysis and the excessive formation of
lactate.
Diabetic hypoglycaemia is most commonly caused by the accidental "overdose" of
insulin or oral hypoglycaemic drugs. As a result, insulin levels are raised inappropriately
when glucose levels are already low.
As well as the acute complications described above there are additional chronic or longterm complications. Indeed, it it were not for these long-term complications, controlled
diabetes would not impose a great threat to the quality and longevity of life. The main longterm complications are:

Microangiopathy
degenerative lesions in the small blood vessels such as capillaries
Retinopathy
the chief cause of new cases of blindness
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Diabetic nephropathy
chronic renal failure
Nerve disorders affecting both the peripheral and autonomic nervous systems

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