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Transcript of Carbohydrate metabolism Glucose is the major energy substrate The body’s source of glucose are...
Carbohydrate metabolism
• Glucose is the major energy substrate
• The body’s source of glucose are dietary carbohydrate and endogenous (principally hepatic) production by glycogenolysis (release of glucose stored as glycogen) and gluconeogenesis (glucose synthesis from, e.g., lactate, glycerol and most amino acids).
• Blood glucose concentration depends on the relative rates of influx of glucose into the circulation and its utilization.
•Blood glucose concentration is normally subject to rigorous control rarely falling below 70mg/dl or rising above 180 mg/dl in healthy individuals whether fasting or recently fed
• The maintenance of plasma glucose concentrations below about 180 mg/dl minimizes loss from the body as well as providing the optimal supply to the brain
The importance of extracellular glucose concentrations• Brain cells are very dependent on the extracellular glucose
concentration for their energy supply; hypoglycaemia is likely to
impair cerebral function. This is because they cannot:
1. Cannot Store glucose in significant amounts
2. Cannot Synthesize glucose
3. Cannot Metabolize substrates other than glucose and ketones. Plasma
ketone bodies concentrations are usually very low and are of little
importance as an energy source under physiological conditions
4. Cannot Extract enough glucose from the extracellular fluid at low
concentrations for their metabolic needs, because entry into brain
cells isn’t facilitated by insulin• The liver is the most important organ maintaining a constant energy
supply for other tissues, including the brain, under a wide variety of
conditions • The integration of the various processes and thus the control of blood
glucose concentration is achieved through the intensive action of
various hormones: these are insulin and the ‘counter regulatory’
hormones, namely glucagon, cortisol, catecholamines and growth
hormone.
Disorders of glucose homeostasis
• The major disorders of glucose homeostasis are diabetes mellitus Diabetes mellitus is characterized by glucose intolerance and thus a tendency to hyperglycaemia,
• Other Various conditions which can cause a pathologically low blood glucose concentration, that is, hypoglycaemia
Diabetes mellitus• Is a group of metabolic disorders of carbohydrate
metabolism in which glucose is underutilized, producing hyperglycaemia.
Aetiology and pathogenesisDiabetes mellitus is a common condition. There are two
distinct types: 1. In Type I (insulin-dependent diabetes mellitus-IDDM) there
is destruction of pancreatic cells and effectively no insulin secretion (autoimmune destruction of the pancreatic -cells).
2. In Type II (non insulin-dependent diabetes mellitus-NIDDM) either insulin is secreted in amounts insufficient to prevent hyperglycaemia or there is insensitivity to its actions.
Overall some 20% of patients are insulin dependent; most patients with NIDDM can be treated by diet, with or without hypoglycaemic drugs, for example, sulphonylureas and biguanides.
Major characteristics of insulin-dependent (IDDM) and non insulin-dependent (NIDDM) diabetes mellitus
FeatureIDDMNIDDMTypical age of onsetChildren, young
adultsMiddle-aged, elderly
Onset Acute (days or even weeks)
Gradual (over months)
Habitus (an individual’s general physical appearance)
LeanOften obese (40%)
Weight lossUsualUncommon
Ketosis-proneUsuallyUsually not
Plasma insulin concentration
Low or absentOften normal; may be
Family history of diabetes
Uncommon Common
Other classes of diabetes:
3. Diabetes mellitus associated with other conditions and syndromes:
e.g., Cushing’s disease, due to excessive cortisol production
This was formally known as secondary diabetes
4. Impaired glucose tolerance: impaired glucose tolerance is
diagnosed in individuals who have fasting blood glucose levels
less than those required for a diagnosis of diabetes mellitus, but
who have a plasma glucose response during the oral glucose
tolerance test judged to be between normal and diabetic
An OGTT is required to assign a patient to this class
5. Gestational diabetes mellitus: is carbohydrate intolerance of
variable severity with onset or first recognition during the present
pregnancy
The incidence of GDM is between 1 and 5%. Approximately 30%
of women with GDM develop diabetes mellitus within 20 years
after delivery, but carbohydrate may revert to and remain normal
after delivery
Pathophysiology and clinical features
• There are two aspects to the clinical manifestations of diabetes
mellitus:
1. Those related directly to the metabolic disturbances and
2. Those related to the long-term complications of the condition.
• The prevalence of the long-term complications increases with
duration of the disease and the risk of complications is greater if
glycaemic control is poor:
1. Nephropathy
2. Neuropathy {nerve damage}
3. Retinopathy {leading to blindness}
4. Arteriopathy {may result in stroke, gangrene or coronary disease}.
Abnormalities of lipoprotein metabolism occur frequently in
patients with diabetes mellitus and may predispose to
atherosclerosis
5. Infections which are common in diabetic patients and may
aggravate renal and peripheral vascular disease
• The hyperglycaemia of diabetes mellitus is mainly a result of
increased production of glucose by the liver and of decreased
removal of glucose from the blood.
• In the kidneys, filtered glucose is normally completely reabsorbed
in the proximal tubules, but a blood glucose concentrations much
above 200 mg/dL, reabsorption becomes saturated and glucose
appears in the urine.
• Glycosuria results in an osmotic diuresis, increasing water excretion
and raising the plasma osmolality, which in turn stimulates the thirst
centre.
• Osmotic diuresis and thirst cause the classical symptoms of
polyuria and polydipsia.
• Untreated, the metabolic disturbances may become deep with the
development of life-threatening ketoacidosis, non-ketotic
hyperglycaemia or lactic acidosis.
Diagnostic Criteria for Diabetes Mellitus1. Random plasma glucose ≥ 200 mg/dL (11.1 mmol/L) +
symptoms of diabetes2. Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L)3. Two hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during
an oral glucose tolerance test
Any of the three criteria must be confirmed on a subsequent day by any of the three methods
• Categories of Fasting Plasma Glucose (FPG).Normal fasting glucose FPG < 110 mg/dLImpaired fasting glucose FPG ≥ 110 mg/dL and < 126 mg/dLDiabetes likely FPG ≥ 126 mg/dL
• Categories of Oral Glucose ToleranceNormal glucose tolerance 2-h PG < 140 mg/dLImpaired glucose tolerance 2-h PG ≥ 140 mg/dL and < 200 mg/dLDiabetes likely 2-h PG ≥ 200 mg/dL
Metabolic complications of diabetes
• Patients with diabetes mellitus may develop one of several metabolic
complications needing emergency treatment: diabetic ketoacidosis and
hyperosmolal non-ketotic coma
Diabetic ketoacidosis
During fasting: when exogenous glucose is unavailable and the plasma
insulin concentration is therefore low, endogenous triglycerides are
converted to free fatty acids and glycerol by lipolysis. Both are
transported to the liver in plasma. Glycerol enters the hepatic
gluconeogenic pathway; the synthesised glucose can be released from
these cells, thus minimising the fall in glucose concentrations.
Most tissues, other than the brain, can oxidise fatty acids to acetyl CoA,
which can then be used as an energy source. When the rate of synthesis
exceeds its use the hepatic cells produce ketone bodies (acetoacetic
acid, -hydroxybutyric acid which can be decarboxylated to acetone.
These ketones can be used as energy source by brain and other tissues
at a time when glucose is in relatively short supply. Therefore ketosis
occurs when fat stores are the main energy source and may result from
fasting.
Diabetic ketoacidosis
• The development of ketosis requires changes in both adipose
tissue and the liver.
• In uncontrolled diabetes, the low insulin levels results in increased
lipolysis and decreased re-esterification increasing plasma free
fatty acids. There will be enhanced hepatic gluconeogenesis and
impaired glucose entry into cells. The increased glucagon/insulin
ratio enhances fatty acid oxidation in the liver. Thus, increased
hepatic ketone production.
• Excessive formation of ketone bodies results in increased blood
levels (ketonemia) and increased excretion in the urine
(ketonuria). This process is observed in conditions associated with
decreased availability of carbohydrates (such as starvation or
frequent vomiting) or decreased use of carbohydrates (such as in
diabetes mellitus and glycogen storage disease).
• Ketoacidosis may be the presenting feature of IDDM, or may
develop in a patient known to be diabetic who neglect to take his
insulin
Clinical features of diabetic ketoacidosis
• Thirst, polyuria, dehydration, hypotension, tachycardia and peripheral circulatory failure, ketosis, hyperventilation, vomiting, abdominal pain and drowsiness and coma.
Metabolic features: hyperglycaemia, glycosuria, non-respiratory acidosis, ketonaemia, uraemia, hyperkalaemia, hypertriglyceridaemia and haemoconcentration.
The deep, noisy respiration and the odour of acetone on the breath are classical features of diabetic ketoacidosis.
Hyperkalaemia is commonly present and is a result of the combined effects of decreased renal excretion and a shift of intracellular potassium (due to insulin lack, since insulin promotes cellular potassium uptake, and to acidosis and tissue catabolism). However, in spite of hyperkalaemia, there is always considerable potassium depletion due to increased urinary potassium loss in the presence of osmotic diuresis.
The plasma sodium concentration is usually decreased because of sodium depletion and the osmotically driven shift of water from intracellular compartment.
Diabetic and fasting ketoacidosis
• Diabetic ketoacidosis is differentiated from that of fasting
by hyperglycaemia and is usually more sever. Despite the
differences in plasma glucose concentration, the ketone
production in both cases is due to intracellular glucose
deficiency. In diabetic ketosis this is due to low insulin
activity.
• Ketosis always reflects excessive use of fat as an energy
source due to: intracellular glucose deficiency and low
insulin activity. The low insulin activity increases the rate
of production of gluconeogenic substrates by glycolysis
and proteolysis, and the rate of hepatic gluconeogenesis.
The resultant increased rate of glucose released into the
extracellular fluid is appropriate in starvation, but
aggravates the hyperglycaemia in diabetes mellitus.
Hyperosmolal non-ketotic comma
• The term hyperosmolal coma or precoma is usually
limited to a condition in which there is marked
hyperglycaemia but no detectable ketoacidosis.
• It has been suggested that insulin activity is
sufficient to suppress lipolysis but insufficient to
suppress hepatic gluconeogenesis or to facilitate
glucose transport into cells.
• It is commoner in older patients. Plasma glucose
concentrations may exceed 50mmol/L (900mg/dl).
• Glycosuria which lead to cerebral cellular
dehydration contributes to the coma and
hyperventilation.
Long-term complications in diabetes mellitus
1. Nephropathy: Microvascular changes characterized by
thickening of the capillary basement membrane, ultimately
leads to renal insufficiency or failure.
2. Neuropathy: any disease of the peripheral nerves, usually
causing weakness and numbness. Manifesting as sensory loss,
impotence, postural hypotension, constipation and diarrhoea.
Peripheral neuropathy may give rise to impaired perception of
pain and temperature (particularly in lower extremities).
Ischemia may cause skeletal muscle atrophy and motor
abnormalities.
3. Retinopathy {leading to blindness}, is a consequence of
microvascular changes. It might lead to retinal microaneurysm
and retinal detachment, secondary glaucoma and vision loss.
Premature cataracts are common. New formation of capillaries,
and haemorrhage.
Long-term complications in diabetes mellitus
4. Arteriopathy {may result in stroke, gangrene or coronary
disease}.
Atherosclerosis is a multistage process set in motion when cells lining
the arteries are damaged as a result of high blood pressure, smoking,
toxic substances in the environment, and other agents. Plaques
develop when high density lipoproteins (LDL) accumulate at the site
of arterial damage and platelets act to form a fibrous cap over this
fatty core
Prevention appears to be the primary means of attacking
atherosclerosis: through low-fat diets, regular vigorous exercise,
control of high blood pressure or diabetes, and avoidance of tobacco.
5. Infections which are common in diabetic patients and may
aggravate renal and peripheral vascular disease. Including
tuberculosis, pneumonia. Eruptive xanthomas occurs most often in
long-standing, poorly controlled diabetes mellitus.
Injury, infection, neuropathy, vascular disease or ischemia may lead
to gangrene
Glycated hemoglobin: Glycated hemoglobin:
Hemoglobin A1cHemoglobin A1c
• Under physiologic conditions
HbA is slowly and non-
enzymatically glycosylated
• The extent of glycosylation is
dependent on the plasma level
of particular hexoses
• The most abundant glycosylated
Hb is HbA1c which has glucose
unit that covalently linked to
amino group of N-terminal
valines of the beta chain
• In the case of Diabetes mellitus,
the amount of HbA1c will
increase
Glycated hemoglobin:
• Glucose reacts non-enzymatically with NH2-terminal amino acid
of the -chain of human haemoglobin, resulting in the formation
of haemoglobin A1c.
• This haemoglobin is formed slowly and continuously throughout
the 120 days life-span of the red cell. There is a two to three
fold increase in red cells of patients with diabetes mellitus.
• Formation of glycated haemoglobin is irreversible, it on both the
life span of the red blood cell (average 120 days) and the blood
glucose concentration.
• The amount of HbA1c therefore represents the integrated
values for glucose over the preceding 6 to 8 weeks and provides
an additional criterion for assessing glucose control. Values are
free of day-to-day glucose fluctuations and unaffected by
exercise or recent food ingestion. The interpretation of glycated
haemoglobin depends on the red blood cells having a normal life
span.
Glycated proteins
• Measurement of glycated proteins is useful in monitoring
long-term glucose control
• The amount of Hb A1c represents the integrated values
for glucose over the preceding 6 to 8 weeks and provides
an additional criterion for assessing glucose control.
• Not subject to the wide fluctuations observed when blood
glucose levels are assayed. Values are free of day-to-day
glucose fluctuations and unaffected by exercise or recent
food ingestion.
• Glycated protein levels, therefore, are a valuable addition
to blood glucose determinations in the assessment of
glycaemic control.
Glycated hemoglobin• Correlation of glycated haemoglobin to glucose level: there is a
lag time of several weeks between an increase of blood glucose and an increase of glycated haemoglobin. A similar lag time exists between the return of blood glucose to normal and the return of glycated haemoglobin values to normal.
• Glycated haemoglobin should be routinely monitored every 3 to 4 months.
Advantages over blood and urine glucose measurements:1. only one assay per month2. not influenced by hour-to-hour variations due to food,
exercise,...3. can be used in the detection of diabetes (good correlation with
glucose tolerance test).Reference intervals: values for glycated haemoglobins are
usually expressed as a percentage of total blood haemoglobin. Healthy subjects have values less than 6.5% in patients with poorly
controlled diabetes mellitus, values may extend to twice the upper limit of normal or more but rarely exceed 20%.
Role of the clinical lab in diabetes mellitus
• The clinical lab has a vital role in both the diagnosis and
management of diabetes mellitus
• The diagnosis of diabetes is made solely by the
demonstration of hyperglycaemia
Other assays, such as the OGTT, contribute to the
classification and characterization.
Management
• There are many aspects to the management of diabetes
mellitus:
1. Education of patients is vital; they will have diabetes for the
rest of their lives and must be responsible for their own
treatment with guidance from a physician.
2. Regular follow-up is essential to monitor treatment and
detect early signs of complications, particularly retinopathy
which can in many cases be treated successfully.
Management
• The aim of treatment is:
1. To alleviate symptoms and prevent the acute metabolic complications of diabetes can be attained with dietary control (restriction of carbohydrates, an increase in dietary fiber) with or without oral hypoglycaemic agents in patients with NIDDM, and with diet and insulin in patients with IDDM
2. To prevent the long-term complications
• Whatever the treatment, the fluctuations in blood glucose concentration that occur in most diabetic patients are still greater than those which occur in normal subjects.
Hypoglycaemia
• Hypoglycaemia is a blood glucose concentration below the fasting
range, but it is difficult to define specific limits.
• It is defined as a blood glucose concentration of less than 45mg/dl
Clinical features
• The clinical features of hypoglycaemia are the result of dysfunction
of the nervous system and the effects of catecholamines which are
released in response to the stimulus provided by the low blood
glucose.
• Clinical features include: weakness, tiredness, confusion, shakiness,
sweating, nausea, rapid pulse, light-headedness, hunger and epigastric
discomfort, convulsions and coma.
• The brain is totally dependent on blood glucose, and very low levels
of plasma glucose (less than 20 or 30 mg/dl) causes sever central
nervous system dysfunction.
• Restoration of plasma glucose usually produces a rapid recovery, but
irreversible damage may occur.
Causes of hypoglycaemia
Types of hypoglycaemia :
1. Hypoglycaemia that follows a stimulus (reactive
hypoglycaemia), including the stimulus of a meal
(post-prandial hypoglycaemia)
2. Hypoglycaemia that occurs during fasting
It is usually possible to distinguish between these
categories from the patient’s history
Hypoglycaemic syndromes
Reactive hypoglycaemia (stimulus)
1. Drug-induced hypoglycaemia: most patients with IDDM may
have occasional episodes of hypoglycaemia. Most frequently,
hypoglycaemia is related to a missed meal, increase in physical
activity or accidental insulin over dosage.
The diagnosis must depend on the blood glucose concentration, but if
there is any doubt, it is always safe to give glucose to a confused
or unconscious diabetic patient awaiting the result becoming
available.
Diabetic patients should always carry sugar and a means of
identification to facilitate treatment in emergency.
Hypoglycaemia due to drugs other than those used to treat diabetes
is uncommon. Children, but not adults, poisoned with salicylates
may develop sever hypoglycaemia. It has also been reported in
patients who have taken overdoses of paracetamol and, in these
cases, it is probably related to the severe liver damage that this
drug can cause.
Hypoglycaemic syndromes
Reactive hypoglycaemia (stimulus)
2. Post-prandial hypoglycaemia: in patients who
have undergone gastric surgery, hypoglycaemia
developing 90-150 min after a meal, particularly a
meal rich in sugar, is common. There is a rapid
passage of glucose into the small intestine and
release of hormones which stimulates insulin
secretion. The insulin response is excessive and
hypoglycaemia occurs as glucose absorption from
the gut falls down rapidly, rather than slowly as it
does when gastric emptying is normal.
Hypoglycaemic syndromes
Reactive hypoglycaemia (stimulus)
Alcohol and reactive hypoglycaemia:
hypoglycaemia may develop between 2-10 hours
after ingestion of large amounts of alcohol.
Hypoglycaemia is caused by suppression of
gluconeogenesis during metabolism of alcohol.
Insulin- and drug-induced reactive hypoglycaemia are
potentiated by alcohol.
Alcohol also increases insulin release in response to an
oral glucose load.
Hypoglycaemic syndromes
Fasting hypoglycaemia
• Symptoms occur typically at night or in the early morning, or
may be precipitated by a prolonged fast and strenuous
exercise.
• Fasting hypoglycaemia is rare but usually signals serious
underlying pathology and may be life-threatening.
• Autonomic symptoms usually begin at plasma glucose
concentrations below 45 mg/dl, and cerebral function
deteriorates when glucose is less than 25 mg/dl.
Insulinoma: insulinomas are tumours of the insulin-secreting -
cells of the pancreatic islets. C-peptide should be measured.
Although secreted in equimolar amounts with insulin, C-peptide
is cleared from the circulation more slowly, so that it may be
more reliable marker of endogenous insulin secretion than
insulin itself.
Hypoglycaemic syndromes
Fasting hypoglycaemia
Hepatic and renal disease: it may complicate very
sever hepatitis, hypoxic liver disease associated
with congestive cardiac failure or liver necrosis of
the whole liver is affected.
The kidneys are capable of gluconeogenesis to little
extent; they are also responsible for insulin
degradation. These facts may in part explain the
sever hypoglycaemia that is occasionally a feature
of terminal renal disease.
Treatment of hypoglycaemia
Hypoglycaemia should be treated by urgent iv.
administration of 10 to 20 ml of at least 10%, and in
adults 50%, glucose solution after withdrawal of a blood
sample for glucose determination.
If hypoglycaemia is suspected glucose should be given
immediately while waiting for the laboratory results.
It is less dangerous to give glucose to a patient with
hyperglycaemia than to give insulin to a patient with
hypoglycaemia
Determination of glucose in body fluids
Specimen collection and storage
• Plasma or serum is used for the majority of glucose determinations in
labs, whereas most methods of self-monitoring of glucose use whole
blood.
• Red blood cells in vitro continue to utilize glucose (it decreases serum
glucose by approximately 5% to 7% in 1 hour; 5 to 10 mg/dl), with the
result that unless a blood sample can be analyzed immediately, it is
essential to collect it into a tube containing sodium fluoride to inhibit
glycolysis.
• Fluoride ions prevent glycolysis by inhibiting enolase, an enzyme that
requires Mg+2. The inhibition is due to the formation of an ionic
complex consisting of Mg+2, inorganic phosphate and fluoride ions.
Fluoride is also weak anticoagulant because it binds calcium; however,
clotting may occur after several hours.
• Potassium oxalate is used as an anticoagulant in such ‘fluoride-oxalate’
tubes, and plasma obtained from this blood is thus unsuitable for the
measurements of potassium concentration.
• Many analytical procedures are used to measure blood glucose levels.
Almost all commonly used techniques are now enzymatic, and older
methods, such as colorimetric or oxidation-reduction techniques, are
rarely used.
Urinary albumin excretion
• Patients with diabetes mellitus are at high risk of suffering renal
damage.
• Approximately one third of patients with IDDM develop end-stage
renal disease requiring dialysis or transplantation.
• Persistent proteinuria, which is detectable by routine screening
tests (equivalent to a urinary albumin excretion rate 200g/min),
suggests the presence of diabetic nephropathy. This is usually
associated with long-standing disease and its occurrence less
than 10 years after the onset of diabetes is unusual.
• Once diabetic nephropathy occurs, renal function deteriorates
rapidly and renal insufficiency evolves.
• Treatment at this stage can slow down progression of disease, but
it cannot stop or reverse it. The presence of increased urinary
albumin excretion signals an increase in the transcapillary escape
rate of albumin and is therefore a marker of microvascular
disease.
Urinary albumin excretion
• Prospective studies have demonstrated that
increased urinary albumin excretion precedes and is
highly predictive of diabetic nephropathy, end-stage
renal disease, and proliferate retinopathy in IDDM.
• Variation in urine flow rate in an individual may be
corrected by expressing albumin as a ratio of
creatinine (i.e., albumin/ creatinine). At least three
separate samples should be assayed because of the
high intraindividual variation (30% to 40%) and
diurnal variation (higher during the day).
Urinary albumin excretion
Reference intervalsUrinary albumin excretion
g/min mg/24 hrAlbumin/Creatinine
Normal10150.01
IDDM20-20030-3000.02-0.2
Diabetic nephropathy
200300 0.2