Disorders of Carbohydrate Metabolism

DISORDERS OF
CARBOHYDRATE
METABOLISM
BY: IRAM IQBAL (PHD. PHARMACOLOGY)
Department of Pharmacology
Faculty of Pharmacy
Bahauddin Zakariya University Multan

Disorders of Carbohydrate Metabolism
IRAM IQBAL (PHD. PHARMACOLOGY) | 1
Carbohydrate metabolism
• Carbohydrate metabolism is a fundamental biochemical process that ensures a constant
supply of energy to living cells.
• The most important carbohydrate is glucose, which can be broken down via glycolysis,
enter into the Kreb's cycle and oxidative phosphorylation to generate ATP.
• Metabolism of carbohydrates that are galactose fructose and glucose is linked through
interactions between different enzymatic pathways and disorders that affect these pathways
may have symptoms ranging from mild to severe or even life threatening.
Disorders of carbohydrate metabolism
• Acquired disorders: most common are acquired disorders
1. Diabetic ketoacidosis
2. Hypoglycemia
3. Hyperosmolar coma
All of them effect CNS. Various forms of peripheral nerve disease are also
• Inherited disorders: rare form of disorders. Inherited metabolic defect disorders
discovered so far are inherited as autosomal recessive traits.
1. Galactosemia
2. Hereditary fructose intolerance (HFI)
3. Lactose intolerance

Galactosemia:
Galactosemia is a condition in which the body is
unable to use (metabolize) the simple sugar
galactose. A small amount of galactose is
present in many foods. It is primarily part of a
larger sugar called lactose, which is found in all
dairy products and many baby formulas.
Causes:
Lactose in food (such as dairy products) is broken down by the enzyme lactase
into glucose and galactose. In individuals with galactosemia, the enzymes needed for further
metabolism of galactose (Galactokinase and galactose-1-phosphate uridyltransferase) are
severely diminished or missing entirely, leading to toxic levels of galactose or galactose 1-
phosphate (depending on which enzyme is missing) in various tissues.

Sign and symptoms:
Affected children can have serious, irreversible effects or even die within days from
birth. It is important that newborns be screened for metabolic disorders without
delay. These begins when milk feeding is started. If feeding is not stopped, infants
may develop
 Lethargy
 Jaundice
 progressive liver dysfunction
 kidney disease
 Weight loss.
 Patient is susceptible to severe bacterial infection, especially E.coli.
 brain damage
 Intellectual disability
Without treatment, mortality in infants with galactosemia is about 75%.

Diagnosis:
Clinical manifestation including congenital cataract and presence of galactose in urine as well as
elevated blood galactose levels will help in the diagnosis.
Treatment:
The only treatment for classic galactosemia is
eliminating lactose and galactose from the
diet. Even with an early diagnosis and a
restricted diet, however, some individuals
with galactosemia experience long-term
complications such as speech
difficulties, learning disabilities, neurological
impairment (e.g. tremors, etc.). Exclusion of
galactose from diet causes reversal of major
symptoms but if brain damage occurs
children may have normal intelligence
although they may have learning difficulty.
Key point: Galactosemia is sometimes confused with lactose intolerance, but galactosemia is a
more serious condition. Lactose intolerant individuals have an acquired or inherited shortage of
the enzyme lactase, and experience abdominal pains after ingesting dairy products, but no long-
term effects. In contrast, a galactosemic individual who consumes galactose can cause permanent
damage to their bodies.

Hereditary fructose
intolerance (HFI)
Fructose is a simple sugar, known as a
monosaccharide that comes mostly
from fruit and some vegetables. It’s
also found in honey, agave nectar, and
many processed foods that contain
added sugars.
This is a rare genetic condition that affects 1 in 20,000 to 30,000 people and occurs because the
body doesn’t make the enzyme needed to break down fructose.
This can lead to serious health issues such as liver failure if a strict fructose-free diet isn’t
followed. The condition is most often detected when a baby starts consuming baby food or
formula.
Causes:
Mutations in the ALDOB gene cause hereditary
fructose intolerance. The ALDOB gene provides
instructions for making the aldolase B enzyme. This
enzyme is found primarily in liver and is involved in the
breakdown (metabolism) of fructose so this sugar can be
used as energy. Aldolase B is responsible for the second
step in the metabolism of fructose, which breaks down
the molecule fructose-1-phosphate into other molecules
called glyceraldehyde and dihydroxyacetone phosphate.
Key point: Hereditary fructose intolerance is inherited, which means it can be passed down
through families. If both parents carry a nonworking copy of the aldolase B gene, each of their
children has a 25% (1 in 4) chance of being affected.

Key point: Hereditary fructose intolerance should not be confused with a condition called fructose
malabsorption. In people with fructose malabsorption, the cells of the intestine cannot absorb
fructose normally, leading to bloating, diarrhea or constipation, flatulence, and stomach pain.

Sign and symptoms:
Soon after fructose is added to the diet of an
infant with HFI, symptoms become apparent.
These may include
• failure to gain weight satisfactorily
• vomiting
• Gas
• Bloating
• Abdominal discomfort
• hypoglycemia
• liver dysfunction
• Kidney defects
Key point: Patients with Hereditary Fructose Intolerance usually develop a strong dislike for
sweets and fruit.
Diagnosis:
A diagnosis of HFI can be definitively confirmed by either of two tests:
1. An enzyme assay:
Requiring a liver biopsy, to determine the level of aldolase activity. The aldolase is
obtained from patient liver tissue in an invasive surgical procedure called a liver biopsy.
2. Fructose tolerance test
In which the patient's response to intravenous fructose feeding is carefully monitored.
Fructose is injected intravenously under controlled conditions where acute glucose,
fructose, and phosphate levels are monitored.
3. A non-invasive DNA test is increasingly being recommended instead.
It should be carefully noted, however, that each of these tests carries with it a substantial risk,
especially to a newborn child.

Treatment:
 Strict fructose free diet.
 This involves exclusion of anything containing fructose, sucrose, or sorbitol.
 In extreme cases of life-threatening liver damage, liver transplants have been performed.

Lactose intolerance
 As the name suggests, Lactose
Intolerance refers to a condition when
the patient becomes intolerant to lactose.
 According to studies, 70% of adults
are lactose intolerant.
• It can also be termed as hypolactasia.
Types:
Primary Lactose Intolerance
Primary lactose intolerance is the most common. It is caused by a decrease in lactase production
with age, so that lactose becomes poorly absorbed.
This form of lactose intolerance may be partially caused by genes, because it’s more common in
some populations than others.
Population studies have estimated that lactose intolerance affects 5–17% of Europeans, around
44% of Americans and 60–80% of Africans and Asians.
Secondary Lactose Intolerance
Secondary lactose intolerance is rare. It is caused by illness, such as a stomach bug or a more
serious issue like celiac disease. This is because inflammation in the gut wall can lead to a
temporary decline in lactase production
Causes:
Deficiency of lactase is the basic cause of lactose
intolerance.
 Lactase is present in the Brush border region of
small intestine. Lactase hydrolyses lactose to
glucose and galactose. Therefore, deficiency of this
enzyme, either genetic or age related, causes
accumulation of lactose in body.

 This lactose cannot be directly absorbed to the wall of small intestine, so it passes intact
into colon where bacteria metabolize lactose and resulting fermentation produces copious
amount of H2, CO2, CH3. This cause various abdominal symptoms.
Sign and symptoms:
Principal symptom of lactose intolerance is adverse reaction to products containing lactose such
as milk, etc.
Other symptoms include
 abdominal bloating
 Diarrhoea
 Nausea
 Vomiting
Some people also experience urgency to go to the toilet, nausea, vomiting, pain in the lower
belly and occasionally constipation.
Diarrhea occurs due to undigested lactose in your small intestine, which causes water to move
into your digestive tract.
Once it reaches your colon, the lactose is fermented by the bacteria in your gut, forming short-
chain fatty acids and gas. This causes the bloating, flatulence and pain.
The severity of symptoms can vary, depending on how much lactose you can tolerate and how
much you have eaten.
Diagnosis:
H2 Breath Test
 It is the most accurate test
 After an overnight fast, 25g of lactose is
swallowed
 If lactose cannot be digested, enteric
bacteria metabolize it and produce H2
which can be detected in patient’s breath by
clinical gas chromatography.
 If H2 level in patient’s breathe is high, they
may have lactose intolerance.

Treatment:
People with lactose intolerance may need to cut back or
remove dairy products from their diets, potentially missing
out on some nutrients. Dairy products are highly nutritious
and important sources of protein, calcium and vitamins like
A, B12 and D. This nutrient combination is great for your
bones. Including dairy in your diet is linked to higher bone
mineral density, which may help reduce the risk of bone
fractures as you get older. Dairy products have also been
linked with a reduced risk of type 2 diabetes and obesity
To avoid deficiency of essential nutrients
 Lactase pill prior to eating
 To use lactase treated products
 Restriction of lactose containing products in diet
 Curd and Yeast
Key point: Most people with lactose intolerance can tolerate
small amounts of lactose. For example, some people can
tolerate the small amount of milk in tea but not the amount
you would get from a bowl of cereal.

HYPOGLYCEMIA
Glucose is your body's main energy source.
Hypoglycemia is a condition in which your
blood sugar (glucose) level is lower than
normal. When the blood glucose
concentration falls to less than 45mg/dl,
the symptoms of hypoglycemia appear.
Types:
 Post-prandial hypoglycemia:
This is called reactive hypoglycemia and is observed in subjects with an elevated insulin
secretion following a meal. This causes transient hypoglycemia associated with mild
symptoms.
 Fasting hypoglycemia:
Low blood glucose concentration in fasting is not very common. However fasting
hypoglycemia is observed in patients with pancreatic beta-cell tumor and hepatocellular
damage.

Symptoms –
 headache,
 anxiety,
 confusion,
 sweating,
 slurred speech,
 seizures
 Coma and if not corrected death.
Causes:
 Due to alcohol intake:
This is due to accumulation of NADH which diverts the pyruvates and oxaloacetate to
form, respectively, lactate and malate.
 Due to insulin overdose:
Observed in patients who are in intense insulin therapy regime.
 In premature infants:
Premature and underweight infants have smaller store of liver glycogen and are susceptible
to hypoglycemia.

Diabetes Mellitus
Diabetes mellitus is a disorder in which
the body does not produce enough or
respond normally to insulin, causing blood
sugar (glucose) levels to be abnormally
high. Urination and thirst are increased,
and people may lose weight even if they
are not trying to.
Symptoms: Weight loss; Polydipsia
Classification:
Divided into 2 groups
 IDDM
 NIDDM
Insulin dependent Diabetes Mellitus
 Type 1 Diabetes -Juvenile onset diabetes
 Occurs in childhood
 10-20% on known diabetics
 Characterized by almost total deficiency of insulin-> due to destruction of Beta cells of
Pancreas
 Symptoms appear after 80-90% of Beta cells have been destroyed.
 Pancreas fails to secrete insulin in response to carbs ingestion
 Therefore, patient require insulin therapy
Non-Insulin dependent Diabetes Mellitus
 Type 2 diabetes- Adult onset diabetes
 Most common, 80-90% of diabetic population
 Occurs in adults
 Commonly occurs in obese individuals
 Decreasing insulin receptors on insulin responsive
cells.
 Increased level of Tumor Necrosis Factor

Diagnosis:
1. OGTT
Diagnosis is made on basis of individual’s response to oral glucose load, oral glucose test.
(OGTT)
 Take carbohydrate for at least 3 days prior to test
 All drugs influencing carbohydrate metabolism should be discontinued
 Avoid strenuous exercise on days previous to test.
 Be in overnight fasting state.
 Conducted preferably in morning (9-11 am)
 Fasting blood sample is drawn and urine collected
 Subject given 75g glucose orally, dissolved in 300mL of water, to be drunk in 5 min.
 Blood and urine samples collected at 30 minute intervals for at least 2 hours.
 Glucose estimation of all blood samples.
 Urine sample qualitatively tested for glucose

Interpretation of results:
 Fasting plasma glucose level = 75-110mg/dL in
normal person
 Persons-> impaired glucose tolerance -> fasting
(110-126mg/dL) and 2 hour (140-200mg/dL) plasma
glucose levels are elevated
Key point:
2. Glycosuria:
 Commonest cause of glucose excretion in urine.
 It is first line screening test for diabetes
 Normally, glucose does not appear in urine until plasma glucose concentration exceeds
renal threshold (180mg/dL)
3. Metabolic alterations
Diabetes mellitus is associated with several metabolic alterations. Most important among
them are
 Hyperglycemia
 Ketoacidosis
 Hypertriglyceridemia

Long term effects:
 Atherosclerosis
 Retinopathy
 Nephropathy
 Neuropathy
Management of diabetes:
 Dietary management:
Low calori , High protein and fiber rich diet, reduce fat intake,exercise
 Hypoglycemic drugs:
Sulfonylureas (Acetohexamide , tolbutamide)and Biguanides
 Insulin:
Short acting (for 6 hours) and Long acting ( for several hours )
Biochemical Indicators of Diabetes Management
Glycated hemoglobin:
Most abundant is HbA1c which is produced by condensation of glucose with N terminal valine of
each Beta chainof HbA
Diagnostic importance:
As the rate of synthesis of HbA1c is directly related to the exposure of RBC to glucose , Thus
serves as indication of blood glucose concentration over 3 months period prior to measurement.
Key facts: Diabetes is not caused just by eating too much sugar

Disorders of Carbohydrate Metabolism

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