This is just the general sense of disorder of carbohydrate metabolism.

1. Disorders
of
carbohydrate
metabolism
Dr. suyi
15.9.2017

2. Contents
– Introduction
– Disorders of glucose metabolism
– Disorders of fructose metabolism
– Disorder of galactose metabolism
– Conclusion
– References

3. Introduction
– Carbohydrates are widely distributed in plants and animals
– Major source of energy
– If there is any defect in carbohydrate metabolism, there will
be clinical consequences and may evenly lead to death

4. – Inborn error may occur in metabolism of all biomolecules
– Errors occur due to defective enzyme
– The effected enzyme may be absent or deficient
– The defect occur due to mutation in coding gene of the enzyme
– If the enzyme
– totally inactive  the reaction will not occur (absent enzyme)
– Decreased activity  the reaction velocity will decrease (deficient enzyme)
– When an enzyme of a metabolic pathway is absent or deficient, the
entire pathway become abnormal.
– Such abnormalities can occur in carbohydrate metabolism.

5. Disorders of glucose metabolism
– Pyruvate kinase deficiency
– Pyruvate dehydrogenase deficiency
– Muscle phosphofructokinase deficiency
– Glucose 6 phosphate dehydrogenase deficiency
– Essential pentosuria
– Glycogen storage diseases

6. Pyruvate kinase deficiency
– Autosomal recessive disease
– The most common enzyme defect in glycolytic pathway

7. – Almost all individuals with PK deficiency have mutant enzyme
– The enzyme may show
– Abnormal response to the activator Fructose 1,6-bisphosphate
– Abnormal Km or Vmax for substrate or coenzyme
– Altered enzyme activity
– Amount of enzyme decrease

8. – 90% of energy in RBC comes from glycolysis
– ATP is needed for maintenance of membrane structure
– Defect in PK  reduced rate of glycolysis  decreased ATP production 
alterations in RBC membrane  phagocytosed by the RE system  hemolytic
anaemia
– Symptoms due to hemolytic anaemia, splenomegaly, hepatomegaly
– Treatment include blood transfusion, splenectomy

9. – The effect restricted to RBC
– Hepatic PK is encoded by the same gene as the RBC isozyme.
– Liver cells show no effect because they have mitochondria and can generate
ATP by oxidative phosphorylation
– Individuals with heterozygous for PK deficiency have resistance to the most
severe forms of malaria

10. Pyruvate dehydrogenase
deficiency
– Most common cause of congenital lactic acidosis
– The PDH complex is a protein aggregate containing three enzymes
– pyruvate dehydrogenase (E1)
– dihydrolipoyl transacetylase (E2), and
– dihydrolipoyl dehydrogenase (E3)
– E1  thiamine pyrophosphate (TPP)
– E2  lipoic acid and CoA
– E3  flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide
(NAD+)

11. Oxidative decarboxylation of pyruvate

12. Mechanism of action of PDH complex
• Pyruvate is decarboxylated by PDH
forming hydroxyethyl TDP
• Reacts with oxidized lipoamide group of
E2 forming acetyl lipoamide
• Reacts with coenzyme A forming acetyl
CoA
• Reduced lipoamide is oxidized by FAD
which is bound to E3
• FADH2 is then oxidized back to FAD by
NAD

14. – Symptoms
– varies
– Neurodegeneration
– muscle spasticity
– in the neonatal onset form, early death
– Treatment
– dietary restriction of carbohydrate
– supplementation with thiamine

15. – Deficiencies of thiamine or niacin can cause serious central nervous system
problems. This is because brain cells are unable to produce sufficient ATP (via
the TCA cycle) if the PDH complex is inactive.
– Wernicke-Korsakoff, an encephalopathy-psychosis syndrome due to thiamine
deficiency, may be seen with alcohol abuse.
– Arsenic and mercury ions react with the SH group of the lipoic acid and inhibit
the PDH

16. Muscle phosphofructokinase
deficiency
– Rare
– The exercise capacity of the muscle is low
– Symptoms worsen after carbohydrate rich diet
– Provide lipid as alternative fuel
– Work capacity is improved when blood FFA or ketone bodies level are increased

17. • Found in liver, lactating
mammary gland,
adipocyte, adrenal cortex,
RBC
• Irreversible oxidative
reactions
• Reversible non-oxidative
reactions
• Provide  NADPH, ribose
5 phosphate
Hexose
monophosphate
shunt

18. Glucose 6 phosphate
dehydrogenase deficiency
– Common in Mediterranean and Afro Caribbean people
– 400 million people carries mutated gene
– caused by point mutation
– many mutant enzymes show
– decreased catalytic activity
– decreased stability, or
– an alteration of binding affinity for NADP +, NADPH, or glucose 6-phosphate
– The severity of the disease usually correlates with the amount of residual
enzyme activity in the patient’s RBC.

19. • Present on X chromosome
q28locus
• Mainly affect males

20. Uses of NADPH
– Reductive synthesis
– Reduction of H2O2
– Cytochrome P450 monooxygenase system
– Phagocytosis
– Synthesis of NO

21. Reduction of H2O2
– Hydrogen peroxide (H2O2) is one of a family of reactive oxygen species (ROS)
that are formed from the partial reduction of molecular oxygen.
– These compounds are formed continuously as byproducts of aerobic
metabolism.
– When the level of antioxidants is diminished, oxidative stress will occur.
– The highly reactive oxygen intermediates can cause damage to DNA, proteins,
and unsaturated lipids and can lead to cell death.
– The cell has several protective mechanisms that minimize the toxic potential of
these compounds.

22. Pathways of glucose 6-phosphate metabolism in the erythrocyte

23. Role of G6PD in RBC
– Defect in G6PD  NADPH reduce
– Decrease level of reduced glutathione
– Decrease in cellular detoxification of free radicals and peroxides
– Oxidation of sulfhydryl groups of proteins, including Hb  Heinz bodies
– Oxidation of membrane protein
– RBC membrane become rigid and nondeformable
– Destroyed by RE cells

24. Precipitating factors in G6PD deficiency
– Most individuals do not show symptoms
– Present neonatal jaundice
– Develop hemolytic anaemia if they are exposed to
– Oxidant drugs (A=antibiotic, A=antimalarial, A=antipyretics)
– Favism (the hemolytic effect of ingesting fava beans is not seen in all
individuals with G6PD deficiency, but all patients with favism have G6PD
deficiency)
– Infections (the inflammatory response to infection generate free radicals in
macrophage which can diffuse into RBC causing oxidative damage )

25. • Rare benign hereditary
condition
• Deficiency of xylulose
reductase
• No clinical consequence
except pentosuria which
can give false positive
benedict test
Essential
pentosuria

26. Glycogen storage disease
– Generic term to describe A group of inherited disorders
– Autosomal recessive disorder
– Caused by deficiency of enzymes of glycogen metabolism in both liver and
muscle
– Characterized by deposition of an abnormal type or quantity of glycogen in
tissues or failure to mobilize glycogen
– Lead to liver damage and muscle weakness
– Sometimes , early death

27. Glycogen
– Storage form of glucose
– Present in
– Liver  maintain blood glucose level
– Muscle  server as a fuel reserve during muscle exercise

30. Lysosomal degradation of glycogen
– A small amount of glycogen is continuously degraded by the lysosomal enzyme,
glycosidase
– Purpose is unknown
– Deficiency of this enzyme  accumulation of glycogen in lysosome  Pompe
disease

32. Disorders of fructose metabolism
– Essential fructosuria
– Hereditary fructose intolerance

34. Essential fructosuria
– Fructokinase deficiency
– Benign
– Autosomal recessive
– Fructose accumulate in urine

35. Hereditary fructose intolerance
– Aldolase B deficiency
– Severe clinical condition
– Symptoms begin when the baby is exposed to sucrose or fructose diet
– Fructose 1P trapped in the cell  drop in Pi level  ATP falls, AMP rises
 AMP degraded in the absence of Pi  hyperuricaemia
– Hepatic ATP falls  gluconeogenesis decrease  severe hypoglycaemia
– Hepatic ATP falls  decrease protein synthesis  decrease CF and
essential proteins
– Treatment
– Rapid detection and removal of sucrose and fructose in the diet

36. Disorder of galactose metabolism
– Galactosemia

38. Classic galactosemia
– Uridyltransferase deficiency
– Autosomal recessive disorder
– Accumulation of Gal 1-P  liver
damage, severe mental
retardation, ovarian failure and
cataracts
– Therapy  rapid diagnosis and
removal of lactose from the diet
Galcactokinase deficiency
– Galcactokinase deficiency
– Rare autosomal recessive disorder
– Benign condition
– Causes elevation of galactose in
blood and urine
– Causes galactitol accumulation if
galactose is present in the diet

39. Diabetes Mellitus
– Not one disease, but rather is a heterogeneous group of multifactorial,
polygenic syndromes characterized by an elevated fasting blood glucose (FBG)
caused by a relative or absolute deficiency in insulin.
– Diabetes is the leading cause of adult blindness and amputation and a major
cause of renal failure, nerve damage, heart attacks, and strokes.
– Two types
– type 1 formerly called insulin-dependent diabetes mellitus and
– type 2 formerly called noninsulin-dependent diabetes mellitus

40. Type I DM
– Characterized by an absolute deficiency of insulin caused by an autoimmune
attack on the β cells of the pancreas
– Over a period of years, this autoimmune attack on the β cells leads to gradual
depletion of the β-cell population
– Symptoms appear abruptly when 90% of the β cells have been destroyed
– At this point, the pancreas fails to respond adequately to ingestion of glucose,
and insulin therapy is required

41. Metabolic changes in Type I DM
– Affect liver, muscle and adipocyte
– Hyperglycaemia
– increased hepatic production of glucose via gluconeogenesis
– Decreased peripheral utilization (muscle and adipose tissue have the insulinsensitive
glucose transporter GLUT-4
– Ketoacidosis
– Increased mobilization of fatty acids (FAs) from adipose tissue
– Accelerated hepatic β-oxidation which lead to Increased synthesis of ketone bodies
– Hypertriacylglycerolemia
– fatty acids  triacylglycerol (TAG), which is packaged and secreted in VLDLs
– Decreased lipoprotein lipase
– Increased chylomicron and VLDL

42. Type II DM
– Common
– Due to insulin resistance
– Obesity usually present
– Frequently age 37
– Symptoms develop gradually

43. Metabolic changes in Type II DM
– Result of insulin resistance on liver, muscle and adipose tissue
– Hyperglycaemia
– increased hepatic production of glucose, combined with diminished
peripheral use
– Hypertriacylglycerolemia
– chylomicron and VLDL levels are elevated

44. – The long-standing elevation of blood glucose is associated with the
chronic complications of diabetes including
– atherosclerosis (macrovascular)
– retinopathy, nephropathy, and neuropathy (microvascular)
– Both fructose and sorbitol are found in the lens in increased
concentration in DM  diabetic cataract
– The sorbitol pathway (not in liver) is responsible for fructose
formation from glucose and increases in activity in tissues that are
not insulin sensitive

45. Conclusion
– Defects in carbohydrate metabolism not only affect the carbohydrate
metabolic pathways but also other metabolic pathways
– Some diseases are fatal, so early detection and adequate treatment is
required.

46. References
– John W Baynes and Marek H Dominiczak; Medical Biochemistry 3rd edition
– Robert K. Murray, David A. Bender, Kathleen M. Botham, Peter J. Kennelly,
Victor W. Rodwell, P. Anthony Weil; Harper’s Illustrated Biochemistry 30th
edition
– MN Chatterjae, Rana Shinde; Japee’s Textbook of Medical Biochemistry 8th
edition
– Lippincott’s Illustrated Biochemistry 6th edition

47. Thank You