A brief presentation for quick and easy learning on carbohydrate metabolism and inborn errors.

1. CARBOHYDRATE
METABOLISM

4. Glucose transporters

5. Carbohydrate metabolism
• Embden-Meyerhof Pathway
• Glucose is split into two 3 carbon pyruvate molecules under aerobic
conditions; or lactate under aenorobic condtions
• All steps in cytoplasm
• Glycolysis is a definite sequence of ten reactions involving
intermediate compounds

6. Significance
• Only pathway taking place in all cells of the body
• Only source of energy in RBCs
• In strenuous exercise, when muscle tissue lacks
oxygen, anaerobic glycolysis forms major source of
energy for muscles
• Preliminary step before complete oxidation

11. Anaerobic Glycolysis

12. Energetics

14. Gluconeogenesis

17. Regulation of blood glucose

21. Cori cycle

22. Clinical Significance
1. Pyruvate Kinase deficiency: Hemolytic anemia
ATP amount is decreased so ATPase pump is disturbed in RBCs leading
to hemolysis.
2. Muscle cramps: due to excessive exercise leading to anaerobic
glycolysis causing accumulation of lactic acid in muscles.

23. TCA CYCLE

24. • The citric acid cycle — also known as the tricarboxylic acid cycle (TCA
cycle), the Krebs cycle, or the Szent-Gyorgyi-Krebs cycle
• In eukaryotic cells, the citric acid cycle occurs in the matrix of the
mitochondrion.
• In aerobic organisms, the citric acid cycle is part of a metabolic
pathway involved in the chemical conversion of carbohydrates, fats
and proteins into carbon dioxide and water to generate a form of
usable energy.

25. Functions of TCA cycle
1. It is the final common oxidative pathway that oxidizes acetyl CoA to
CO2.
2. It is the source of reduced coenzymes that provide the substrate for
the respiratory chain.
3. It acts as a link between catabolic and anabolic pathways
(amphibolic role).
4. It provides precursors for synthesis of amino acids and nucleotides.
5. Components of the cycle have a direct or indirect controlling effect
on key enzymes of other pathways.

27. PDH complex

29. Energetics

30. TCA is anaplerotic and amphibolic reaction

31. Inhibitors of TCA cycle
Aconitase (citrate to aconitate) is inhibited by fluoro-acetate. This is
non-competitive inhibition.
Alpha ketoglutarate dehydrogenase (alpha ketoglutarate to succinyl
CoA) is inhibited by Arsenite. This again is non-competitive inhibition.
Succinate dehydrogenase (succinate to fumarate) is inhibited by
malonate; this is competitive inhibition

32. GLYCOGEN METABOLISM

33. • Glycogen: Storage form of glucose
• Polysaccharide of glucose
• Stored in liver and muscles

40. Von gierke disease

42. HMP Shunt

43. • Alternate pathway for oxidation of glucose
• In cytosol
• Provides NADPH and pentoses
• Most common site: liver, adipose tissue, lactating mammary glands,
adrenal cortex, testes, RBCs.

48. FRUCTOSE METABOLISM

49. 49
❖ Sources of fructose:- sucrose from diet, fruits & honey
❖ Fructose is absorbed into intestinal cells via facilitated diffusion
(GLUT 5)
❖ Fructose enters blood stream, along with glucose and galactose via
GLUT II transporter.
❖ Uptake of fructose by cells is insulin independent.
❖ Fructose is metabolized differently in Liver and Muscle &
Extrahepatic tissues.
❖ Fructose undergoes more rapid glycolysis than does glucose, as it
bypasses regulatory step catalyzed by PFK
FRUCTOSE

51. 51
GLYCOLYSIS
FRUCTOSE
METABOLISM IN
LIVER

52. 52
FRUCTOSE
METABOLISM
IN MUSCLE &
EXTRAHEPATIC
TISSUES

54. 54
SORBITOL/ POLYOL PATHWAY
➢ Fructose is found in seminal plasma.
➢ Aldose reductase is responsible for the secretion of sorbitol into the
fetal blood.
➢ The presence of sorbitol dehydrogenase in the liver, including the
fetal liver, is responsible for the conversion of sorbitol into
fructose.
➢ This pathway is also responsible for the occurrence of fructose in
seminal fluid.

56. DEFECTS IN FRUCTOSE METABOLISM
ESSENTIAL FRUCTOSURIA
• Autosomal recessive
•Lack of fructokinase
•fructose accumulates in blood
and is excreted into the urine
HEREDITARY FRUCTOSE
INTOLERANCE
•Lack of aldolase B
•Autosomal recessive
•F-1-P accumulates in the liver cells
to such an extent that most of the Pi
is removed from the cytosol.
T/t:- Fructose
free diet.

57. 57
❖ Galactose is derived from intestinal hydrolysis of the disaccharide
lactose, the sugar found in milk.
❖ It is readily converted in the liver to glucose.
❖ Galactose is required in the body :-
• For the formation of lactose in lactation,
• As a constituent of glycolipids (cerebrosides), proteoglycans, and
glycoproteins.
GALACTOSE

58. GALACTOSE METABOLISM

59. 59
PATHWAY OF CONVERSION OF
GALACTOSE TO GLUCOSE IN THE LIVER

60. 60
PATHWAY OF CONVERSION OF GLUCOSE
TO LACTOSE IN THE LACTATING
MAMMARY GLAND

61. 61
GALACTOSEMIA
• Hereditary deficiency of Gal-1-P uridyl transferase
(CLASSIC GALACTOSEMIA.)
•Also, due to deficiency of Galactokinase/ UDP hexose
4 epimerase.
• Accumulation of galactose-1-P
•T/t:- Restriction of milk and milk-products in the diet
atleast 4-5 yrs of life.
•Galactose 1 phosphate pyrophosphorylase becomes
active by 4-5 yrs of life which can reduce gal-1-
phosphate.
•Breast milk is avoided.

62. Lactose intolerance
• Deficiency of lactase enzyme.
• Lactose is not digested in such individuals, leading to
lactose accumulation.
• Diagnosis:
❑intestinal biopsy,
❑lactose loading test,
❑hydrogen breath test

63. Regulation of blood glucose level

65. Stages of maintenance of blood glucose level
A)Absorptive stage
Starts from feeding and lasts upto 3-4 hours after meals.
Dietary glucose goes to liver and then to most of tissues– used as fuel
Excess is stored as glycogen in liver and muscles
B)Post absorptive phase
Lasts for 16-18 hours after absorption is completed.
Liver glycogenolysis become major source of blood glucose
Muscle uses its glycogen stores for energy
Gluconeogenesis starts gradually and peaks about 24 hours after last meals
Glycogenolysis declining after 16- 18 hours and about 24- 30 hours negligible

66. C)Starvation
After 1-1.5 day of starvation, gluconeogenesis is main source
Fatty acids mobilized from adipose tissues
Lactate and glycerol are reutilised for gluconeogenesis
D)Prolonged starvation
Beyond 2-3 days and extends into weeks
Gluconeogenesis in kidneys become significant
Proteins in muscle broken down
Lipid stores are also depleted and complications like
ketoacidosis, dehydration etc

68. insulin

69. Facts regarding Insulin secretion -
No insulin is produced when the blood glucose is below < 50
mg/dL.
Insulin acts to reduce blood glucose immediately by enhancing glucose
transport into adipose tissue and muscle by recruitment of glucose
transporters (GLUT4) from interior of the cell to the plasma membrane.

70. Glucagon
• Produced by alpha cells of the pancreatic
islets in response of
hypoglycemia
• In liver stimulates glycogenolysis by
activating glycogen phosphorylase
• No effect on muscle phosphorylase
• Also enhances gluconeogenesis from amino
acids and lactate
• Action through generation of cAMP.
• Hyperglycemic effect

71. GH & ACTH
decreases glucose uptake in muscles.
stimulates mobilization of non esterified fatty acids from adipose tissues
which inhibit glucose utilisation
GLUCOCORTICOIDS
increase hepatic catabolism of amino acids → gluconeogenesis (due to
induction of amino transferases and key enzymes of gluconeogenesis).
inhibit utilization of glucose by extrahepatic tissues.
Other hormones affecting blood glucose

72. Oral Glucose Tolerance Test
Indication -
1. Diagnosis of gestational diabetes
2. Population study for epidemiological data
3. Evaluation of unexplained nephro, retino and neuropathy.

73. Oral glucose tolerance test
• Glucose load: adults- 75g anhydrous glucose in 250-300mL water.
• Children- 1.75g/Kg body weight
• Pregnancy- 50g for glucose challenge test and 75g in GTT.
• Samples: modern GTT called as mini GTT: only 2 samples. Fasting and
2hr post glucose load urine and blood sample.

74. • GLUCOSE CHALLENGE TEST: only 2 hr blood post glucose load
• GLUCOSE TOLERANCE TEST in pregnancy: 3 samples are taken, fasting,
1hour and 2 hour.

75. NORMAL DIABETES MELLITUS IMPAIRED GLUCOSE
TOLERANCE
FASTING <100mg/dL (<5.6mmol/L) >126mg/dL (>7mmol/L) 110-125mg/dL
1HR POST GLUCOSE LOAD <160mg/dL (<9mmol/L) -- --
2 HR POST GLUCOSE LOAD <140mg/dL (<7.8mmol/L) >200mg/dL (>11.1mmol/L) 140-199mg/dL
HbA1C <5.6% >6.5% 5.6-6.4%

76. Glucose tolerance test:

77. Diabetes mellitus
• The classic symptoms are:
Polyuria
Polyphagia
Polydypsia
Diabetes mellitus is 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.

78. • Complications:
Increased risk for infections
Delayed healing
Neuropathy
nephropathy

80. Type 1 DM
• The disease is characterized by an absolute deficiency of insulin
caused by an autoimmune attack on the β cells of the pancreas.
• The onset of T1D is typically during childhood or puberty, and
symptoms develop suddenly
• Polyuria (frequent urination), polydipsia (excessive thirst), and
polyphagia (excessive hunger), often triggered by physiologic stress
such as an illness, fatigue and weight loss
• Diagnosis: glycosylated hemoglobin concentration ≥ 6.5 mg/dl
(normal is less than 5.7), or a FBG ≥ 126 mg/dl (normal is 70–99)

81. TREATMENT:
• Insulin therapy, Immunotherapy, Gene therapy, pancreas
transplant, Stem cell based therapy.

82. Type 2 DM
• T2D is the most common form of the disease
• many individuals with T2D have symptoms of polyuria and polydipsia
of several weeks’ duration. Polyphagia may be present but is less
common
• Patients with T2D have a combination of insulin resistance and
dysfunctional β cells but do not require insulin to sustain life,
although insulin eventually will be required to control hyperglycemia
• Pathogenesis: insulin resistance, Dysfunctional Beta cells of pancreas

83. TREATMENT:
• Weight reduction, exercise, and medical nutrition therapy (dietary
modifications)
• Hypoglycemic agents (for example, metformin, which decreases
hepatic output of glucose), sulfonylureas (increase insulin secretion),
thiazolidinediones (increase peripheral insulin sensitivity), α-
glucosidase inhibitors (decrease absorption of dietary carbohydrate)
or insulin therapy may be required to achieve satisfactory plasma
glucose levels.

86. Various investigations for DM
• Diabetes mellitus (type 1 or IDDM) is characterized by impaired
glucose tolerance as a result of decreased insulin secretion
• Investigations:
• 1. Blood fasting gluose – monthly
• 2. Glycated Hb – quarterly
• 3. Lipid and Renal Profile – 6 monthly
• 4. Microalbuminuria – once a year.

87. Diagnosis of DM

88. Glycated Hemoglobin
• Beta chain of Hb that has been modified by the non
enzymatic addition of glucose residues (at valine).
• HbA + Glucose rapid Pre Hb A1c
fast HbA1c
• It represents integrated values for glucose over the
preceding 8 to 12 weeks.
• > 6.5% - diagnosis of diabetes
• 5.7-6.4% - high risk of developing
diabetes

89. • Treatment:
Lifestyle modifications
Nutrional care
Oral hypoglycemic drugs like sulfonylureas, biguanides etc.
Insulin therapy

90. Inborn errors of carbohydrate metabolism
• A genetically determined biochemical disorder in which a specific
enzyme defect produces a metabolic block that may have pathologic
consequences at birth or in later life;also known as enzymopathy and
genetotrophic disease.

91. INBORN ERRORS OF CARBOHYDRATE METABOLISM
1. GLYCOGEN STORAGE DISORDERS
2. DISORDERS OF FRUCTOSE METABOLISM
3. GALACTOSEMIA
4. HEMOLYTIC DISEASE due to G6PD deficiency
5. HEMOLYTIC ANEMIA due to PK deficiency
6. LACTOSE INTOLERANCE

93. DISORDERS OF FRUCTOSE METABOLISM
• Hereditary fructose intolerance- deficiency of aldolase B
• Essential fructosuria- deficiency of fructokinase
GALACTOSEMIA: Deficiency of galactose-1-phosphate uridyl
transferase or galactokinase or UDP-galactose-4-epimerase

94. Disorders of glucose metabolism:
• Pyruvate kinase deficiency: hemolytic anemia
• Pyruvate dehydrogenase deficiency: causes lactic acidosis.