1. Introduction to glucose metabolism

2. Overview of glucose metabolism

3. Objectives
Recognizing the critical importance of glucose as the main carbohydrate of blood & main fuel of human cells.
Recalling the sources of blood glucose in feed & fasting states.
Recognizing glucose transport into cells
Understand the basic concepts & directions (pathways) of metabolism.

4. General importance of carbohydrates in human body
1- Provide energy through metabolism pathways and cycles
2- Store energy in the form of:
starch (in plants)
glycogen (in animals and humans)
3- Supply carbon for synthesis of other compounds.
4- Form structural components in cells and tissues.

5. Critical importance of glucose
A constant source of GLUCOSE is an absolute requirement for human life as it is: Preferred energy of the brain Required energy source for cells with no or few mitochondria (as RBCs) Essential source of energy for exercising muscles (substrate for anerobic glycolysis)

6. Metabolic Pathways of Glucose Production and Utilization
HMP/PPP
Glycogenolysis
Hexose interconversion
Glucose
Gluconeogenesis
Glycogenesis
Hexose interconversion
Utilization
Production
Glycolysis
Krebs cycle

7. Metabolism of Glucose GLUCOSE Glycogen Pyruvate NADPH Acetyl CoA
Citric Acid Cycle
NADH & FADH2
Electron transport chain (flow of electrons)
Formation of ATP
(oxidative phosphorylation)
HEXOSE MONOPHOSPHATE
PATHWAY
GLYCOGEN
SYNTHESIS
Ribose-5 Phosphate
Glycogen
NADPH
GLYCOLYSIS
No Oxygen
No Mitochondria
OR BOTH
Metabolism of
Glucose
Lactate
Oxygen
&
Mitochondria

8. Pathways of glucose metabolism
1- Catabolic pathways:
1- For providing energy (ATP): Glycolysis
Anaerobic Glycolysis: end product is lactate
Aerobic Glycolysis: end product is pyruvate
2- For providing synthetic products: Hexose monophosphate pathway
(Produces NADPH & Ribose 5-Phosphate)
2- Synthetic pathways:
Glycogen synthesis

9. Sources of Glucose to human Body
Glucose can be obtained from three primary sources:
Carbohydrate in Diet:
Carbohydrates are sources for glucose of the body after meals.
Excess glucose is stored in the form of glycogen in liver & skeletal muscles.
Glycogen degradation (Glycogenlysis):
Glycogen (synthesized from glucose molecules) is stored in liver & skeletal muscles.
In cases of fasting, liver glycogen is degraded to yield glucose for blood.
In cases of muscular exercise, muscle glycogen is degraded to secure glucose for muscles as a source of energy.
Gluconeogenesis (Glucose Synthesis):
It is the synthesis of glucose from non carbohydrate sources (as some amino acids)
It occurs in prolonged fasting

10. Sources of glucose of carbohydrate diet
1- Free Monosaccharides:
mainly glucose & fructose
Fructose is converted into glucose in liver
2- Disaccharides:
- Sucrose (glucose & fructose)
- Lactose (glucose & galactose)
- Maltose (glucose & glucose)
They are digested into monosaccharides (glucose, fructose & galactose) in the intestine.
Fructose & galactose are converted into glucose in the liver
3-Polysaccharides:
- Starch (plant source e.g. rice, potato, flour)
- Glycogen (animal source)
They are digested into glucose in the GIT

11. Sources of glucose of carbohydrate diet

12. Glucose transport into cells
1- Na+-independent facilitated diffusion transport:
Transport occurs with concentration gradient
No requirement for ATP
It is conducted by a group of at least 14 glucose transporters (GLUT-1 to 14)

13. Glucose transport into cells

14. Glucose transport into cells
GLUT-1 is abundant in RBCs & Brain GLUT-2 is found in liver, kidney & b-cells of the pancreas Function in both directions (from blood to cells & from cells to blood) GLUT-3 primary glucose transporter in neurons GLUT-4 is abundant in adipose tissue & skeletal muscles Number is increased by insulin GLUT-5 is the primary transporter of fructose GLUT-7 is expressed in gluconeogenic tissue (as the liver) mediates glucose flux across ER membrane

15. Glucose transport into cells
2- Na+-monosaccharide cotransporter system
Energy-requiring process that transports glucose against a concentration gradient from low glucose concentrations outside the cell to higher concentrations within the cell
It is a carrier-mediated process in which the movement of glucose is coupled to the concentration gradient of Na+, which is transported into the cell at the same time
This type of transport occurs in the epithelial cells of the intestine & renal tubules

16. GLUCOSE TRANSPORT & INSULIN16

17. Glycolysis

18. Glycolysis
Glycolysis is the breakdown of glucose to: 1- Provide energy (in the form of ATP) 2- Provide intermediates for other metabolic pathways. It occurs in cytosols of all tissues All sugars can be converted to glucose & thus can be metabolized by glycolysis.

19. End products of glycolysis
1- In cells with mitochondria & an adequate supply of oxygen (Aerobic glycolysis) - Pyruvate: enters the mitochondria & is converted into acetyl CoA. Acetyl CoA enters citric acid cycle (Krebs cycle) to yield energy in the form of ATP - NADH: utilizes mitochondria & oxygen to yield energy 2- In cells with no mitochondria or adequate oxygen (or Both) (Anaerobic glycolysis) Lactate: formed from pyruvate (by utilizing NADH)

20. End products of glycolysis
NADH
is an end product
of aerobic glycolysis
Pyruvate
is the end product
of aerobic glycolysis
Lactate
is the end product
of anaerobic glycolysis

21. Overall reactions of glycolysis

22. Key enzymes in glycolysis
1- Hexokinase & Glucokinase
Glucose Glucose 6-phosphate
2- Phosphofructokinase (PFK)
Fructose 6-phosphate Fructose 1,6 bisphosphate
3- Pyruvate Kinase (PK)
Phosphoenel pyruvate Pyruvate

23. Overall reactions of glycolysis
Steps catalyzed By
key enzymes

24. Hexokinase & gluockinase
HEXOKINASE
GLUCOKINASE
LOCALIZATION
Most tissues
Hepatocytes & Pancreas
Specificity
Broad specificity for all hexoses
Same
Kinetics Km
Low Km
High Affinity
Permits efficient phosph. of glucose even when tissue concentration of glucose is low
High Km
Low Affinity
Requires high concentration of glucose for 1/2 saturation So
It permits metabolism of glucose when I.C. concentration of glucose in liver cells are increased
Vmax
Low Vmax
Cannot trap glucose more than cell need
High Vmax
Allow liver to remove flux of glucose from blood (after absorption) To
Reduce hyperglycemia after diet & absorption.
Effect of insulin
(regulation by insulin)
Synthesis not affected by insulin
Synthesis is increased by insulin

26. Energy yield from glycolysis
1- Anerobic glycolysis
2 molecule of ATP for each one molecule of glucose converted to 2 molecules of lactate
It is a valuable source of energy under the following conditions
1- Oxygen supply is limited as in muscles during intensive exercise
2- Tissues with no mitochondria
Kidney medulla
RBCs
Leukocytes
Lens & cornea cells
Testes
2-Aerobic glycolysis
2 moles of ATP for each one mol of glucose converted to 2 moles of pyruvate
2 molecules of NADH for each molecule of glucose
2 or 3 ATPs for each NADH entering electric transport chain (ETC) in mitochondria.

27. Genetic defects of glycolytic enzymes
Pyruvate kinase deficiency (95% of cases)
PK deficiency leads to a reduced rate of glycolysis with decreased ATP production.
PK deficiency effect is restricted RBCs.
As RBCs has no mitochondria & so get ATP only from glycolysis.
RBCs needs ATP mainly for maintaining the bio- concave flexible shape of the cell.
PK deficiency leads to severe deficiency of ATP for RBCs. So, RBCs fail to maintain bi-concave shape ending in liability to be lysed (hemolysis).
Excessive lysis of RBCs leads to chronic hemolytic anemia.

28. Energy yield from glycolysis
In anaerobic glycolysis:
2 ATP for one glucose molecule
In aerobic glycolysis
Glycolysis: 2 ATP
2 NADH: 2 X 3 = 6 ATP
NADH
Pyruvate Acetyl CoA
2 Pyruvate produce 2 Acetyl CoA (& 2 NADH): 2 X 3 = 6 ATP
2 Acetl CoA in citric acid cycle: 2 X 12 = 24 ATP

29. GLUCOSE Energy yield of aerobic glycolysis Energy yield of
anaerobic glycolysis
GLUCOSE
Net = 38 ATP / glucose molecule
Net = 2 ATP/ glucose molecule
2NAD+
2 ATP
2 NADH
= 2 X 3 = 6 ATP
No Oxygen
No Mitochondria
OR BOTH
Oxygen
&
Mitochondria
2 Lactate
2 PYRUVATE
2NAD+
2 NADH
= 2 X 3 = 6 ATP
2 ACETYL CoA
CITRIC ACID CYCLE
= 2 X 12 = 24 ATP

30. Fate of pyruvate
1- Lactate: in anaerobic glycolysis (in cytosol) 2- Acetyl CoA: in aerobic glycolysis (in mitochondria & available oxygen) 3- Oxalacetate: required for: 1- Citric acid cycle (condenses with acetyl CoA): to yield energy (ATP) OR 2-Gluconeogenesis (to synthesize glucose)

31. Fate of Pyruvate Glucose ACETYL CoA glycolysis Gluconeogenesis
No Oxygen
No Mitochondria
OR BOTH
PYRUVATE
LACTATE
OXALACETATE
Oxygen
&
Mitochondria
ACETYL CoA
CITRIC ACID CYCLE

32. Formation of acetyl CoA from pyruvate
Pyruvate (end product of aerobic glycolysis) is transported into the mitochondria.
In the mitochondrial matrix, pyruvate is converted to acetyl CoA by
pyruvate dehydrogenase complex (multienzyme complex)
This reaction is irreversible
Pyruvate dehydrogenase complex is composed of three enzymes & five coenzymes
Coenzymes of the complex are derived from water soluble vitamins:
1- Thiamine pyruphosphate, TPP (derived from thiamine, vitamin B1)
2- NAD+ (derived from niacin)
3- FAD (derived from riboflavin)
4- Lipoic acid
5- Coenzyme A (derived from pantothenic acid)

33. Pyruvate dehydrogenase complex
ACETYL CoA

34. Citric acid cycle or,(Krebs cycle)

35. Citric acid cycle or,(Krebs cycle)
Citric acid cycle is the final pathway where the oxidative metabolism of Carbohydrates (as glucose), proteins (amino acids) & lipids (fatty acids) to yield energy (ATP)
Acetyl CoA is the end product for oxidation of carbohydrates, lipids & proteins
Acetyl CoA condenses with oxalacetate to form citrate (first reaction of the cycle)
3 NADH are produced = 3 X 3 = 9 ATP (by oxidative phosphorylation)
One FADH2 is produced = 1 X 2 = 2 ATP (by oxidative phosphorylation)
One ATP is produced (by substrate level phosphorylation)
Net = 12 ATP / one acetyl CoA

36. Citric acid cycle or,(Krebs cycle)

37. GLUCONEOGENESIS  
Gluconeogenesis is the synthesis of glucose from glucogenic precursors
which are not of carbohydrate origin (gluconeogenic precursors)
It occurs during prolonged fasting to synthesize glucose for tissues
requiring continuous supply of glucose as a source of energy:
Brain, RBCs, Kidney medulla, Lens, Cornea, Testes, sk.ms
Gluconeogenesis occurs ONLY in the liver & kidneys

38. Gluconeogenic precursors
1- Intermediates of glycolysis
by reverse of steps of glycolysis (except 4 steps that need 4 different enzymes)
2- Intermediates of citric acid cycle
are converted to oxalacetate then to glucose
3- Lactate
Lactic acid formed of anaerobic glycolysis in cells as RBCs & skeletal muscles
are transported in blood to liver to be converted to pyruvate then to glucose (Cori cycle)
4- Glycerol
Glycerol is derived from the lipid triacylglycerol in adipose tissue.
Glycerol is convered into dihydroxyactone phosphate (intermediate of
glycolysis) then to glucose.
5- Glucogenic amino acids of proteins
Glucogenic amino acids are deaminated to form a-ketoacids
a-keto acids are converted to pyruvate or intermediates of citric acid cycle then to glucose

39. GLUCOSE Triacylglycerol in adipose tissue Precursors of
Gluconeogenesis
Fatty acids
Gluconeogenesis
Glycerol
Lactate
Oxalacetate
Pyruvate
Intermediate of
CITRIC ACID CYCLE
Glucogenic amino acids
in proteins as sk. ms.

40. Cori Cycle

41. Unique enzymes of gluconeogenesis are catalyzed by enzymes
Reactions 1, 2, 3 & 4
are catalyzed by enzymes
NOT used in glycolysis
GLUCOSE
1- Pyruvate to oxalacatate
by pyruvate carboxylase
2- oxalacetate to phosphoenol pyruvate
by PEP carboxykinase
3- Fructose 1,6 bisphosphate to fructose 6 phosphate
by fructose 1,6 bisphosphatase
4- Glucose 6-phosphate to glucose
by glucose 6-phosphatase
GLUCONEOGENESIS
Other reactions of gluconeogenesis are catalyzed
by same enzymes of glycolysis in the reverse direction