Gluconeogenesis and glycogen metabolism allow the body to maintain blood glucose levels. Gluconeogenesis occurs in the liver and kidneys and involves converting non-carbohydrate sources into glucose, especially during fasting when carbohydrate intake is low. Glycogen is stored in the liver and muscles and acts as a reserve for glucose. Glycogenesis is the process of glycogen synthesis, while glycogenolysis breaks down glycogen into glucose. Both processes are regulated by enzymes and effectors like insulin and glucagon to control blood glucose levels. Deficiencies in enzymes involved can cause glycogen storage diseases.

1. GLUCONEOGENESIS &
GLYCOGEN METABOLISM
By Dr.Sohil Takodara

2. Definition- “Synthesis of glucose from non-
carbohydrate sources is termed as
gluconeogenesis”
 Gluconeogenesis occurs mainly when the
availability of dietary carbohydrates is low, as
during fasting or when carbohydrates cannot be
metabolised, e.g. in diabetes mellitus

3. • Site – Liver (major), Kidney (Starvation)
• Subcellular site- Mainly Cytosol
Few Precursors in Mitochondria

4.  Though the energy requirements of the organism can be
met by lipids, provision of a certain amount of
carbohydrate is essential
 Certain tissues, e.g. brain and erythrocytes, are
dependent exclusively on glucose as a source of energy
 Adipose tissue requires glucose as a source of glycerol-
3-phosphate( absence of glycerol kinase) for
esterification of fatty acids

5.  Muscles require glucose as a source of energy
under anaerobic conditions
 Glucose is also required for the synthesis of lactose
during lactation
 Therefore, the organism meets the requirement for
glucose by converting non-carbohydrate
compounds into glucose when the availability of
glucose is low

6. Glucose
Lactate
Glucogenic
AA
Glycerol
Propionate

7. • In the past, it was believed that gluconeogenesis
occurred by a simple reversal of the reactions of
glycolytic pathway
• It was shown later that certain reactions of the
glycolytic pathway are because of
liberation of free energy

10. Irreversible glycolytic steps
bypassed
1. Hexokinase
2. Phosphofructokinase-1
3. Pyruvate kinase (PyrK)
by Glucose-6-phosphatase
by Fructose 1,6-bisphosphatase
by Pyruvate Carboxylase and
Phosphoenolpyruvate carboxykinase
Glycolysis Gluconeogenesis

11. ByPass-1

12. Muscle cant contribute towards Blood
Glucose??
• It lacks Glucose 6 Phosphatase
• In muscle Glucose 6 – phosphate gets diverted
to Energy production and glycogen
accumulation
• Liver maintains Blood Glucose

13. ByPass-2
Fructose

14. ByPass-3

16. Glucose
Lactate
Glucogenic
AA
Glycerol
Propionate

17. CORI CYCLE

18. Glucose Alanine [CAHILL] CYCLE

19. Glycerol
CH — OH2 CH — OH2
CH — OH2
| | |
CH — OH CH — OH C = O
| | |
CH — OH2 CH — O — P2
CH — O — P2
ATP ADP NAD
+
NADH+H
+
Glycerol kinase
Glycerol-3-phosphate
dehydrogenase
Glycerol Glycerol-3-
phosphate
Dihydroxyacetone
phosphate

20. Propionate

22. Alcohol ingestion leads to hypoglycemia…???
1) Alcohol inhibits Thiamine absorption.
2) ???

23. Ethanol Metabolism
ETHANOL ACETALDEHYDE
Alcohol
Dehydrogenase
NADH + H+
NAD+
ACETIC ACID
NAD+
NADH + H+

24. OXALOACETATE MALATE
Malate
Dehydrogenase
NAD+
NADH+ H+

25. Regulation
Enzyme Activation Inhibition
PC Glucagon, Cortisol,
Adrenalin , Acetyl Co
A
Insulin , ADP
PEPCK do Insulin
F-1,6 Bisphosohatase do F-1,6 Bisphosphate,
F-2,6 Bisphosphate
G-6 Phosphataase do Insulin

27. Energetics
Glucose Lactate
Glycolysis
(+ 2 ATP)
Gluconeogenesis
(-6ATP)

28. GLYCOGENESIS
Synthesis of glycogen is known as glycogenesis
 Glycogenesis is a mechanism by which excess
glucose can be stored in the tissues, to be used
when the supply of glucose becomes scarce
 Glycogenesis occurs in almost all the tissues in
our body, but the predominant sites for storage
of glycogen are

29. After a meal rich in carbohydrate, glycogenesis
occurs rapidly in liver and muscles
 Glycogenesis occurs in the

30. Requirments
• Glucose
• Glycogenin (Primer)
• Glycogen synthase
• Branching enzyme
• Pyrophosphorylase

31. Glycogenesis
PPi

32. Glycogenesis

33. Amylo-1,4 1,6-
transglucosidase
(branching
enzyme)

1, 6

34. This process of lengthening and branching
continues until a large and highly branched
glycogen molecule is formed
 Two branch points are separated by 8-12
glucose units

35. Regulation Glycogen
Synthase
Glycogen Synthase a
(Non
Phosphorylated)
Glycogen
Synthase b
(Phosphorylated)
Protein
Kinase
Protein
Phosphatase

36. Regulation
 Glycogen synthase is the regulatory enzyme
which is regulated by covalent modification
 The enzyme exists in two forms –
and
 The two forms can be converted into each other
by covalent modification

37. Regulation
 Glycogen synthase is the regulatory enzyme
which is regulated by covalent modification
 The enzyme exists in two forms –
and
 The two forms can be converted into each other
by covalent modification

38.  Addition of some phosphate groups to serine
residues converts glycogen synthase a into
glycogen synthase b
 Removal of the phosphate groups converts
glycogen synthase b into glycogen synthase a
 The dephosphorylated glycogen synthase a is the
active form of the enzyme
 The phosphorylated glycogen synthase b is the
inactive form

39. Phosphorylation of glycogen synthase a is
catalysed by cAMP-dependent protein kinase
(protein kinase A)
 Dephosphorylation of glycogen synthase b is
catalysed by protein phosphatase-1
 The relative activities of protein kinase A and
protein phosphatase-1 determine the amount of
active glycogen synthase in a cell

42. Glycogenesis-Regulation

43. Glycogenolysis
Breakdown of glycogen is known as
glycogenolysis
 Glycogenolysis is not a reversal of glycogenesis
but is a separate pathway having its own
enzymes
 Glycogenolysis occurs in all the tissues in which
glycogen is stored

44. The major sites of glycogenolysis are liver and
muscles in which large amounts of glycogen are
stored

 When blood glucose decreases, glycogenolysis
occurs in liver

45.  Glucose is released into circulation, and blood
glucose level is restored


46.  The key enzyme of glycogenolysis is
phosphorylase (glycogen phosphorylase)
which catalyses the phosphorolytic removal of
glucose from glycogen as glucose-1-phosphate
 This enzyme hydrolyses the terminal a-1,4-
glycosidic bonds at the non-reducing ends of the
glycogen molecule

47. (Glucose) + Pin
Phosphorylase
(Glucose) + Glucose-1-phosphaten–1

48. Glycogenolysis

49.  Presence of a large number of branches in the
glycogen molecule facilitates rapid
glycogenolysis as the terminal glucose units on
all the branches can be split off simultaneously
 The energy present in the glycosidic bond is
conserved by incorporating a phosphate group
into the liberated glucose molecule

50.  The process of stepwise removal of glucose
units from each branch continues until only four
glucose units are left distal to the branch points
 The molecule so formed is known as limit dextrin

51.  After the formation of limit dextrin, oligo-
(a-1,4a–1,4)-glucan transferase transfers a
trisaccharide from one branch to another
 Now, one branch has now got seven glucose
units distal to the branch point and the other has
got only one glucose unit linked to the main chain
by a-1,6-glycosidic bond

52.  The single glucose unit attached to the main
chain by 1,6-glycosidic linkage is split off by
amylo-1,6-glucosidase (debranching enzyme)
 This is not a phosphorolytic breakdown
 The glucose unit is liberated as free glucose

53. Amylo-1,6-glucosidase
(debranching enzyme)
+O

54.  This process of hydrolysis of 1,4- and 1,6-
glycosidic bonds continues until a very small
glycogen molecule is left
 The products of glycogenolysis are glucose-1-
phosphate and free glucose, which are formed in
the ratio of approximately 10:1
 This is due to the fact that branching occurs
approximately after every 10 glucose units in the
glycogen molecule

55.  Glucose-1-phosphate is converted into glucose-
6-phosphate by phosphoglucomutase
 The reaction is reversible as described earlier
 Many tissues, with the notable exception of
muscle, possess glucose-6-phosphatase
which splits off inorganic phosphate from
glucose-6-phosphate and liberates free glucose

56.  Thus, the end product of glycogenolysis is
glucose in most tissues e.g. liver, kidney,
intestine etc
 In muscle, the major end product is glucose-6-
phosphate

57.  Glycogenolysis occurs in muscles only
when energy is required for muscle
contraction
 Glucose-6-phosphate directly enters the
glycolytic pathway
 It is broken down to lactate as the conditions
during muscle contraction are usually
anaerobic

58. Regulation
 The regulatory enzyme is phosphorylase
 It occurs in two forms:
 Phosphorylase a (phosphorylated)
 Phosphorylase b (dephosphorylated)
 Phosphorylase a is the active form of the enzyme
while phosphorylase b is inactive

61. Regulation

62. Regulation of Glycogen Metabolism
Effectors Glycogen
Phosphorylase
Liver
Glycogen
Synthase
Liver
Glycogen
Phosphorylase
Muscle
Glycogen
Synthase
Muscle
Insulin I A I A
Glucagon A I A I
Epinephrine A I
ATP I I I I
AMP A A I
Glucose 6 P I A I A
Calcium A A

63. Glycogen Storage Disease
1.Von Gierke’s Disease
Glucose 6- Phosphatase
2. Pompe’s Disease
Lysosomal maltase or
glycosidase
4.Anderson’s Disease
Branching enzyme
5.McArdle’s Disease
Muscle phosphorylase
6.Her’s Disease
Liver Phosphorylase
3. Cori’s Disease
Debranching enzyme

64. Glycogen Storage Disease
DISEASE Enzyme Deficiency
1. Von Gierke’s Disease Glucose-6-Phosphatase
2. Pompe’s Disease Lysosomal maltase or glycosidase
3. Cori’s Disease Debranching enzyme
4. Anderson’s disease Branching enzyme
5. Mcardle’s disease Muscle Phosphorylase
6. Her’s Disease Liver Phophorylase

65. Von Gierke’s Disease
• Deficiency of Glucose 6 Phosphatase
• Most common Glycogen Storage Disorder
Clinical feature:
1) Hypoglycemia
2) Lactic Acidosis
3) Hyperlipidemia
4) Ketosis
5) Hyperuricemia
6) Hepatomegaly