1. Regulation of carbohydrate metabolism
Alice Skoumalová

2. Glycolysis

3. Gluconeogenesis

4. Metabolism of glycogen

5. Overview of the major pathways of glucose metabolism

6. Regulation of enzymes: Types of regulations Mechanism Example
Substrate concentration
Saturation kinetics (Michaelis-Menten equation)
Glucokinase (activation after a meal - high Km)
Allosterically
A conformational change after an allosteric activator binding
Enzymes of glycolysis and gluconeogenesis (allosteric efectors: ATP, AMP, citrate)
Covalent modification
A conformational change after phosphorylation by a protein kinase
Phosphorylation of glycogen synthase and glycogen phosphorylase (glucagon)
Protein-protein interaction
A conformational change after a modulator protein binding
Muscle glycogen phosphorylase (activation by Ca2+-calmodulin)
Zymogen cleavage
Activation by proteolysis of a precursor molecule
Blood clotting proteins
Enzyme synthesis
Induction or represion of enzyme synthesis
Enzymes of gluconeogenesis (induction during fasting)

7. Michaelis-Menten kinetics

8. Production of cAMP:

9. Regulation of gluconeogenesis and glycolysis:
inactivation of the glycolytic enzymes and activation of the enzymes of gluconeogenesis
1. Pyruvate ↔ PEP
Pyruvate kinase - inactivation by cAMP (glucagon)
Phosphoenolpyruvate carboxykinase - induced by glucagon, epinephrine, and cortisol
2. Fructose 1,6-P ↔ Fructose 6-P
Phosphofructokinase - activated by fructose 2,6-P
Fructose 1,6-bisphosphatase - inhibited by fructose 2,6-P
3. Glucose 6-P ↔ Glucose
Glucokinase - high Km for glucose, induced by insulin
Glucose 6-phosphatase - induced during fasting

10. Regulation of glycogenolysis in the liver by glucagon:
cAMP → protein kinase A:
1. inactivates glycogen synthase
2. activates glycogen phosphorylase

11. Regulation of glycogenolysis in muscle:

12. Regulation of liver and muscle glycogen metabolism:
State
Regulators
Response
Liver
Fasting
Glucagon ↑, Insulin ↓
cAMP ↑
Glycogen degradation ↑
Glycogen synthesis ↓
Carbohydrate meal
Glu ↑, Glucagon ↓, Insulin ↑
cAMP ↓
Glycogen degradation ↓ Glycogen synthesis ↑
Exercise and stress
Adrenalin ↑
cAMP ↑, Ca2+-calmodulin ↑
Glycogen degradation ↑ Glycogen synthesis ↓
Muscle
Fasting (rest)
Insulin ↓
Glucose transport ↓
Carbohydrate meal (rest)
Insulin ↑
Glycogen synthesis ↑
Glucose transport ↑
Exercise
Epinephrine ↑
AMP ↑, Ca2+-calmodulin ↑, cAMP ↑
Glycolysis ↑

13. Glucose homeostasis:
maintenance of blood glucose levels near 80 to 100 mg/dL (4,4-5,6 mmol/l)
insulin and glucagon (regulate fuel mobilization and storage)
Hypoglycemia prevention:
release of glucose from the large glycogen stores in the liver (glycogenolysis)
synthesis of glucose from lactate, glycerol, and amino acids in liver (gluconeogenesis)
release of fatty acids from adipose tissue (lipolysis)
Hyperglycemia prevention:
conversion of glucose to glycogen (glycogen synthesis)
conversion of glucose to triacylglycerols in liver and adipose tissue (lipogenesis)

14. Pathways regulated by the release of:
glucagon (in response to a lowering of blood glucose levels)
insulin (in response to an elevation of blood glucose levels)

15. Major sites of insulin action on fuel metabolism:
The storage of nutriens
glucose transport into muscle and adipose tissue
glucose storage as glycogen (liver, muscle)
conversion of glucose to TG (liver) and their storage (adipose tissue)
protein synthesis (liver, muscle)
inhibition of fuel mobilization

16. Major sites of glucagone action on fuel metabolism:
Mobilization of energy stores
release of glucose from liver glycogen
stimulating gluconeogenesis from lactate, glycerol, and amino acids (liver)
mobilizing fatty acids (adipose tissue)

17. Production of blood glucose
Glycogenolysis
2 hours after a meal
the primary source of blood glucose during the first few hours of fasting
Gluconeogenesis
after consumption of the liver glycogen
lactate (muscle, erythrocytes), amino acids (muscle), glycerol (adipose tissue)

18. Sources of blood glucose in fed, fasting, and starved states:

19. Blood glucose levels at various stages of fasting:
Stage of fasting
Glucose (mg/dL)
Glucose (mM/L)
Normal level
80-100
4,4-5,6
Fasting (12 h) 80
4,4
Starvation (3 d) 70
3,9
Starvation (5-6 wk) 65
3,6

20. Repetition:
3 key enzymes for the regulation of glycolysis (their activation). The role of Fructose 2,6-P in the regulation of glycolysis and gluconeogenesis.
3 key sites for the regulation of gluconeogenesis (their activation).
The signal pathway for the activation of glycogen degradation by glucagon.
Main regulators of glycogen degradation in liver and muscle.
Pathways preventing hypoglycemia and hyperglycemia.

21. Pictures used in the presentation:
Marks´ Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)