L31: Galactose/Glycogen Regulation

Question 1

How is glycogen metabolism mediated?

Answer 1

phosphorylation of glycogen synthase and glycogen phosphorylase

Question 2

What stimulates the liver and muscle to metabolize glycogen (allosterically)?

Answer 2

↑Glucose 6-P → ↑Glycogen synthase

Question 3

What stimulates only muscle to metabolize glycogen (allosterically)?

Answer 3

↑AMP or ↑Ca++ → ↑Glycogen phosphorylase

Question 4

What inhibits the liver and muscle to metabolize glycogen (allosterically)?

Answer 4

↑Glucose 6-P or ↑ATP → ↓Glycogen phosphorylase

Question 5

In glycogen metabolism, kinase is associated with activation of … and inactivation of …

Answer 5

Kinase associated with activation of glycogen phosphorylase and inactivation of glycogen synthase

Question 6

Liver has which hormone receptors for glycogen metabolism?

Answer 6

Glucagon and epinephrine receptors

Question 7

Muscle has which hormone receptors for glycogen metabolism?

Answer 7

epinephrine receptors only

Question 8

What is the role of insulin in glycogen regulation?

Answer 8

stimulate glycogen synthesis via PP1

1. Insulin activates glycogen synthase
2. Insulin inactivates glycogen phosphorylase

Question 9

Explain how insulin activates glycogen synthase.

Answer 9

Insulin activates protein phosphatase 1 (PP1) → PP1 hydrolyzes phosphate from inactive glycogen synthase b → active glycogen synthase a

Question 10

Explain how insulin inactivates glycogen phosphorylase.

Answer 10

Pathway: Insulin activates PP1 → PP1 hydrolyzes phosphate from active glycogen phosphorylase kinase a → inactive glycogen phosphorylase kinase b

Pathway: Insulin activates PP1 → PP1 inactivates glycogen phosphorylase b

Question 11

Explain the glycogen degradation pathway via hormone regulation. (Inhibitory)

Answer 11

Hormone (Glucagon or epipenphrine) binds to receptor → activates adenylyl cyclase (converts ATP to cAMP)
cAMP regulates protein kinase A (PKA) [cAMP binds regulatory subunits of PKA, which dissociate into the active PKA form]
Active PKA phosphorylates active glycogen synthase a → inactive glycogen synthase b → inhibit glycogen synthesis

Question 12

Explain the glycogen degradation pathway via hormone regulation. (Stimulatory)

Answer 12

Same cAMP pathway as above, but there is now an intermediate kinase (glycogen phosphorylase kinase)
Glycogen phosphorylase kinase can be phosphorylated by PKA
Opposite of glycogen synthase A:
Phosphorylation activates glycogen phosphorylase kinase A
Active glycogen phosphorylase kinase A activates glycogen phosphorylase A by phosphorylation→ stimulates glycogen breakdown

Question 13

Glycogen storage diseases (general overview)

Answer 13

Rare hereditary diseases

Mostly involve enzymes involved in degradation

Question 14

Glycogen Storage Disease Type 1

Answer 14

Von Gierke Disease

Enzyme Defect: glucose-6-phosphatase (last enzyme in gluconeogenesis)
Glycogen structure: normal
Organs involved: liver and kidney (tissues that carry out gluconeogenesis)

Type 1A (Glucose 6-Phosphatase Deficiency) Characteristics:
Hypoglycemia (b/c you can’t break down glycogen)
Triggers many other metabolic effects:
Increases glycolysis (due to elevated levels of glucose 6-phosphate)
Glycogen accumulates → enlarged liver
Glucose 6-phosphate activates glycogen synthase permanently (overrides hormonal regulation- even in the phosphorylated form)
Secondary effects: (b/c carbohydrate and lipid metabolism are very integrated)
Lactic acidosis (from lactic acid accumulation and from ketone bodies)
Hyperuricemia: due to elevated lactic acid in the blood (impaired excretion of uric acid → gout)
Hyperlipidemia
Increased fatty acid oxidation
Increased triglyceride breakdown
Ketoacidosis → hyperlipidemia
Increased formation of acetyl coA → form ketone bodies → ketoacidosis
Children affected also have “doll like features” bc it also affects lipid distribution and extra fat deposits on face, and fatty liver
Growth retardation and delayed puberty (probably from prolonged hypoglycemia)

Type 1B (Glucose 6-Phosphate Translocase Deficiency) Characteristics:
Neutropenia and recurrent infections
Glucose 6 phosphate transporter - barrier removed and glucose 6 phosphate can be acted on by hydrolase activity
Glucose 6-phosphate must be transported into the ER lumen where glucose 6-phosphatase is located

No treatment, but can prolong life by supporting blood glucose levels
Nocturnal gastric infusions of glucose
Frequent administration of uncooked cornstarch
Cornstarch - slowly hydrolyzed - allows slower uptake of glucose from GI tract and better maintenance of blood glucose levels

Question 15

Glycogen Storage Disease Type 2

Answer 15

Pompe Disease

Enzyme Defect: alpha glucosidase (lysosomal)
This enzyme is widely distributed so many organs involved
Can be most rapidly fatal type (within 1-2 years of life)
Glycogen structure: normal
Organs involved: generalized
Characteristics: enlarged heart, cardiorespiratory failure
Treatment: enzyme preparation: alglucosidase alfa - can be injected

Question 16

Glycogen Storage Disease Type 3

Answer 16

Cori Disease

Enzyme Defect: glycogen debranching enzyme
Glycogen structure: accumulated glycogen has short outer chains on fasting.
In well-fed individual glycogen structure normal.
Organs involved: Generalized
Characteristics: enlarged liver, moderate hypoglycemia, acidosis
Symptoms are like a milder type I