Glycogen Metabolism and Storage Diseases

Glycogen

- An extensively branched glucose storage polysaccharide found in the liver and muscle of animals; the animal equivalent of starch.

Role of Glycogen in Muscle/Liver

- Muscle: For its OWN use (cannot release glucose into circulation)

- Liver: For the body (able to release glucose)

Glycogen Structure

- Large glucose polysaccharide

- Branches have alpha(1,6) bonds; Linkages have alpha(1,4) bonds.

Why is glycogen branched?

- Makes it more soluble

- Makes it possible for the body to store more of it

Glycogen synthesis is an offshoot of what?

- Glycolysis (Glucose-6-Phosphate)

What happens if glucose-6-phosphate is shunted to glycogen synthesis?

- Cells then use a 4 step process to convert G6P → Glycogen

Steps of Glycogen Synthesis

1. Glucose-6-Phosphate → Glucose-1-Phosphate

2. G1P → UDP-Glucose

3. UDP-Glucose → Unbranched Glycogen (1;4)

4. Unbranched Glycogen → Branched Glycogen (1;6)

Glucose-6-Phosphate → Glucose-1-Phosphate: What enzyme?

- Phosphoglucomutase

G1P → UDP-Glucose: What Enzyme?

- UDP-Glucose Phosphorylase

UDP-Glucose → Unbranched Glycogen (1;4): What Enzyme?

- Glycogen Synthase

Unbranched Glycogen → Branched Glycogen (1;6): What Enzyme?

- Branching Enzyme

Steps of Glycogen Breakdown

1. Branched → Unbranched via Debranching Enzyme

2. Unbranched → G1P via Glycogen phosphorylase

3. G1P ↔ G6P in reversible rxn

Glycogen Breakdown: Where does Glucose-6-Phospghate go after its free from glycogen storage?

- Muscles lack Glucose-6-Phosphatase → goes to glycolysis

- Liver has Glucose-6-Phosphatase; G6P can be converted to glucose to be released into blood stream to maintain blood sugar levels

α1,4 Glycosidase

- Breaks unbranched glycogen (1;4) → directly into glucose

- Found in lysosomes

Glycogen Phosphorylase: What does it do? When does it stop? Stabilized by what?

- Action: Removes glucose molecules from glycogen polymer → creates G1P

- Stops: When glycogen branches decreased to 2-4 linked glucose molecules

- Stabilized: By Vitamin B6

Limit Dextrins

- Small glucose polymers containing the alpha 1-6 linkages, cannot be broken down by glycogen phosphorylase

Debranching Enzyme

- Takes the alpha 1,6 branching points that have been exposed due to glycogen phosphorylase and moves the whole branch to the terminal end of chain, making a new α1,4 glycosidic bond

Do Glucagon/Epinephrine favor the breakdown or storage of glycogen?

- ↑ During flight, fight, fasting → favors glycogen breakdown into glucose for energy use

Does Insulin favor the breakdown or storage of glycogen?

- Favors glucose → glycogen

Glycogen Storage Diseases: Shared Characteristics

- Most are autosomal recessive diseases of defective breakdown of glycogen

- Hypoglycemia

- Muscle weakness

Von Gierke's Disease: Deficiency and MOA

- Glucose-6-Phosphatase

- G6P cannot be converted into glucose

Von Gierke's Disease: Presentation

- Infancy: 2-6 months of age

- Severe hypoglycemia between meals (bc liver cannot release glucose)

- Lethargy, Seizures, Lactic acidosis

- Enlarged liver (d/t excess glycogen)

Von Gierke's Disease: Treatment

- Cornstarch between meals (prevents hypoglycemia)

- Avoid sucrose, lactose, fructose, galactose (cannot be metabolized into glucose via gluconeogenesis → worsened accumulation of G6P)

Pompe's Disease: Deficiency and MOA

- α-Glucosidase Deficiency

- MOA: Accumulation of glycogen in lysosomes

Pompe's Disease: Presentation

- Enlarged muscles (cardiomegaly, tongue)

- Hypotonia

- Liver enlargement from heart failure

Death from heart failure

Cori's Disease: Deficiency and MOA

- Debranching enzyme deficiency

- MOA: Cannot break down 1-6 linkages

Gluconeogenesis is intact

Cori's Disease: Presentation

- Infant/child with hypoglycemia/hepatomegaly

- Hypotonia/weakness

- Possible cardiomyopathy with hypertrophy

McArdle's Disease: Deficiency and MOA

- Glycogen Phosphorylase Deficiency

- Unable to breakdown Unbranched glycogen → G1P → glycogen not properly broken down in muscle cells

McArdle's Disease: Presentation

- Presents in adolescence/early adulthood

- Exercise intolerance, fatigue, cramps

- Poor insurance, muscle swelling, weakness

- Dark urine after exercise

What can be seen in the urine of McArdle's patients?

- Muscles injury/breakdown during exercise → myoglobin in urine → dark urine

Myoglobinuria

Glycogen Synthase Deficiency

Type: Metabolic Disease

Cause: Glycogen Synthase enzyme deficiency

Sx: Elevated blood glucose, lactate, & lipids after Carb meal. Low glucose & high ketone bodies during fasting. Defect in muscle tissue causes weakness & difficulty with exercise.

Tx: Frequent complex carb meals, and meals high in protein.