Glycogen And Fuel Balance

Comparing Fuel Sources

Fatty acids/triacylglycerols

Pros: High storage density and easy mobilization
Cons: Metabolism requires a lot of oxygen, is slower to generate ATP, and produces reactive oxygen species (ROS)

Ketone Bodies

Pros: Provide brain food under low glucose conditions, will pass through the blood brain barrier faster than fatty acids
Cons: Can create acidic conditions in the blood

Amino Acids/Proteins

Pros: Can be converted to glucose and TCA intermediates
Cons: Use requires destruction of useful molecules

Glucose/Carbohydrates

Pros: Can be used aerobically and anaerobically
Cons: Exerts osmotic pressure limiting storage capacity.

The hydroxyl groups on glucose will react with other macromolecules like proteins, creasing osmotic pressure in the cells. Storing glucose as glycogen reduces the osmotic pressure.

Fuel storage

Glycogen has a chain of glucoses linked via alpha 1-4 bonds. It branches via alpha 1-6 bonds every 9-12 sugars on the chain. Glycogen only has one reducing end and several non-reducing ends. Glucose-1-P (G1P) can be released very quickly from the numerous non-reducing ends, making glycogen good for energy.

However, because glycogen is hydrophilic (will pull water into the cell), it can only be used for short term storage. Depletion of glycogen will occur within 12 hours of fasting.

Glycogenesis

Glucose-1-phospate (G1P) is first added to UDP via UDP-glucose phosphorylase, forming UDP-glucose. This bond energy can then be used with glycogenin to make short primer chains of 8 glucose molecules attached to a tyrosine.

These short chains are then added to a growing glycogen chain with 1,4 bonds catalyzed by glycogen synthase. Glycogen branching enzyme will form the 1,6 linkages from 1,4 linkages, which is endothermic.

Regulation

Glycogen synthase is active when dephosphorylated and is inactivated by phosphorylation via protein kinase A, phosphorylase kinase, and glycogen synthase kinase (GSK-3). Phosphoprotein phosphatase 1 (PP1) can dephosphorylate glycogen synthase, activating it.

Insulin will prevent the glycogen synthase from being inactivated, whereas glucagon and epinephrine inactivate glycogen synthase (and inhibit PP1).

Insulin promotes glycogen synthesis.
Glucagon/epinephrine turn off glycogen synthesis.

Glycogenolysis

Breakdown is mediated by glycogen phosphorylase which can hydrolyze glucose within 4 residues of its branch point. It won't consume the entire branch. Debranching enzyme both will move 1,4 linked sugars near a branch point closer to another non-reducing end for glycogen phosphate and also hydrolyze the remaining 1,6 branch point, popping off the free glucose-1-phospate (G1P). Real trooper this one.

Turning 1,6 bond into a 1,4 bond is endothermic (requires energy). Breaking a 1,6 linkage is exothermic (releases energy).

Debranching is the rate-limiting step of glycogen breakdown.

Products

Skeletal muscle

G1P is converted directly into glucose-6-phosphate (G6P) via phosphoglucomutase for use in glycolysis.

Hexokinase I is present in skeletal muscle (not the liver). It will convert free glucose to G6P even at low glucose levels to keep it in the muscle for use.

Liver/Pancreas

Glucose is converted to glucose-6-phosphate (G6P) through a few intermediate steps. It is then converted to free glucose in the ER via glucose-6-phosphatase which allows it to diffuse into the blood.

Glucokinase (hexokinase IV) is present in the liver (not skeletal muscle). It will convert free glucose to G6P only when glucose is abundant so as to allow glucose to freely diffuse out of the cell and maintain a stable blood concentration.

Regulation

Glycogen phosphorylase is activated by phosphorylase kinase, which is activated by glucagon, catecholamines, Ca2+, and protein kinase A. Phosphorylase kinase is inactivated by phosphoprotein phosphatase 1 (PP1), turning off glycogen breakdown.

Clinical Pearls

Glycogen Storage Disease Type I (Von Gierke's Disease)

A deficiency in Glucose 6-phosphatase causes hypoglycemia as G6P cannot enter the blood.

Andersen's Disease

A deficiency in branching enzyme causes rapid glycogen depletion, diminished hyperglycemic response to epinephrine (less non-reducing ends to mobilize glycogen), and cirrhosis of the liver.

McArdle's Disease

A deficiency in muscle glycogen phosphorylase impairs glycogen breakdown. This will result in no elevation of blood lactate and pyruvate after exercise as there is no anaerobic glycolysis in muscle. pH, therefore, will be unchanged with exercise.