Glycogen metabolism

Summary

Glycogen is an essential storage molecule for carbohydrates in the human body. It is a complex polymer consisting of multiple chains of glucose molecules and is present in all types of cells, with the exception of erythrocytes. Liver and skeletal muscle are the main storage organs. Fully replenished glycogen stores can provide blood glucose for approx. 12–48 hours when fasting. Regulation of glycogen metabolism is mediated through hormonal activities, mainly those of insulin, glucagon, and epinephrine.

Overview

  • Function: Glycogen is the most important carbohydrate storage medium in the human body, found in cytosolic granules.
  • Total glycogen storage (provides glucose for 12–48 hours): ∼ 400–450 g
  • Chemical structure:
    • Branched polymer; consisting of multiple linked glucose chains
    • Branches: α-1,6-glycosidic bonds
    • Linkages: α-1,4-glycosidic bonds

Periodic acid–Schiff stain is an immunohistochemical technique used to visualize polysaccharides such as glycogen.

Glycogen synthesis

1.) Synthesis of UDP-glucose

2.) Starting point of glycogen synthesis

  • Glycogenin
    • Homodimer protein at the core of each glycogen unit
    • Creates the starting point of glycogen synthesis by polymerizing a few glucose molecules

3.) Chain elongation

4.) Branching of glycogen chains

  • Branching enzyme
    • Creates α-1,6-glycosidic bonds: hydrolyzes a chain of 6 glucose units off the original chain → attachment of molecules to C6-atom of another glucose unit within the original chain
    • Branches are introduced at least 4 glucose units apart from each other

Sequence of glycogen synthesis starting from glucose: Glc → Glc-6-P Glc-1-P → UDP-Glc → glycogen

The rate-determining enzyme of glycogenesis is glycogen synthase!

Glycogenolysis

Release of glucose

A part of glycogen is not degraded by glycogen phosphorylase and debranching enzymes but in lysosomes by lysosomal alpha-glucosidase. Deficiency of this enzyme results in Pompe Disease (glycogen storage disease II).

Glucose utilization

  • Phosphoglucomutase (isomerase): glucose-1-P glucose-6-P
  • In muscle:
    • Instant metabolization of glucose-6-P during exercise in muscle (glycolysis)
    • Hexokinase: converts free glucose to glucose-6-P
  • In liver:
    • Glucose-6-phosphatase: glucose-6-P → free glucose → release into systemic circulation → increases serum glucose levels

The rate-determining enzyme in glycogenolysis is glycogen phosphorylase.

Disruptions in glycogen degradation lead to an accumulation of normal or pathologically structured glycogen in cells. Glycogen storage diseases are caused by inherited enzyme deficiencies of glycogenolysis and primarily affect skeletal muscles and the liver, the main glycogen stores in the body.

Regulation

Glycogen metabolism is regulated mainly by hormones. It is based on the phosphorylation and dephosphorylation of glycogen phosphorylase and glycogen synthase by the cAMP-dependent protein kinase A. Since the glycogen in the liver has different functions from that in skeletal muscle, each is regulated differently. For example, skeletal muscle also has allosteric (non-hormonal) regulation via ATP, AMP, and calcium ions.

Key regulatory enzymes

The increased presence of phosphate in cells is a starvation signal: All enzymes that raise blood sugar levels are active in their phosphorylated form!

Hormonal regulation

Overview

Glycogenesis (↑ glycogen)

Key enzyme: glycogen synthase

Glycogenolysis (↓ glycogen)

Key enzyme: glycogen phosphorylase

Serum glucose
Anabolic Insulin
Glucagon
Catabolic Epinephrine
Anabolic (liver) and catabolic (muscle) Cortisol

Insulin

Insulin stimulates storage of lipids, proteins, and glycogen.

Glucagon

Epinephrine

Glycogen synthase is stimulated by glucose-6-phosphate, insulin, and cortisol! It is inhibited by epinephrine and glucagon!

Allosteric / non-hormonal regulation

Glycogen synthesis

Glycogenolysis Serum glucose
Anabolic Glucose-6-P
ATP
Catabolic Muscle contraction :
AMP

These regulatory processes are only present in skeletal muscle, not in the liver.

Clinical significance

last updated 11/25/2019
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