Glycogen Phosphorylase - Clinical Significance

Clinical Significance

The inhibition of glycogen phosphorylase has been proposed as one method for treating type 2 diabetes. Since glucose production in the liver has been shown to increase in type 2 diabetes patients, inhibiting the release of glucose from the liver’s glycogen’s supplies appears to be a valid approach. The cloning of the human liver glycogen phosphorylase (HLGP) revealed a new allosteric binding site near the subunit interface that is not present in the rabbit muscle glycogen phosphorylase (RMGP) normally used in studies. This site was not sensitive to the same inhibitors as those at the AMP allosteric site, and most success has been had synthesizing new inhibitors that mimic the structure of glucose, since glucose-6-phosphate is a known inhibitor of HLPG and stabilizes the less active T-state. These glucose derivatives have had some success in inhibiting HLPG, with predicted Ki values as low as 0.016 mM.

Mutations in the muscle isoform of glycogen phosphorylase (PYGM) are associated with McArdle's Disease (glycogen storage disease type V). More than 65 mutations in the PYGM gene that lead to McArdle disease have been identified to date. Symptoms of McArdle disease include muscle weakness, myalgia, and lack of endurance, all stemming from low glucose levels in muscle tissue.

Mutations in the liver isoform of glycogen phosphorylase (PYGL) are associated with Hers' Disease (glycogen storage disease type VI). Hers' disease is often associated with mild symptoms normally limited to hypoglycemia, and is sometimes difficult to diagnose due to residual enzyme activity.

The brain isoform of glycogen phosphorylase (PYGLB) has been proposed as a biomarker for gastric cancer.