Using Glycogen Synthase Assays in the Quest for Type 2 Diabetes Therapies  

Although millions of Americans are living with diabetes thanks to medical intervention, it still ranks among the top ten causes of death; Type 2 being the most common.¹ Energy producing glucose is maintained so that we can withstand times of fasting as well as feasting. Think about the person that survives weeks in the wilderness without food or all the moments you have overeaten. Our amazing bodies are capable of balancing glucose levels without getting too high or deadly low.

Unfortunately, this balance gets out of whack for various reasons, resulting in diabetes. A defect in glycogen synthase (GS), a required enzyme for glycogen storage, is a contributor. It’s in the storing of glucose that makes surviving the wilderness possible.

After eating, glucose levels increase, recruiting insulin to initiate the process of glycogen storage and consequently regulating sugar levels. When this fine-tuned arrangement doesn’t go as planned, such as the case with insulin resistance individuals, blood sugar levels could get too high, and glycogen storage is interrupted.

Storing Glucose via Glycogen Synthase

GS is an enzyme that is responsible for taking glucose in the form of Glucose 6-phosphate (G6P) and converting to the chain of glycogen molecules.^² The regulation of GS isn’t completely understood as of yet. There are multiple phosphorylation sites on the protein allowing for activation by means of more than one protein; glycogen synthase kinase 3 (GSK-3), AMP-activated protein kinase (AMPK), and protein kinase A (PKA) are all examples of proteins that inactivate GS via phosphorylation.^¹ Additionally, GS has an allosteric site where G6P can bind, resulting in activation of the enzyme.^²

With the many proteins involved in the regulation of GS, there are various ways the functionality can be disturbed. Diet and exercise contribute as well since sugar intake and muscle contraction alter genes involved in GS regulation.

Glycogen Synthase Activity Assay 

Transcreener UDP Glycosyltransferase Assays are perfect for measuring GS activity as it is an enzyme that converts G6P to UDP-glucose in order to create glycogen, forming UDP as a product which can be measured by using a specific antibody labeled with a fluorophore. The single-step, direct detection method can be used in high-throughput screening (HTS) or for smaller projects. Since the malfunction of GS could result in insulin resistance, research and drug discovery could lead to treatments to help individuals with Type 2 diabetes. Measuring enzymatic activity is a step in the right direction.

References

1. Control D, Cdc P. National Diabetes Statistics Report, 2017 Estimates of Diabetes and Its Burden in the United States. 2017;(Cdc).
2. Bouskila M, Hunter RW, Ibrahim AFM, et al. Article Allosteric Regulation of Glycogen Synthase Controls Glycogen Synthesis in Muscle. Cell Metab. 2010;12(5):456-466. doi:10.1016/j.cmet.2010.10.006
3. Kleinert M, Sylow L, Richter EA. Regulation of glycogen synthase in muscle and its role in Type 2 diabetes. 3(2013):81-90.