New insights into impaired muscle glycogen synthesis.

Leif Groop,Marju Orho-Melander

doi:10.1371/journal.pmed.0050025

Abstract

Glucose is the most rapidly accessible substrate in the body. Its storage as glycogen in muscle and liver is of central importance as a first source of energy for muscle contractions and prevention against hypoglycemia. Glycogen synthesis and breakdown are regulated by insulin and catecholamines as well as by glucose-6-phosphate and the amount of glycogen. There are two isoforms of glycogen synthase (GS), one in muscle and one in liver, encoded by different genes (GYS1 and GYS2, respectively) [1]. Insulin stimulates glycogen synthesis by activating protein phosphatase 1 (PP1), which activates GS, inactivates glycogen phosphatase, and inactivates glycogen synthase kinase 3, an inhibitor of GS. PP1 has a glycogen-targeting subunit (PPP1R3A), which facilitates localization of PP1 to glycogen.

Highlights

It is well established that patients with type 2 diabetes as well as persons at risk of the disease, i.e., first-degree relatives of patients with type 2 diabetes, are insulin resistant and show impaired insulin-stimulated glycogen synthesis [2,3], possibly as a consequence of impaired stimulation of glycogen synthase (GS) by insulin [4]
A common variant in the GYS1 gene has been associated with type 2 diabetes and insulin resistance, as well as increased risk of cardiovascular morbidity and mortality [5,6]
The Perspectives section is for experts to discuss the clinical practice or public health implications of a published article that is freely available online. This Perspective discusses the following new study published in PLoS Medicine: Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, et al (2008) A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice

Summary

Introduction

It is well established that patients with type 2 diabetes as well as persons at risk of the disease, i.e., first-degree relatives of patients with type 2 diabetes, are insulin resistant and show impaired insulin-stimulated glycogen synthesis [2,3], possibly as a consequence of impaired stimulation of GS by insulin [4]. A common variant in the GYS1 gene has been associated with type 2 diabetes and insulin resistance, as well as increased risk of cardiovascular morbidity and mortality [5,6]. This Perspective discusses the following new study published in PLoS Medicine: Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, et al (2008) A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice.

Results

Conclusion