Context: Liver glycogen, a highly branched glucose polymer which helps maintain blood-sugar homeostasis, is comprised of large α particles which are composites of many smaller β particles. The binding of β particles into α particles has been proposed to be mediated by protein (1). In db/db mice, this binding is fragile, leading to easy disintegration of the α particles into smaller entities, a process implicated in affecting diabetic hyperglycaemia (2).
Methods: This research used proteomics to study the protein(s) associated with glycogen. This required a stringent purification method to exclude non-glycogen contaminants in the liver (3). The chain length distribution and molecular density of glycogen were measured to characterize the glycogen molecular structure of healthy and db/db mice. A semi-quantitative SWATH proteomics method was applied to identify and compare the abundance of specific proteins in purified α and β particles.
Findings: Glycogenin was the only protein consistently identified in purified glycogen and is therefore a strong candidate to be the “bridge” binding β particles together to form α particles. Diabetic db/db mice had generally longer chains with higher density than healthy mice. Although db/db and healthy mice had about the same amount of glycogenin, they showed different distributions of the protein between α and β particles. We propose a novel model to explain the fragility of db/db mice liver glycogen.
Innovative contribution to research: Our novel model for glycogen α particle assembly and fragility in diabetes suggests that new drug targets for diabetes management could be found from agonists and antagonists of glycogen synthesis and degradation.