Liver-glycogen metabolism: A structural perspective

Liver glycogen, a highly branched glucose polymer, has a critical role in the maintenance of blood glucose homeostasis. Liver glycogen consists of glucose units that are attached to form linear chains via alpha-(1→4) linkages. These chains are connected via alpha-(1→6)-linked branch points to form highly branched glycogen “beta” particles (~20 nm in diameter) that can further join to form much larger “alpha” particles (~100-200 nm). Given the characteristically poor blood-glucose control associated with type 2 diabetes, a link between the structure/function relationships of liver glycogen and type 2 diabetes is probable. It is shown that diabetic (db/db) mice have an impaired ability to synthesize the large composite glycogen alpha particles present in normal, healthy mice and that alpha particles are held together via a bond more acid labile than normal glycosidic linkages, with the most likely bond being proteinaceous. The structure of healthy mouse liver glycogen over the diurnal cycle is characterized using size exclusion chromatography and transmission electron microscopy. Glycogen is observed to be initially formed as smaller beta particles, only being assembled into the larger alpha particles significantly after the time when glycogen content reaches a maximum. This pathway, impaired in diabetic animals, is likely to give optimal blood-glucose control, as explained by the particles’ surface area to volume ratio. Lack of this control may result from, or contribute to, the poor glycaemic regulation associated with diabetes. This discovery suggests novel approaches to diabetes management that promote alpha particle formation. Significant improvements in the extraction and characterization of liver glycogen has also been achieved, paving the way for future experiments exploring glycogen’s role in diabetes. Glycogen can now be effectively and rapidly extracted from formalin-fixed tissues using a novel technique, allowing the analysis of human tissue samples from pathology laboratories that routinely employ this method of fixation. The use of aqueous size exclusion chromatography has been shown to dramatically improve peak resolution when compared to the previously used dimethyl sulfoxide method, achieving separation of alpha-particle and beta-particle peaks. This allows for a more detailed and quantitative analysis and comparison between liver glycogen samples