Glycogen is a highly-branched polysaccharide that is widely distributed across the three life domains. It has versatile functions in physiological activities such as energy reserve, osmotic regulation, blood glucose homeostasis, and pH maintenance. Recent research also confirms that glycogen plays important roles in longevity and cognition. Intrinsically, glycogen function is determined by its structure that has been intensively studied for many years. The recent association of glycogen α-particle fragility with diabetic conditions further strengthens the importance of glycogen structure in its function. By using improved glycogen extraction procedures and a series of advanced analytical techniques, the fine molecular structure of glycogen particles in human beings and several model organisms such as Escherichia coli, Caenorhabditis elegans, Mus musculus, and Rat rattus have been characterized. However, there are still many unknowns about the assembly mechanisms of glycogen particles, the dynamic changes of glycogen structures, and the composition of glycogen associated proteins (glycogen proteome). In this review, we explored the recent progresses in glycogen studies with a focus on the structure of glycogen particles, which may not only provide insights into glycogen functions, but also facilitate the discovery of novel drug targets for the treatment of diabetes mellitus.
Glycogen is an important polysaccharide that is widely present in both prokaryotes and eukaryotes. Due to the sophisticated regulation and heterogeneous nature of glycogen particles, there are still many unknowns in terms of glycogen metabolism and structure. Recently, a series of studies discovered that glycogen α particles have two states, that is, fragility and stability, in different species. In addition, delicate studies revealed that fragility of glycogen α particles was associated with the development of diabetes in animal models, which suggested that novel drug targets might exist for diabetic treatment, hence the possibility of developing novel anti-diabetic drugs. However, the molecular mechanisms of glycogen particle assembly and structural fragility are not solved yet. In this review, we thoroughly examined the recent progress in the field of glycogen α particles. The distribution of glycogen α particles from prokaryotes to eukaryotes was reported, which suggested a common evolutionary driving force for α-particle formation. Thus, uncovering the mechanisms of glycogen α-particle assembly and fragility in prokaryotes like E. coli and lower life forms such as C. elegans could be able to help us understand the similar processes in animals and human beings. Moreover, the presence of glycogen α and β particles in different organs, tissues, and cell types was also discussed, which emphasized the importance of glycogen structures in its functions. In addition, the dynamic nature of glycogen particle, such as chain length distribution, glycogen associated proteins, and structural fragility were also addressed in both animals and bacteria, which provided possible explanations for glycogen α-particle fragility at molecular level, such as glycogenin concentration and GS/GBE ratio. Finally, effects of common anti-diabetic drugs such as metformin and berberine on diabetic liver glycogen structure were reviewed, which indicated that the repairment of glycogen α-particle fragility was achievable. Thus, further studies like network pharmacology could be conducted to identify the common targets of these drugs, which may provide clues for their therapeutic effects on glycogen α-particle fragility. In sum, although some progresses have been made in terms of understandings glycogen fragility, more work is needed to gain a better picture of the molecular assembly of glycogen α particles, together with its physiological functions in diabetes.
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