Is liver glycogen fragility a possible drug target for diabetes?

Abstract

Liver glycogen α particles are molecularly fragile in diabetic mice, and readily form smaller β particles, which degrade more rapidly to glucose. This effect is well associated with the loss of blood-glucose homeostasis in diabetes. The biological mechanism of such fragility is still unknown; therefore, there are perceived opportunities that could eventually lead to new means to manage type 2 diabetes. The hierarchical structures of glycogen particles are controlled by the underlying biosynthesis/degradation process that involves various enzymes, including, for example, glycogen synthase (GS) and glycogen-branching enzyme (GBE). Recent studies have shown that fragile glycogen α particles in diabetic mice have longer chains and a higher molecular density compared to wild-type mice, indicating an enhanced enzymatic activity ratio of GS to GBE in diabetes. Furthermore, it has been shown that with an improved blood glucose homeostasis, the glycogen fragility in diabetic mice can be restored by treatment with active ingredients from traditional Chinese medicine, yet the underlying mechanism is unknown. In this review, we summarize recent advances in understandings glycogen fragility from the perspectives of glycogen biosynthesis/degradation, glycogen hierarchical structures, and its relation to diabetes. Importantly, we for the first time set GS/GBE activity ratio as the therapeutic target for diabetes. K E Y W O R D Schain-length distribution, glycogen biosynthesis, glycogen degradation, particle size distribution 4 | LI and HU ACKNOWLEDGMENTSWe would like to thank Prof. Robert G. Gilbert (The University of Queensland) for his mentor guidance and intelligent work in the research field of studying molecular structure of glycogen. We would also like to thank the financial support from

From Prokaryotes to Eukaryotes: Insights Into the Molecular Structure of Glycogen Particles

“…In mammals and human beings, glucose metabolism in diabetic liver is dysregulated and in pathological state ( Petersen et al, 2017 ), which leads to abnormal structure of glycogen particles. For example, according to the subtle structure analysis of fluorophore-assisted carbohydrate electrophoresis (FACE), diabetic liver glycogen was consistently observed to have a comparatively longer chain length distribution when compared with glycogen in healthy liver ( Li and Hu, 2019 ; Wang et al, 2020a ; Nawaz et al, 2021 ). In a recent review, Li and Hu argued that the abnormally long chain length distribution in diabetic liver was controlled by the imbalance of enzymatic activities between glycogen synthase (GS) and GBE, which could also serve as a therapeutic target for diabetes ( Li and Hu, 2019 ).…”

“…For example, according to the subtle structure analysis of fluorophore-assisted carbohydrate electrophoresis (FACE), diabetic liver glycogen was consistently observed to have a comparatively longer chain length distribution when compared with glycogen in healthy liver ( Li and Hu, 2019 ; Wang et al, 2020a ; Nawaz et al, 2021 ). In a recent review, Li and Hu argued that the abnormally long chain length distribution in diabetic liver was controlled by the imbalance of enzymatic activities between glycogen synthase (GS) and GBE, which could also serve as a therapeutic target for diabetes ( Li and Hu, 2019 ). Wang et al (2020a) studied the influences of glucose concentration on glycogen chain length distribution via the model organism Caenorhabditis elegans , according to which, high glucose diet did facilitate the shift of chain length distribution toward longer regions ( Liu et al, 2020a ).…”

“…Thus, up-regulation of glycogen branching enzyme level in diabetic liver might increase the stability of glycogen particles. After an intensive literature review, Li and Hu proposed that the decreased activity of glycogen synthase and the increased activity of glycogen branching enzyme could increase shorter chains in glycogen particles and stabilize glycogen α-particle fragility; thus, GS/GBE ratio might serve as a therapeutic target for diabetes ( Li and Hu, 2019 ).…”

“…Although glycogen has multi-facet roles, its function is intrinsically determined by its unique structure ( Meléndez-Hevia et al, 1993 ; Wang and Wise, 2011 ). In general, the structure of glycogen particles could be divided into three levels: level (1) short-chain oligomers; level (2) spherical β particles with an average diameter of 20 nm; and level (3) large rosette-shaped α particles aggregated together by β particles, the diameter of which ranges roughly up to 300 nm ( Li and Hu, 2019 ). It has also been proposed that level 1 structure is a roughly 3 nm protein-rich γ particle that is highly electro-condense ( Prats et al, 2018 ).…”

The effect of n-butanol fraction of gaharu (Aquilaria microcarpa Baill.) leaves on blood glucose and liver glycogen levels in alloxan-induced male rats

“…The normal mechanism is that liver glycogen is able to maintain glucose levels, an increase in blood glucose levels is followed by a decrease in glucagon, then glucose will be stored as glycogen [12]. Glycogen production will reduce blood glucose levels [13]. This study aimed to evaluate the activity of reducing pre-prandial and postprandial blood glucose levels and increasing liver glycogen levels of the n-butanol fraction of A. microcarpa leaves against alloxaninduced male rats.…”