Background: Hepatic glycogen is organised into small β particles that associate into larger α particles. In diabetes, α particles exhibit increased structural fragility, but the relationship between blood glucose concentration and this abnormal glycogen architecture remains unclear.
Methods: Hepatic glycogen structure was examined in healthy C57BL/6J mice during fasting and following either single or repeated glucose administration, and in fasted and non-fasted db/db mice. Blood glucose and liver glycogen content were measured, while glycogen chain-length distributions and molecular size distributions were assessed using fluorophore-assisted carbohydrate electrophoresis and size-exclusion chromatography. Glycogen α-particle fragility was quantified from structural changes following dimethyl sulfoxide treatment. Correlation, mediation and piecewise regression analyses were used to examine relationships between glycaemia, glycogen chain length and particle fragility.
Results: In healthy mice, higher blood glucose was associated with longer average glycogen chain length and greater α-particle fragility. During fasting, declining blood glucose was accompanied by shorter chains and progressively increased structural stability. Average chain length significantly mediated approximately 22–33% of the association between blood glucose and glycogen fragility. In db/db mice, α particles remained comparatively fragile under both fasting and non-fasting conditions, and the relationship between blood glucose and fragility was markedly attenuated. Piecewise regression identified a plateau in the glucose–fragility relationship, with estimated thresholds of approximately 14–20 mmol/L depending on the structural measure examined.
Conclusions: Hepatic glycogen undergoes a dynamic, glucose-dependent transition between stable and fragile structural states. Chronic hyperglycaemia appears to disrupt this regulation, producing persistently fragile glycogen that becomes relatively insensitive to further increases in blood glucose. These findings identify glycogen chain architecture as a potential mechanism linking glycaemia with impaired hepatic glycogen stability in diabetes