Differences in glycogen molecular structure in healthy and diabetic livers in humans and animal models: implications for blood-sugar control — ASN Events
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  3. Differences in glycogen molecular structure in healthy and diabetic livers in humans and animal models: implications for blood-sugar control

Differences in glycogen molecular structure in healthy and diabetic livers in humans and animal models: implications for blood-sugar control (#233)

Robert G Gilbert 1 , Bin Deng 2 , Xinle Tan 1 2 , Mitchell A Sullivan 1 3 , Ben L Schulz 1 , Jialun Li 2 , Chen Cheng 4 , Zhenxia Hu 2
  1. University of Queensland, Brisbane, QLD, Australia
  2. Huazhong University of Science & Technology, Wuhan, China
  3. Hospital for Sick Children, Toronto, Ontario, Canada
  4. Endocrinology, Wuhan General Hospital of Guangzhou Military Command, Wuhan, Hubei, China

Glycogen is a complex branched glucose polymer which functions as the body’s blood-sugar reservoir, and is formed as blood-sugar levels rise after a meal. As well as glucose monomer, it also contains small but significant amounts of protein(s) whose precise nature has not been unambiguously determined. Glycogen has a complex morphology, and generally contains small β particles which in certain circumstances can be joined to form much large composite α particles, especially in the liver (see figure). The composite α particles are formed some time after a meal, and well after blood-sugar concentration has passed its maximum; they are then degraded when the body needs the glycogen back to glucose for energy [1]. The molecular structures of glycogen in humans, pigs, rats and mice are qualitatively similar (although with important quantitative differences) [2-4]; this suggests that animal models for diabetes (e.g. with db/db mice) are probably indicative of the situation in humans. It has been found [5,6] that in diabetic liver, the binding holding the β particles together is much more fragile than in healthy liver. The rate of degradation of glycogen back to glucose when the body needs energy is probably controlled by the surface area of the glycogen molecule; because β particles have a much higher surface area (per mass of glucose monomer) than do α particles, this discovery is consistent with the compromised blood-sugar control characteristic of diabetes. Thus the body’s triggers for assembly of α particles and the nature of this β/α binding are potential targets for new drugs for diabetes management and control. It is likely that the binding agent is some protein. New data from proteomic characterization of the binding agent, and data on structural differences in liver glycogen upon administration of some standard diabetes drugs, are the first steps in identifying these targets.

Figure: Transmission electron micrograph of human-liver glycogen, showing a composite α article made of component β particles.

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  1. Sullivan, M.A.; Aroney, S.T.N.; Li, S.; Warren, F.J.; Joo, L.; Mak, K.S.; Stapleton, D.I.; Bell-Anderson, K.S.; Gilbert, R.G., “Changes in glycogen structure over feeding cycle sheds new light on blood-glucose control”, Biomacromolecules 2014, 15, 660.
  2. Deng, B.; Sullivan, M.A.; Wu, A.C.; Li, J.; Chen, C.; Gilbert, R.G., “The mechanism for stopping chain and total-molecule growth in complex branched polymers, exemplified by glycogen”, Biomacromolecules 2015, 16, DOI 10.1021/acs.biomac.5b00459.
  3. Powell, P.O.; Sullivan, M.A.; Sheehy, J.J.; Schultz, B.L.; Warren, F.J.; Gilbert, R.G., “Acid hydrolysis and molecular density of phytoglycogen and liver glycogen helps with understanding the bonding in alpha (composite) glycogen molecules”, PLoS One 2015, 10, e0121337.
  4. Sullivan, M.A.; Li, S.; Aroney, S.T.; Deng, B.; Li, C.; Roura, E.; Schulz, B.L.; Harcourt, B.E.; Forbes, J.M.; Gilbert, R.G., “A rapid extraction method for glycogen from formalin-fixed liver”, Carbohydrate Polymers 2015, 118, 9.
  5. Deng, B.; Sullivan, M.A.; Li, J.; Tan, X.; Zhu, C.; Schulz, B.L.; Gilbert, R.G., “Molecular structure of glycogen in diabetic liver”, Glycoconjugate Journal 2015, in press, DOI 10.1007/s10719.
  6. Sullivan, M.A.; Li, J.; Li, C.; Vilaplana, F.; Zheng, L.; Stapleton, D.; Gray-Weale, A.A.; Bowen, S.; Gilbert, R.G., “Molecular structural differences between type-2-diabetic and healthy glycogen”, Biomacromolecules 2011, 12, 1983.