title: Impairment of Liver Glycogen Storage in the db/db Animal Model of Type 2 Diabetes: A Potential Target for Future Therapeutics?
abstract: After the discovery of the db gene in 1966, it was determined that a blood-borne satiety factor was produced excessively, but was not responded to, in db/db mice. This model for type 2 diabetes is widely used since it phenocopies human disease and its co-morbidities including obesity, progressive deterioration in glucose tolerance, hypertension and hyperlipidaemia. Db/db mice, unlike their non-diabetic controls, have consistently elevated levels of liver glycogen, most likely due to hyperphagia. In transmission electron micrographs, liver glycogen usually shows a composite cauliflower-like morphology of large "α particles" (with a wide range of sizes) made up of smaller "β particles" bound together. New studies have explored the size distribution of liver glycogen molecules and found that α particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller β particles. There is evidence that smaller glycogen particles have a higher association with glycogen phosphorylase, a key enzyme involved in glycogen degradation, as well as being degraded more rapidly in vitro; therefore the inability to form stable large glycogen α particles is predicted to result in a faster, less controlled degradation into glucose. The implications of this for glycaemic control remain to be fully elucidated. However, "rescuing" the more fragile diabetic glycogen to decrease hepatic glucose output in type 2 diabetes, may provide a potential therapeutic target which is the subject of this review.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Sullivan
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Harcourt
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.affiliation: The University of Queensland, Centre for Nutrition and Food Sciences, Queensland Alliance for Agriculture and Food Innovation, Brisbane, QLD 4072, Australia. b.gilbert@uq.edu.au.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism* / Q000648:ultrastructure; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission
chemical_list: D020738:Leptin; D008112:Liver Glycogen