Impairment of Liver Glycogen Storage in the db/db Animal Model of Type 2 Diabetes: A Potential Target for Future Therapeutics?

Author(s): Mitchell A. Sullivan, Brooke E. Harcourt, Ping Xu, Josephine M. Forbes, Robert G. Gilbert

Journal Name: Current Drug Targets

Volume 16 , Issue 10 , 2015

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Graphical 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.

Keywords: Db/db, diabetes, drug targets, glycogen, glycogenolysis, liver, molecular structure.

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Article Details

Year: 2015
Page: [1088 - 1093]
Pages: 6
DOI: 10.2174/1389450116666150727123115
Price: $65

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