Impairment of liver glycogen storage in the db/db animal model of type 2 diabetes: a potential target for future therapeutics?

Sullivan, Mitchell A., Harcourt, Brooke E., Xu, Ping, Forbes, Josephine M. and Gilbert, Robert G. (2015) Impairment of liver glycogen storage in the db/db animal model of type 2 diabetes: a potential target for future therapeutics?. Current Drug Targets, 16 10: 1088-1093. doi:10.2174/1389450116666150727123115

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Author Sullivan, Mitchell A.
Harcourt, Brooke E.
Xu, Ping
Forbes, Josephine M.
Gilbert, Robert G.
Title Impairment of liver glycogen storage in the db/db animal model of type 2 diabetes: a potential target for future therapeutics?
Journal name Current Drug Targets   Check publisher's open access policy
ISSN 1389-4501
1873-5592
Publication date 2015-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.2174/1389450116666150727123115
Open Access Status Not Open Access
Volume 16
Issue 10
Start page 1088
End page 1093
Total pages 6
Place of publication Bussum, Netherlands
Publisher Bentham Science Publishers
Language eng
Subject 1313 Molecular Medicine
3004 Pharmacology
3002 Drug Discovery
1308 Clinical Biochemistry
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.
Keyword Db/db
Diabetes
Drug targets
Glycogen
Glycogenolysis
Liver
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 2011CB910600
31470809
2014DFB30020
GNT1092451
GNT1072086
DP130102461
Institutional Status UQ

 
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