期刊
CURRENT DRUG TARGETS
卷 16, 期 10, 页码 1088-1093出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1389450116666150727123115
关键词
Db/db; diabetes; drug targets; glycogen; glycogenolysis; liver; molecular structure
资金
- Chinese National Basic Research Programs [2011CB910600]
- National Natural Science Foundation of China [31470809]
- International Collaboration Program [2014DFB30020]
- NHMRC CJ Martin fellowship [GNT1092451]
- NHMRC Peter Doherty fellowship [GNT1072086]
- Australian Research Council [DP130102461]
- 1000-Talents Program of the Chinese State Administration of Foreign Expert Affairs
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 alpha particles (with a wide range of sizes) made up of smaller beta particles bound together. New studies have explored the size distribution of liver glycogen molecules and found that alpha particles in db/db mice are more chemically fragile than those in healthy mice, and can readily break apart to smaller beta 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 alpha 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.
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