| Prolonged inhibition of glycogen phosphorylase in livers of Zucker Diabetic Fatty rats models human glycogen storage diseases. | |
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MedLine Citation:
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PMID: 20215584 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The preclinical efficacy and safety of GPi921, a glycogen phosphorylase inhibitor, was assessed following twenty-eight days of administration to Zucker Diabetic Fatty (ZDF) rats. The ZDF rat is an animal model of type 2 diabetes mellitus (TTDM) which develops severe hyperglycemia. Inhibition of glycogen phosphorylase throughout the duration of the study was demonstrated by reductions in twenty-four-hour glucose profiles and glycated hemoglobin levels. In addition, progression towards hyperglycemia was halted in treated but not control animals, which developed hyperglycemia over the twenty-eight days of the study. Biochemical and histopathological analysis revealed large increases in hepatic glycogen, which closely paralleled the development of hepatomegaly and ultimately resulted in increases in hepatic lipids. Furthermore, prolonged glycogen phosphorylase inhibition resulted in an increased incidence and severity of other adverse pathological findings in the liver, such as inflammation, fibrosis, hemorrhage, and necrosis. The observed biochemical and histopathological phenotype of the liver closely resembled that seen in severe cases of human glycogen storage diseases (GSD) and hepatic glycogenosis in poorly controlled diabetes mellitus. These findings revealed that although glycogen phosphorylase inhibitors are efficacious agents for the control of hyperglycemia, prolonged treatment might have the potential to cause significant clinical hepatic complications that resemble those seen in GSD and hepatic glycogenosis. |
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Authors:
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Eike Floettmann; Laraine Gregory; Joanne Teague; John Myatt; Clare Hammond; Simon M Poucher; Huw B Jones |
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Publication Detail:
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Type: Journal Article Date: 2010-03-09 |
Journal Detail:
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Title: Toxicologic pathology Volume: 38 ISSN: 1533-1601 ISO Abbreviation: Toxicol Pathol Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-30 Completed Date: 2010-08-03 Revised Date: 2012-01-05 |
Medline Journal Info:
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Nlm Unique ID: 7905907 Medline TA: Toxicol Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 393-401 Citation Subset: IM |
Affiliation:
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Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Eike.Floettmann@astrazeneca.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Area Under Curve Blood Glucose / drug effects Diabetes Mellitus, Type 2 / complications, drug therapy Disease Models, Animal Enzyme Inhibitors / adverse effects, pharmacokinetics Glycogen Phosphorylase / antagonists & inhibitors* Glycogen Storage Disease / chemically induced*, pathology* Humans Hyperglycemia / drug therapy, etiology Hypoglycemic Agents / adverse effects*, pharmacokinetics Liver / drug effects*, pathology Male Rats Rats, Zucker |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 0/Enzyme Inhibitors; 0/Hypoglycemic Agents; EC 2.4.1.-/Glycogen Phosphorylase |
| Comments/Corrections | |
Comment In:
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Toxicol Pathol. 2010 Oct;38(6):1000-2
[PMID:
21037203
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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