Prolonged Inhibition of Glycogen Phosphorylase in Livers of Zucker Diabetic Fatty Rats Models Human Glycogen Storage Diseases
| Autor: | Simon M. Poucher, John Myatt, Joanne Teague, Laraine Gregory, Eike Floettmann, Clare D. Hammond, Huw B. Jones |
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| Rok vydání: | 2010 |
| Předmět: |
Blood Glucose
Male medicine.medical_specialty endocrine system diseases Biology Toxicology Hepatic Complication Pathology and Forensic Medicine Glycogen debranching enzyme chemistry.chemical_compound Glycogen phosphorylase Internal medicine Diabetes mellitus medicine Animals Humans Hypoglycemic Agents Glycogen storage disease Enzyme Inhibitors Molecular Biology Glycogen Glycogen Phosphorylase nutritional and metabolic diseases Type 2 Diabetes Mellitus Cell Biology Glycogen Storage Disease medicine.disease Rats Rats Zucker Disease Models Animal Endocrinology Diabetes Mellitus Type 2 Liver chemistry Area Under Curve Hyperglycemia Glycated hemoglobin |
| Zdroj: | Toxicologic Pathology. 38:393-401 |
| ISSN: | 1533-1601 0192-6233 |
| DOI: | 10.1177/0192623310362707 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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