Prolonged inhibition of glycogen phosphorylase in livers of Zucker Diabetic Fatty rats models human glycogen storage diseases.
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.
Floettmann
Eike
E
Global Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Eike.Floettmann@astrazeneca.com
Gregory
Laraine
L
Teague
Joanne
J
Myatt
John
J
Hammond
Clare
C
Poucher
Simon M
SM
Jones
Huw B
HB
D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006008:Glycogen Storage Disease / Q000139:chemically induced* / Q000473:pathology*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000209:etiology; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D011924:Rats, Zucker
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D024981:Glycogen Phosphorylase