Chronic treatment with the thiazolidinedione, MCC-555, is associated with reductions in nitric oxide synthase activity and beta-cell apoptosis in the pancreas of the Zucker Diabetic Fatty rat.
The Zucker Diabetic Fatty (ZDF) rat is a model of impaired insulin sensitivity arising from hyperphagia owing to a mutation in the leptin receptor. In time, young ZDF rats, which are not initially diabetic, develop impaired pancreatic beta-cell function leading to apoptotic cell death. This results in an inability to fully compensate for the reduction in insulin sensitivity with hypersecretion of insulin. Young, pre-diabetic ZDF rats were treated, over a 4-week period, with the thiazolidinedione compound MCC-555, and the islet morphology studied in comparison to ZDF rats not given MCC-555. In particular, changes in the apoptotic incidence, as measured using TUNEL staining to localize apoptotic cells, were studied over the 4-week period. Changes in the induction of nitric oxide synthase and in the accumulation of nitrate/nitrite within the pancreas were also studied during the time course of administration of MCC-555. The study has demonstrated that the administration of MCC-555 significantly decreases the apoptotic incidence in the islets of Langerhans of pre-diabetic ZDF rats given the compound, as compared to those not given MCC-555, as well as decreasing the accumulation of nitrate/nitrite within the pancreas.
Pickavance
Lucy C
LC
Department of Medicine, University of Liverpool, Liverpool, Merseyside, UK. lucyp@liverpool.ac.uk
Widdowson
Peter S
PS
Foster
John R
JR
Williams
Gareth
G
Wilding
John P H
JP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D004334:Drug Administration Schedule; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000201:enzymology / Q000473:pathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones
D001786:Blood Glucose; D007328:Insulin; D013844:Thiazoles; D045162:Thiazolidinediones; D019001:Nitric Oxide Synthase; C115174:netoglitazone