title: The intracellular mechanism of insulin resistance in the hamster pancreatic ductal adenocarcinoma model.
abstract: Diabetes associated with pancreatic cancer is characterized by profound peripheral insulin resistance. The intracellular mechanism of insulin resistance was investigated in skeletal muscles from N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters. Effects of high-fat diet and exercise also were studied. BOP (20 mg/kg body weight) was administrated weekly for 2 weeks. Hyperinsulinemia was found in BOP-treated hamsters at 20 weeks after BOP treatment, suggesting the peripheral insulin resistance is an early feature in pancreatic cancer. Hamsters were killed at 42 weeks, and soleus muscles were taken for the analysis. Skeletal muscle insulin-receptor binding and insulin receptor tyrosine kinase activities were similar between the control and BOP-treated hamsters. However, maximal muscle glycogen synthase activity was significantly reduced in BOP-treated hamsters compared with the control group. Muscle glycogen phosphorylase activity was increased in the BOP-treated group fed with high-fat diet as well as in BOP-treated groups with exercise. These findings indicate that insulin resistance in the hamster pancreatic cancer model is caused by a postreceptor defect, which led to significant decrease of muscle glycogen synthase activity. Whereas a high-fat diet causes more severe insulin resistance in BOP-treated hamsters, high-fat diet and exercising had no significant effects on skeletal muscle insulin-receptor function and glycogen synthase activity. Furthermore, both high-fat diet and exercise enhanced glycogen phosphorylase activity in BOP-treated hamsters.
authors.affiliation: Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: K
authors.initials: K
authors.lastname: Kazakoff
authors.forename: P M
authors.initials: PM
authors.lastname: Pour
authors.forename: T E
authors.initials: TE
authors.lastname: Adrian
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D002273:Carcinogens; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008647:Mesocricetus; D018482:Muscle, Skeletal / Q000378:metabolism; D009602:Nitrosamines; D010183:Pancreatic Ducts; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000503:physiopathology*; D006005:Phosphorylases / Q000378:metabolism; D005082:Physical Exertion; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004041:Dietary Fats; D007328:Insulin; D009602:Nitrosamines; C013622:nitrosobis(2-oxopropyl)amine; D006005:Phosphorylases; D006006:Glycogen Synthase; D011972:Receptor, Insulin