Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin.
BACKGROUND
To study the pathogenesis of diabetic cardiomyopathy, reliable animal models of type 2 diabetes are required. Physiologically relevant rodent models are needed, which not only replicate the human pathology but also mimic the disease process. Here we characterised cardiac metabolic abnormalities, and investigated the optimal experimental approach for inducing disease, in a new model of type 2 diabetes.


RESULTS
Male Wistar rats were fed a high-fat diet for three weeks, with a single intraperitoneal injection of low dose streptozotocin (STZ) after fourteen days at 15, 20, 25 or 30 mg/kg body weight. Compared with chow-fed or high-fat diet fed control rats, a high-fat diet in combination with doses of 15-25 mg/kg STZ did not change insulin concentrations and rats maintained body weight. In contrast, 30 mg/kg STZ induced hypoinsulinaemia, hyperketonaemia and weight loss. There was a dose-dependent increase in blood glucose and plasma lipids with increasing concentrations of STZ. Cardiac and hepatic triglycerides were increased by all doses of STZ, in contrast, cardiac glycogen concentrations increased in a dose-dependent manner with increasing STZ concentrations. Cardiac glucose transporter 4 protein levels were decreased, whereas fatty acid metabolism-regulated proteins, including uncoupling protein 3 and pyruvate dehydrogenase (PDH) kinase 4, were increased with increasing doses of STZ. Cardiac PDH activity displayed a dose-dependent relationship between enzyme activity and STZ concentration. Cardiac insulin-stimulated glycolytic rates were decreased by 17% in 15 mg/kg STZ high-fat fed diabetic rats compared with control rats, with no effect on cardiac contractile function.


CONCLUSIONS
High-fat feeding in combination with a low dose of STZ induced cardiac metabolic changes that mirror the decrease in glucose metabolism and increase in fat metabolism in diabetic patients. While low doses of 15-25 mg/kg STZ induced a type 2 diabetic phenotype, higher doses more closely recapitulated type 1 diabetes, demonstrating that the severity of diabetes can be modified according to the requirements of the study.
Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, OX1 3PT, Oxford, UK. Lisa.heather@dpag.ox.ac.uk.
Latt S
LS
Mansor
Eileen R
ER
Gonzalez
Mark A
MA
Cole
Damian J
DJ
Tyler
Jessica H
JH
Beeson
Kieran
K
Clarke
Carolyn A
CA
Carr
Lisa C
LC
Heather
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat; D004734:Energy Metabolism; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D015415:Biomarkers; D001786:Blood Glucose; D008055:Lipids; D006003:Glycogen