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1 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada
2 Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada
* To whom correspondence should be addressed. E-mail: severson{at}ucalgary.ca.
Diabetic db/db mice exhibit profound insulin resistance in vivo, but the specific degree of cardiac insensitivity to insulin has not been assessed. Therefore, the effect of insulin on cardiomyocytes from db/db hearts was assessed by measuring two metabolic responses
(deoxyglucose uptake and fatty acid oxidation) and the phosphorylation of two enzymes in the insulin signalling cascade (Akt and AMP kinase). Maximal insulin-stimulated
deoxyglucose transport was reduced to 58% and 40% of control in cardiomyocytes from db/db mice at two ages (6 and 12 weeks). Insulin-stimulated deoxyglucose uptake was also reduced in myocytes from transgenic db/db mice over-expressing the insulinsensitive glucose transporter (db/db-hGLUT4). Treatment of db/db mice for one week with an insulin-sensitizing peroxisome proliferator-activated receptor-
agonist (COOH) completely normalized insulin-stimulated deoxyglucose uptake. Insulin had no direct effect on palmitate oxidation by either control or db/db cardiomyocytes, but the combination of insulin and glucose reduced palmitate oxidation, likely an indirect effect secondary to increased glucose uptake. Insulin had no effect on AMP-activated protein kinase phosphorylation from either control or db/db cardiomyocytes. Insulin increased the phosphorylation of Akt in all cardiomyocyte preparations (control, db/db, COOHtreated db/db) to the same extent. Thus, insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased but FA oxidation and AMPK phosphorylation are unchanged. Insulin resistance in db/db cardiomyocytes is manifested by reduced insulin-stimulated deoxyglucose uptake.
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