Résumé
Obesity, insulin resistance, and type 2 diabetes are leading causes of heart failure, and defective cellular [Ca.sup.2+] handling seems to be a fundamental problem in diabetes. Therefore, we studied the effect of insulin on [Ca.sup.2+] homeostasis in normal, freshly isolated mouse ventricular cardiomyocytes and whether [Ca.sup.2+] handling was changed in an animal model of obesity and type 2 diabetes, ob/ob mice. Electrically evoked [Ca.sup.2+] transients were smaller and slower in ob/ob compared with wild-type cardiomyocytes. Application of insulin (6 or 60 nmol/l) increased the amplitude of [Ca.sup.2+] transients in wild-type cells by ~30%, whereas it broadened the transients and triggered extra [Ca.sup.2+] transients in ob/ob cells. The effects of insulin in ob/ob cells could be reproduced by application of a membrane-permeant inositol trisphosphate (I[P.sub.3]) analog and blocked by a frequently used I[P.sub.3] receptor inhibitor, 2-aminoethoxydiphenyl borate. In ob/ob cardiomyocytes, insulin increased the I[P.sub.3] concentration and mitochondrial [Ca.sup.2+] handling was impaired. In conclusion, we propose a model where insulin increases I[P.sub.3] in ob/ob cardiomyocytes, which prolongs the electrically evoked [Ca.sup.2+] release. This, together with an impaired mitochondrial [Ca.sup.2+] handling, results in insulin-mediated extra [Ca.sup.2+] transients in ob/ob cardiomyocytes that may predispose for arrhythmias in vivo.