Abstract

Obesity, insulin resistance, and type 2 diabetes are leading causes of heart failure, and defective cellular Ca²⁺ handling seems to be a fundamental problem in diabetes. Therefore, we studied the effect of insulin on Ca²⁺ homeostasis in normal, freshly isolated mouse ventricular cardiomyocytes and whether Ca²⁺ handling was changed in an animal model of obesity and type 2 diabetes, ob/ob mice. Electrically evoked Ca²⁺ 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 Ca²⁺ transients in wild-type cells by ∼30%, whereas it broadened the transients and triggered extra Ca²⁺ transients in ob/ob cells. The effects of insulin in ob/ob cells could be reproduced by application of a membrane-permeant inositol trisphosphate (IP₃) analog and blocked by a frequently used IP₃ receptor inhibitor, 2-aminoethoxydiphenyl borate. In ob/ob cardiomyocytes, insulin increased the IP₃ concentration and mitochondrial Ca²⁺ handling was impaired. In conclusion, we propose a model where insulin increases IP₃ in ob/ob cardiomyocytes, which prolongs the electrically evoked Ca²⁺ release. This, together with an impaired mitochondrial Ca²⁺ handling, results in insulin-mediated extra Ca²⁺ transients in ob/ob cardiomyocytes that may predispose for arrhythmias in vivo.