Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2 transients and reveal mitochondrial Ca2 handling defects in cardiomyocytes of ob/ob mice.

Fauconnier J; Lanner JT; Zhang S; Tavi P; Bruton JD; Katz A; Westerblad H; Fauconnier, Jérémy; Lanner, Johanna T; Zhang, Shi-Jin; Tavi, Pasi; Bruton, Joseph D; Katz, Abram; Westerblad, Håkan

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 approximately 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.

Diabetes, 2005, Vol 54, Issue 8, p2375

0012-1797

Academic Journal

10.2337/diabetes.54.8.2375