Molecular mechanisms of diastolic dysfunction in diabetic cardiomyopathy

The early stage of diabetes mellitus (DM)-related cardiomyopathy (DMCM) is characterized by left ventricular (LV) diastolic dysfunction. The aim of this study was to elucidate the mechanism of the defective Ca2+ signaling underlying diastolic dysfunction in DMCM. In the streptozotocin (STZ)-induced DMCM model mice 4 weeks after STZ treatment, diastolic function was impaired without reduction of ejection fraction. In the isolated LV myocytes from DM mice, the Ca2+ transient decay rate was slower than that from control. In the ventricle of DM mice, the expression level of junctophilin2 protein was significantly lower, although expression levels of CaV1.2, RyR2 and SERCA2 were the same as those of control mice, suggesting that uncoupling of dyad junction starts at the early stage. The phosphorylation level of phospholamban (p-PLN) was significantly lower. Insulin treatment recovered the p-PLN level and the relaxation rate of the isolated ventricular myocardium from DM mice. Furthermore, PKA-independent insulin/PKG signaling turned out to be required for maintaining basal p-PLN. These results indicate that the reduction of p-PLN caused by insulin signaling defect is responsible for the LV diastolic dysfunction in the early stage of DMCM.