インスリンシグナル破綻に起因した糖尿病性心筋症早期にみられる拡張障害

• Published in: 日本薬理学会年会要旨集 p. 3-O-115
• Main Authors: 三上, 義礼, 伊藤, 雅方, 冨田, 太一郎, 大島, 大輔, 赤羽, 悟美
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2020
• Subjects: cardiac myocyte; hyperglycemia; sarcoplasmic reticulum; streptozotocin
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.93.0_3-O-115

Left ventricular diastolic dysfunction is one of the earliest cardiac changes in the patients with diabetic cardiomyopathy (DMCM). Ca2+ signaling dysfunction has been shown to occur in human and animal models of DMCM. However, its molecular mechanism remains controversial. We aimed to elucidate the underlying mechanism of Ca2+ signaling defects in DMCM. In the type 1 diabetes mellitus (T1DM) model mice 4 weeks after injection of streptozotocin (STZ-4W), diastolic function was impaired without reduction of ejection fraction and ventricular fibrillation was not observed, which mimics the early stage of DMCM. In the ventricles of STZ-4W mice, the basal phosphorylation level of phospholamban-Ser16 (p-PLN) was significantly lower than that of control. Furthermore, the maintenance of basal p-PLN was found to require insulin signaling and the downstream NO/cGMP/PKG pathway in primary cultured neonatal mouse ventricular myocytes. Chronic insulin administration via sustained release implant restored the p-PLN level and diastolic function. These effects were not correlated with blood glucose level. These results indicate that the loss of cardiac insulin signaling in T1DM plays a crucial role in the impairment of Ca2+ cycling system and diastolic function in the early onset of DMCM.