内科学
胰岛素抵抗
内分泌学
糖尿病性心肌病
内质网
收缩性
钙
兰尼碱受体2
胰岛素
农奴
医学
发病机制
心肌病
生物
心力衰竭
兰尼定受体
ATP酶
细胞生物学
生物化学
酶
作者
Chao Quan,Sangsang Zhu,Ruizhen Wang,Jiamou Chen,Qiaoli Chen,Min Li,Shu Su,Qian Du,Minjun Liu,Hongyu Wang,Shuai Chen
标识
DOI:10.1093/lifemeta/loac013
摘要
Abstract Diabetic cardiomyopathy (DCM) is currently a progressive and nonstoppable complication in type 2 diabetic patients. Metabolic insults and insulin resistance are involved in its pathogenesis; however, the underlying mechanisms are still not clearly understood. Here we show that calcium dysregulation can be both a cause and a consequence of cardiac insulin resistance that leads to DCM. A western diet induces the development of DCM through at least three phases in mice, among which an early phase depends on impaired Thr484-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr484 to a nonphosphorylatable alanine delays calcium re-uptake into the sarcoplasmic reticulum in the cardiomyocytes and decreases cardiac function at the baseline. Importantly, this mutation blunts the early phase of DCM, but has no effect on disease progression in the following phases. Interestingly, impairment of sarcoplasmic reticulum calcium re-uptake caused by the SERCA2a-Thr484 mutation inhibited processing of insulin receptor precursor through FURIN convertase, resulting in cardiac insulin resistance. Collectively, these data reveal a bidirectional relationship between insulin resistance and impairment of calcium homeostasis, which may underlie the early pathogenesis of DCM. Our findings have therapeutic implications for early intervention of DCM.
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