Quan Chao, Zhu Sangsang, Wang Ruizhen, Chen Jiamou, Chen Qiaoli, Li Min, Su Shu, Du Qian, Liu Minjun, Wang Hong-Yu, Chen Shuai
MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu 210061, China.
State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, Jiangsu 210061, China.
Life Metab. 2022 Jul 28;1(1):54-66. doi: 10.1093/lifemeta/loac013. eCollection 2022 Aug.
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 Thr-phosphorylation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) elicited by insulin resistance. Mutation of SERCA2a-Thr 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-Thr 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.
糖尿病性心肌病（DCM）目前是2型糖尿病患者中一种进行性且不可阻挡的并发症。代谢损伤和胰岛素抵抗参与其发病机制；然而，潜在机制仍未完全明确。在此我们表明，钙调节异常可能既是导致DCM的心脏胰岛素抵抗的原因，也是其结果。西方饮食在小鼠中至少通过三个阶段诱导DCM的发生，其中早期阶段取决于胰岛素抵抗引起的肌浆网/内质网钙ATP酶2a（SERCA2a）苏氨酸磷酸化受损。将SERCA2a苏氨酸突变为不可磷酸化的丙氨酸会延迟心肌细胞中钙重新摄取到肌浆网中，并降低基线时的心脏功能。重要的是，这种突变使DCM的早期阶段变钝，但对后续阶段的疾病进展没有影响。有趣的是，由SERCA2a苏氨酸突变引起的肌浆网钙重新摄取受损通过弗林蛋白酶抑制胰岛素受体前体的加工，导致心脏胰岛素抵抗。总体而言，这些数据揭示了胰岛素抵抗与钙稳态受损之间的双向关系，这可能是DCM早期发病机制的基础。我们的发现对DCM的早期干预具有治疗意义。
