β2肾上腺素受体依赖性的胰岛素诱导的PDE4在糖尿病心功能不全中的作用

Type 2 diabetes mellitus (T2DM) is one of the well-known risk factors for cardiomyopathy and heart failure. A common feature of T2DM is hyperinsulinemia, which results from chronically insulin-resistant state. The impact of hyperinsulinemia on the development of diabetic cardiomyopathy is not yet well defined. Epidemiological studies suggested that hyperinsulinemia is independently associated with heart failure and insulin treatment has been associated with increased mortality in subjects with advanced heart failure. These observations suggest that hyperinsulinemia per se, could contribute to cardiac dysfunction in type 2 diabetes. Recent studies from our lab suggest that increased insulin signaling in cardiomyocytes impairs β1 adrenergic receptor (β1AR)-mediated stimulation of cardiac function by reducing β1AR/cAMP/PKA signaling in β2AR dependent manner. We found that in hearts of type 2 diabetic patients, PDE4 was upregulated. Furthermore, hearts of mice with deletion of β2AR have significantly lower quantity of PDE4 protein induced by insulin. Based on these observations, we hypothesize that chronic insulin treatment selectively induces PDE4D expression in cardiomyocytes leading to reduced intracellular cAMP accumulation/propagation and impaired β1AR signaling. The overall research hypothesis is that hyperinsulinemia in conditions of insulin resistance and type 2 diabetes impairs β1AR signaling, leading to LV dysfunction and eventually heart failure. We will test this hypothesis through a combination of physiological, biochemical and genetic approaches and attempt to identify the signaling cascades involved, and to decipher the mechanisms by which insulin attenuates β1AR signaling in the heart. This project highlights a novel and important pathophysiological role of hyperinsulinemia in the development of diabetic cardiomyopathy that may lead to the discovery of potential new therapeutic targets for intervention.

糖尿病患者常因并发心力衰竭而死亡。临床胰岛素治疗可能增加糖尿病合并心衰患者的死亡率，提示胰岛素在糖尿病心衰并发症中的作用。我们研究发现糖尿病心脏病患者心肌磷酸二酯酶PDE4表达特异性增加。同时发现心脏胰岛素受体和β2肾上腺素受体(β2AR)形成复合体，胰岛素可通过β2AR促进磷酸二酯酶PDE4表达，并抑制β1AR介导的心肌收缩功能。这些发现提示胰岛素可能通过PDE4抑制β1AR-cAMP-PKA信号通路参与糖尿病心衰的发病。本项目拟在胰岛素诱导的β2AR依赖性的促PDE4表达的基础上，建立动物模型深入研究高胰岛素血症在糖尿病并发心衰中的作用及机制。并研究PDE4抑制剂，以及不同 βAR阻断剂和胰岛素受体信号通路抑制剂对糖尿病心功能不全的影响，为临床合理使用胰岛素和βAR阻断剂治疗糖尿病心功能不全提供指导，并为PDE4成为治疗新靶点的可行性提供理论基础。

2型糖尿病并发症心力衰竭发病率和死亡率是非糖尿病患者的4～8倍，研发具有心血管安全性的糖尿病药物是目前研究热点。胰岛素抵抗伴随高胰岛素血症是2型糖尿病的标志性特征，而高胰岛素血症是心力衰竭的独立危险因素，虽然胰岛素治疗强化血糖控制可以显著改善微血管病变，但对心血管疾病并无改善作用，甚至会增加心血管事件的风险，提高糖尿病心衰患者的死亡率。因此研究糖尿病高胰岛素血症在心力衰竭发生发展的影响和机制，对降低糖尿病患者心血管事件死亡率具有重要的临床意义。.本项目研究发现（1）胰岛素和心脏G蛋白偶联受体蛋白激酶及胰岛素受体底物IRS2形成复合体，通过促进β2AR磷酸化及内吞，抑制βAR信号通路介导的心肌细胞收缩的作用机制；（2）发现高脂饮食诱导的小鼠糖尿病早期即出现高胰岛素血症，基础心功能正常，但对βAR激动剂介导的心功能反应减弱，与临床糖尿病患者的早期表现相一致。提出高胰岛素血症可通过促进βAR磷酸化损伤糖尿病早期心脏功能储备，若基因敲除β2AR可改善高胰岛素血症所引起的心脏储备功能损伤。本研究提出对于糖尿病早期患者即应检查心脏储备功能，进行心脏功能保护的早期干预，对于预防糖尿病心力衰竭发生具有重要意义；（3）阐明胰岛素可以通过β2AR诱导PDE4表达而抑制心脏功能，而GRK2抑制剂Paroxetine和βAR阻断剂卡维地洛通过干预胰岛素诱导的PDE4表达可改善糖尿病心功能不全，从而解释了过度胰岛素治疗往往会增加糖尿病心衰发病率的现象，对于临床合理应用胰岛素治疗糖尿病降低心力衰竭发病风险具有重要意义；同时也明确β2AR和GRK2是糖尿病心力衰竭治疗的重要靶点，并对临床选择不同βAR阻断剂治疗糖尿病心力衰竭具有指导意义。.通过本项目研究提出胰岛素通过和介导心脏收缩的β肾上腺素信号通路的相互作用，调控心脏功能，并阐明胰岛素在糖尿病心衰发展中的作用及机制。这些研究将为研发治疗糖尿病心脏病药物的靶点提供新的概念和策略。