Merck & Co., Inc., South San Francisco, CA, USA.
Merck & Co., Inc., Kenilworth, NJ, USA.
Sci Rep. 2020 Feb 25;10(1):3417. doi: 10.1038/s41598-020-60290-1.
Insulin resistance increases patients' risk of developing type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and the germline Grb14-knockout (KO) mice have improved insulin signaling in liver and skeletal muscle. Here, we show that Grb14 knockdown in liver, white adipose tissues, and heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and impaired systolic function, which could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in cardiac function as measured by echocardiography in the Grb14-knockdown mice fed a high-fat diet for a period of four months. While additional studies are needed to further confirm the efficacy and to de-risk potential negative cardiac effects in preclinical models, our data support the therapeutic strategy of inhibiting Grb14 to treat diabetes and related conditions.
胰岛素抵抗增加了患者患 2 型糖尿病（T2D）、非酒精性脂肪性肝炎（NASH）和一系列其他合并症的风险，包括心血管疾病和癌症。在分子水平上，胰岛素通过胰岛素受体（IR）发挥作用，IR 是一种跨膜受体酪氨酸激酶。来自人类遗传研究的数据表明，Grb14 作为 IR 活性的负调节剂发挥作用，并且胚系 Grb14 敲除（KO）小鼠的肝脏和骨骼肌中的胰岛素信号得到改善。在这里，我们表明，用 AAV-shRNA（Grb14-shRNA）在肝脏、白色脂肪组织和心脏中敲低 Grb14 可改善饮食诱导肥胖（DIO）小鼠的葡萄糖稳态。先前的报告表明，Grb14 在小鼠中的胚系缺失导致心肌肥大和收缩功能受损，这可能严重限制靶向 Grb14 的治疗潜力。在本报告中，我们证明在高脂肪饮食喂养四个月的 Grb14 敲低小鼠中，心脏功能没有通过超声心动图测量发生显著变化。虽然需要进一步的研究来进一步确认疗效，并降低临床前模型中潜在的负面心脏效应的风险，但我们的数据支持抑制 Grb14 治疗糖尿病和相关疾病的治疗策略。
