Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes
Intravascular Follistatin gene delivery improves glycemic control in a mouse model of type 2 diabetes
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DOI：
10.1096/fj.201802059rrr
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发表时间：
2020-04-01
期刊：
影响因子：
4.8
通讯作者：
Gregorevic, Paul
中科院分区：
文献类型：
--
作者：
Davey, Jonathan R.;Estevez, Emma;Gregorevic, Paul
2型糖尿病（T2 D）表现为由于胰岛素抵抗、低胰岛素血症和胰腺β细胞功能恶化而导致的葡萄糖控制不足。促炎因子激活素已经被认为是T2 D患者中严重程度的正相关，并且是骨骼肌葡萄糖摄取和小鼠中胰腺β细胞表型的负调节剂。因此，我们试图确定用激活素拮抗剂卵泡抑素干预是否可以改善糖尿病病理学。在这里，我们报告了静脉内卵泡抑素基因递送干预与横纹肌向性降低血清浓度的激活素B和改善血糖控制的db/db小鼠模型的T2 D。治疗逆转了高血糖的进展，相应地降低了血红蛋白的百分比，使其水平与瘦的健康小鼠相似。卵泡抑素基因递送促进了胰岛素血症和胰岛素阳性胰腺β细胞的丰度，即使当向患有晚期糖尿病的小鼠施用治疗时，也是如此，这支持了与维持功能性β细胞相关的改善血糖控制的机制。我们的数据表明，单剂量血管内Follistatin基因递送可以改善糖尿病的进展，并改善疾病的预后标志物。这些发现与激活素介导的机制在肥胖和糖尿病模型中产生有害影响的其他观察结果一致，并表明减弱激活素信号传导的干预措施可能有助于进一步了解T2 D和开发新型T2 D治疗方法。
Type 2 diabetes (T2D) manifests from inadequate glucose control due to insulin resistance, hypoinsulinemia, and deteriorating pancreatic beta -cell function. The pro-inflammatory factor Activin has been implicated as a positive correlate of severity in T2D patients, and as a negative regulator of glucose uptake by skeletal muscle, and of pancreatic beta -cell phenotype in mice. Accordingly, we sought to determine whether intervention with the Activin antagonist Follistatin can ameliorate the diabetic pathology. Here, we report that an intravenous Follistatin gene delivery intervention with tropism for striated muscle reduced the serum concentrations of Activin B and improved glycemic control in the db/db mouse model of T2D. Treatment reversed the hyperglycemic progression with a corresponding reduction in the percentage of glycated-hemoglobin to levels similar to lean, healthy mice. Follistatin gene delivery promoted insulinemia and abundance of insulin-positive pancreatic beta -cells, even when treatment was administered to mice with advanced diabetes, supporting a mechanism for improved glycemic control associated with maintenance of functional beta -cells. Our data demonstrate that single-dose intravascular Follistatin gene delivery can ameliorate the diabetic progression and improve prognostic markers of disease. These findings are consistent with other observations of Activin-mediated mechanisms exerting deleterious effects in models of obesity and diabetes, and suggest that interventions that attenuate Activin signaling could help further understanding of T2D and the development of novel T2D therapeutics.