Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis.
Munc18b Increases Insulin Granule Fusion, Restoring Deficient Insulin Secretion in Type-2 Diabetes Human and Goto-Kakizaki Rat Islets with Improvement in Glucose Homeostasis.
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DOI：
10.1016/j.ebiom.2017.01.030
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Gaisano HY
中科院分区：
文献类型：
--
作者：
Qin T;Liang T;Zhu D;Kang Y;Xie L;Dolai S;Sugita S;Takahashi N;Ostenson CG;Banks K;Gaisano HY
Munc 18 a/SNARE复合蛋白的胰岛水平降低被认为是2型糖尿病（T2 D）中葡萄糖刺激的胰岛素分泌（GSIS）不足的原因。虽然许多以前的工作声称Munc 18 a/SNARE复合物（Syntaxin-1A/VAMP-2/SNAP 25）主要参与predocked分泌颗粒（SG）融合，但对融合前在质膜上经历最短对接时间的新SG知之甚少。新来的SG融合已经被假定涉及不同的SM/SNARE复合物（Munc 18 b/Syntaxin-3/VAMP 8/SNAP 25），我们发现其水平在T2 D人类和T2 D Goto-Kakizaki（GK）大鼠的胰岛中也降低。腺病毒感染的Munc 18 b过表达（Ad-Munc 18 b），通过增加Munc 18 b/SNARE复合物的组装，不仅介导了T2 D人和GK大鼠胰岛中新SG的融合，而且介导了预对接SG的融合，从而挽救了缺陷的双相GSIS。将Ad-Munc 18 b输注到GK大鼠胰腺中导致葡萄糖稳态的持续改善。然而，正常胰岛中Munc 18 b过表达仅增加新生SG融合。因此，Munc 18 b可以潜在地部署在人类T2 D中以拯救缺陷的GSIS。人T2 D胰岛β细胞表现出减少的预对接和新分泌颗粒（SG）的融合。Munc 18 b增加参与新来的和预对接的SG的融合的SNARE复合物。Munc 18 b拯救新来者和预对接的SG增加了人T2 D β细胞中的双相分泌。T2 D Goto-Kakizaki大鼠β细胞分泌的Munc 18 b拯救改善葡萄糖稳态。2型糖尿病（T2 D）中胰岛β细胞的胰岛素分泌不足部分是由于许多蛋白质的表达减少，这些蛋白质组装成介导胰岛素分泌颗粒（SG）与质膜融合的特异性复合物，称为胞吐作用。我们在这里展示了我们可以将含有SG融合蛋白之一Munc 18 b的构建体的病毒注入T2 D大鼠的胰管中以到达胰岛，从而恢复胰岛素分泌并改善血糖控制。Munc 18 b的作用是促进SG融合复合物的组装。该策略可能通过内窥镜输注应用于治疗人类T2 D。
Reduced pancreatic islet levels of Munc18a/SNARE complex proteins have been postulated to contribute to the deficient glucose-stimulated insulin secretion (GSIS) in type-2 diabetes (T2D). Whereas much previous work has purported Munc18a/SNARE complex (Syntaxin-1A/VAMP-2/SNAP25) to be primarily involved in predocked secretory granule (SG) fusion, less is known about newcomer SGs that undergo minimal docking time at the plasma membrane before fusion. Newcomer SG fusion has been postulated to involve a distinct SM/SNARE complex (Munc18b/Syntaxin-3/VAMP8/SNAP25), whose levels we find also reduced in islets of T2D humans and T2D Goto-Kakizaki (GK) rats. Munc18b overexpression by adenovirus infection (Ad-Munc18b), by increasing assembly of Munc18b/SNARE complexes, mediated increased fusion of not only newcomer SGs but also predocked SGs in T2D human and GK rat islets, resulting in rescue of the deficient biphasic GSIS. Infusion of Ad-Munc18b into GK rat pancreas led to sustained improvement in glucose homeostasis. However, Munc18b overexpression in normal islets increased only newcomer SG fusion. Therefore, Munc18b could potentially be deployed in human T2D to rescue the deficient GSIS. Human T2D islet β-cells exhibit reduced fusion of predocked & newcomer secretory granules (SGs). Munc18b increases SNARE complexes involved in fusions of both newcomer & predocked SGs. Munc18b rescue of newcomer & predocked SGs increased biphasic secretion in human T2D β-cells. Munc18b rescue of T2D Goto-Kakizaki rat β-cell secretion improves glucose homeostasis. Deficient insulin secretion from pancreatic islet β-cells in type-2 diabetes (T2D) is partly due to reduced expression of many proteins that assemble into specific complexes that mediate fusion of insulin secretory granules (SGs) with plasma membrane, termed exocytosis. We here show we can infuse a virus that contains the construct of one of the SG fusion proteins, Munc18b, into pancreatic ducts of T2D rats to reach the islets, which restored insulin secretion and improved glycemic control. Munc18b acts to promote the assembly of SG fusion complexes. This strategy could potentially be applied to treat human T2D by endoscopic infusion.