The Role of Microtubule Sliding in Regulation of Insulin Secretion

摘要 糖尿病是一种主要的代谢紊乱疾病，目前影响着西部地区5%-10%的人口。 社会。在2型糖尿病中，占所有糖尿病的90%，胰岛素不会释放到 充足的血液流动。胰岛素分泌是胰岛β细胞的一种功能。贝塔细胞必须 分泌有限剂量的胰岛素，以便将血糖降至正常水平，但不能完全 消耗它；这需要细胞内胰岛素储存和分泌之间的紧密协调。我们的数据显示 这种协调由细胞骨架聚合物微管(MT)调节，微管被认为是 细胞内的高速公路；分子马达，如Kinesin-1，沿MTS移动以运输和停放细胞膜 位于特定细胞位置的细胞器和胰岛素颗粒。我们的实验室已经证明了密集的MTS 胰岛β细胞抑制“笼”中的胰岛素颗粒，限制胰岛素颗粒对葡萄糖的可获得性。 刺激胰岛素分泌。先前的研究表明，激动素-1的靶向失活会导致 高血糖和作者的结论是，这是由于失去了由激动素-1运输的胰岛素。是否 MT网络也是由该Kinesin重塑和配置的，因此可能是 在靶向灭活常规激动素中观察到的潜在高血糖表型 胰腺。解决这些笼子的一种可能性是通过激动素主动转运MTS 马达。有趣的是，我发现葡萄糖刺激促进了β细胞中新颖的MT滑动过程。我 假设MT滑动分解了笼子中的胰岛素颗粒和/或影响了MT的网络配置 胰岛β细胞的正常功能。我的具体目标是(1)确定葡萄糖依赖 促进MT滑动的途径和机制；(2)阐明MT滑动在MT中的作用 胰岛素释放的依赖性调节。我建议使用高端方法来实现高端和超 分辨率生物成像、计算建模和各种葡萄糖分泌分析来实现这些 目标。在贝塔细胞中发现MTS作为调节成分是一个新的令人兴奋的话题 菲尔德。

Abstract Diabetes mellitus is a major metabolic disorder currently affecting 5–10% of the population in the western societies. In type-2 diabetes, which accounts for 90% of all diabetes, insulin is not released into the bloodstream in sufficient amounts. Insulin secretion is a function of pancreatic beta cells. Beta cells have to secrete restricted doses of insulin, in order to reduce blood sugar to normal levels but do not completely deplete it; this requires tight coordination between intracellular insulin storage and secretion. Our data indicate that this coordination is regulated by cytoskeletal polymers microtubules (MTs), which are known to serve as intracellular highways; molecular motors such as kinesin-1, move along MTs to transport and park membrane organelles and insulin granules at specific cellular locations. Our lab has shown that the dense MTs in pancreatic beta cells restrain insulin granules in “cages”, restricting insulin granule availability for glucose- stimulated insulin secretion. Previous studies have shown that targeted inactivation of kinesin-1 leads to hyperglycemia and the authors concluded that this is due to loss of trafficking of insulin by kinesin-1. Whether the MT network is remodeled and configured by this kinesin as well is not known and therefore may be part of the underlying hyperglycemic phenotype observed in the targeted inactivation of conventional kinesin in the pancreas. One possibility for resolution of these cages is through the active transport of MTs by a kinesin motor. Interestingly, I have found that glucose stimulation promotes the novel MT sliding process in beta cells. I hypothesize that MT sliding resolves “caged” insulin granules and/or impacts MT network configuration in pancreatic beta cells for their proper function. My specific aims are (1) to determine glucose-dependent pathways and mechanisms that facilitate MT sliding and (2) to elucidate the role of MT sliding in MT- dependent regulation of insulin release. I proposed to utilize high-end approaches for high- and super- resolution biological imaging, computational modeling, and various glucose secretion assays to achieve these aims. The discovery of MTs serving as regulatory components in beta cells is a new and exciting topic in the field.