Lab. of Molecular and Cellular Basis of Embryonic Development, Max-Delbrueck Center for Molecular Medicine, Robert-Roessle Strasse 10, Berlin 13125, Germany.
Max-Delbrueck Center for Molecular Medicine, Robert-Roessle Strasse 10, Berlin 13125, Germany.
Mol Metab. 2018 Feb;8:96-105. doi: 10.1016/j.molmet.2017.12.013. Epub 2017 Dec 28.
Actin cytoskeleton remodeling is necessary for glucose-stimulated insulin secretion in pancreatic β-cells. A mechanistic understanding of actin dynamics in the islet is paramount to a better comprehension of β-cell dysfunction in diabetes. Here, we investigate the Rho GTPase regulator Stard13 and its role in F-actin cytoskeleton organization and islet function in adult mice.
We used Lifeact-EGFP transgenic animals to visualize actin cytoskeleton organization and dynamics in vivo in the mouse islets. Furthermore, we applied this model to study actin cytoskeleton and insulin secretion in mutant mice deleted for Stard13 selectively in pancreatic cells. We isolated transgenic islets for 3D-imaging and perifusion studies to measure insulin secretion dynamics. In parallel, we performed histological and morphometric analyses of the pancreas and used in vivo approaches to study glucose metabolism in the mouse.
In this study, we provide the first genetic evidence that Stard13 regulates insulin secretion in response to glucose. Postnatally, Stard13 expression became restricted to the mouse pancreatic islets. We showed that Stard13 deletion results in a marked increase in actin polymerization in islet cells, which is accompanied by severe reduction of insulin secretion in perifusion experiments. Consistently, Stard13-deleted mice displayed impaired glucose tolerance and reduced glucose-stimulated insulin secretion.
Taken together, our results suggest a previously unappreciated role for the RhoGAP protein Stard13 in the interplay between actin cytoskeletal remodeling and insulin secretion.
肌动蛋白细胞骨架重塑对于胰腺β细胞中葡萄糖刺激的胰岛素分泌是必要的。了解胰岛中肌动蛋白动力学对于更好地理解糖尿病中β细胞功能障碍至关重要。在这里，我们研究了Rho GTPase 调节剂 Stard13 及其在成年小鼠胰岛中 F-肌动蛋白细胞骨架组织和胰岛功能中的作用。
我们使用 Lifeact-EGFP 转基因动物在体内可视化小鼠胰岛中的肌动蛋白细胞骨架组织和动力学。此外，我们应用该模型研究了选择性在胰腺细胞中缺失 Stard13 的突变小鼠中的肌动蛋白细胞骨架和胰岛素分泌。我们分离了转基因胰岛进行 3D 成像和灌注研究，以测量胰岛素分泌动力学。同时，我们对胰腺进行了组织学和形态计量学分析，并使用体内方法研究了小鼠的葡萄糖代谢。
在这项研究中，我们提供了第一个遗传证据，表明 Stard13 调节葡萄糖刺激的胰岛素分泌。出生后，Stard13 的表达仅限于小鼠胰岛。我们表明，Stard13 的缺失导致胰岛细胞中肌动蛋白聚合的显著增加，这伴随着灌注实验中胰岛素分泌的严重减少。一致地，Stard13 缺失的小鼠表现出葡萄糖耐量受损和葡萄糖刺激的胰岛素分泌减少。
总之，我们的结果表明 RhoGAP 蛋白 Stard13 在肌动蛋白细胞骨架重塑和胰岛素分泌之间相互作用中具有以前未被认识到的作用。
