Department of Nutrition and Integrative Physiology (M.T.I., S.I.B., A.J.D., W.L.H., L.A.L.), The University of Utah, Salt Lake City.
Division of Geriatrics, Department of Internal Medicine (J.C., S.A., D.G.M., R.C.B., J.M., A.J.D., L.A.L.), The University of Utah, Salt Lake City.
Arterioscler Thromb Vasc Biol. 2024 May;44(5):1101-1113. doi: 10.1161/ATVBAHA.123.319375. Epub 2024 Mar 28.
Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance.
We used mouse models of constitutive endothelial cell-specific Arf6 deletion (Arf6 Tie2Cre) and tamoxifen-inducible Arf6 knockout (Arf6 Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy.
Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability.
Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.
我们对胰岛素抵抗的了解在很大程度上基于对代谢活跃组织（如肝脏、脂肪组织和骨骼肌）的研究。新出现的证据表明，血管内皮在全身胰岛素抵抗中起着至关重要的作用；然而，其潜在机制尚不完全清楚。Arf6（ADP 核糖基化因子 6）是一种小 GTP 酶，在内皮细胞功能中发挥关键作用。在这里，我们检验了这样一个假设，即内皮细胞特异性 Arf6 的缺失会导致全身胰岛素抵抗。
我们使用了内皮细胞特异性 Arf6 缺失（Arf6 Tie2Cre）和他莫昔芬诱导的 Arf6 敲除（Arf6 Cdh5CreER+）的小鼠模型。使用压力肌动描记法评估内皮依赖性血管舒张。使用一系列代谢评估，包括葡萄糖和胰岛素耐量试验以及高胰岛素正常血糖钳夹来评估代谢功能。我们使用荧光微球为基础的技术来测量组织血流。使用活体显微镜评估骨骼肌毛细血管密度。
内皮细胞 Arf6 的缺失损害了白色脂肪组织和骨骼肌进料动脉的胰岛素刺激血管舒张。血管舒张的损害主要是由于胰岛素刺激的一氧化氮生物利用度降低，但与改变乙酰胆碱介导或硝普钠介导的血管舒张无关。内皮细胞特异性 Arf6 的缺失也导致了正常饲料喂养的小鼠出现系统性胰岛素抵抗和高脂肪饮食喂养的肥胖小鼠的葡萄糖不耐受。葡萄糖不耐受的潜在机制是骨骼肌中胰岛素刺激的血流和葡萄糖摄取减少，且与毛细血管密度或血管通透性的变化无关。
这项研究的结果支持内皮细胞 Arf6 信号对维持胰岛素敏感性是必要的这一结论。内皮细胞 Arf6 表达的减少损害了胰岛素介导的血管舒张，并导致全身胰岛素抵抗。这些结果对与内皮细胞功能障碍和胰岛素抵抗相关的疾病（如糖尿病）具有治疗意义。
