Department of Medicine, Division of Endocrinology and Metabolism, UCSD, La Jolla, California, USA.
Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
J Clin Invest. 2018 Apr 2;128(4):1458-1470. doi: 10.1172/JCI94330. Epub 2018 Mar 5.
We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.
我们之前报道过，趋化因子（FKN）/CX3CR1 系统是调节胰岛素分泌和β细胞功能的新机制。在这里，我们证明了长效形式的 FKN（FKN-Fc）的慢性给药可以发挥持久作用，改善肥胖啮齿动物模型的葡萄糖耐量，增加葡萄糖刺激的胰岛素分泌，减少β细胞凋亡。出乎意料的是，慢性 FKN-Fc 给药也导致α细胞胰高血糖素分泌减少。在胰岛细胞中，FKN 通过 ERK 依赖性机制抑制三磷酸腺苷（ATP）敏感性钾通道电导，从而触发β细胞动作电位（AP）发放，并降低α细胞 AP 幅度。这导致葡萄糖刺激的胰岛素分泌增加和胰高血糖素分泌减少。除了对胰岛的作用外，FKN-Fc 还通过抑制胰高血糖素作用发挥外周作用，增强肝胰岛素敏感性。在肝细胞中，FKN 以百日咳毒素敏感的方式减少胰高血糖素刺激的环磷酸腺苷（cAMP）生成和 CREB 磷酸化。总之，这些结果表明，基于 FKN 的治疗方法有可能通过增加胰岛素分泌和胰岛素敏感性来改善 2 型糖尿病。
