MAPK/ERK Signaling Regulates Insulin Sensitivity to Control Glucose Metabolism in Drosophila

The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.

胰岛素/胰岛素样生长因子激活的AKT信号通路（insulin/IGF-activated AKT signaling pathway）在多细胞动物的组织生长与代谢调控中发挥关键作用。尽管该通路的核心组分已明确界定，但针对其对细胞外刺激的敏感性调节机制尚不清楚。在人类中，胰岛素敏感性异常会导致血液中葡萄糖清除受损，这是糖尿病的标志性特征。本研究报道了一项在果蝇中开展的、旨在体内鉴定胰岛素敏感性调控因子的遗传筛选实验结果。研究发现，丝裂原活化蛋白激酶/细胞外调节蛋白激酶（MAPK/ERK）通路的组分可作为细胞胰岛素反应性的修饰因子。持续抑制MAPK/ERK通路会下调胰岛素样受体基因的表达，进而引发胰岛素抵抗。MAPK/ERK通路通过ETS-1转录因子Pointed发挥调控作用。该机制可实现胰岛素敏感性的生理性调节，并维持循环葡萄糖处于适宜水平。