Molecular Physiology Research Unit, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada.
Programme de Biologie Moléculaire, Université de Montréal, Montreal, Quebec, Canada.
Diabetes. 2024 Oct 1;73(10):1648-1661. doi: 10.2337/db23-0802.
Growth arrest-specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL, and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR form a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.
生长停滞特异性蛋白 6（GAS6）是一种分泌蛋白，作为 TAM 受体（TYRO3、AXL 和 MERTK）的配体。在人类中，GAS6 的循环水平和 GAS6 的遗传变异与高血糖和 2 型糖尿病风险增加有关。然而，GAS6 影响葡萄糖代谢的机制尚不清楚。在这里，我们表明，小鼠中 Gas6 的缺乏会增加胰岛素敏感性并防止饮食诱导的胰岛素抵抗。相反，增加 GAS6 的循环水平足以降低体内的胰岛素敏感性。GAS6 抑制胰岛素受体（IR）的激活，并减少体外和体内肌肉细胞中的胰岛素反应。从机制上讲，AXL 和 IR 形成复合物，而 GAS6 重新编程 IR 下游的信号通路。这导致胰岛素治疗后 IR 的内吞作用增加。这项研究有助于更好地理解 GAS6 和 AXL 影响胰岛素敏感性的细胞和分子机制。
