Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We employed electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned media (EPS-CM) enhanced glucose-stimulated insulin secretion (GSIS). Transcriptomics and subsequent targeted validation revealed Growth Differentiation Factor 15 (GDF15) as a central component of the skeletal muscle secretome. Exposure to recombinant GDF15 enhanced GSIS in cells, islets, and mice. GDF15 enhanced GSIS by upregulating the insulin secretion pathway in β-cells, which was abrogated in the presence of a GDF15 neutralizing antibody. The effect of GDF15 on GSIS was also observed in islets from GFRAL-deficient mice. Circulating GDF15 was incrementally elevated in patients with pre- and type 2 diabetes and positively associated with C-peptide in humans with overweight/obesity. Six weeks of high intensity exercise training increased circulating GDF15 concentrations, which positively correlated with improvements in β-cell function in patients with type 2 diabetes. Taken together, GDF15 can function as a contraction-induced protein that enhances GSIS through activating the canonical signaling pathway in a GFRAL-independent manner.

中文翻译：

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GDF15 介导骨骼肌收缩对葡萄糖刺激的胰岛素分泌的影响


运动是 2 型糖尿病的一线治疗方法，并通过迄今未知的机制保持 β 细胞功能。我们假设来自收缩骨骼肌的蛋白质可能充当调节胰腺β细胞功能的细胞信号。我们采用电脉冲刺激 (EPS) 诱导 C2C12 肌管收缩，并发现用 EPS 条件培养基 (EPS-CM) 处理 β 细胞可增强葡萄糖刺激的胰岛素分泌 (GSIS)。转录组学和随后的靶向验证揭示了生长分化因子 15 (GDF15) 是骨骼肌分泌组的核心组成部分。暴露于重组 GDF15 可以增强细胞、胰岛和小鼠中的 GSIS。 GDF15 通过上调 β 细胞中的胰岛素分泌途径增强 GSIS，而 GDF15 中和抗体存在时该途径会被消除。在 GFRAL 缺陷小鼠的胰岛中也观察到 GDF15 对 GSIS 的影响。患有 2 型糖尿病前期和 2 型糖尿病的患者中，循环 GDF15 逐渐升高，并且与超重/肥胖人群中的 C 肽呈正相关。六周的高强度运动训练增加了循环 GDF15 浓度，这与 2 型糖尿病患者的 β 细胞功能改善呈正相关。总而言之，GDF15 可以作为收缩诱导蛋白发挥作用，通过以不依赖于 GFRAL 的方式激活规范信号通路来增强 GSIS。