Rachmin Inbal, O'Meara Caitlin C, Ricci-Blair Elisabeth M, Feng Yilin, Christensen Emily M, Duffy Jeanne F, Zitting Kirsi M, Czeisler Charles A, Pancoast James R, Cannon Christopher P, O'Donoghue Michelle L, Morrow David A, Lee Richard T
Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts.
Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
Am J Physiol Endocrinol Metab. 2017 Dec 1;313(6):E663-E671. doi: 10.1152/ajpendo.00168.2017. Epub 2017 Sep 5.
Soluble IL-13 receptor-α1, or sIL13rα1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13rα1 remains unclear, but it has been hypothesized to act as a decoy receptor for IL-13. Recent studies have identified a role for IL-13 in glucose metabolism, suggesting that a decoy receptor for IL-13 might increase circulating glucose levels. Here, we report that delivery of sIL13rα1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13rα1 was preserved in mice lacking IL-13, demonstrating that IL-13 was not required for the effect. In contrast, deletion of IL-4 in mice eliminated the hypoglycemic effect of sIL13rα1. In humans, endogenous blood levels of IL13rα1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13rα1 in normal human volunteers. Delivery of sIL13rα1 fused to a fragment crystallizable (Fc) domain provided sustained glucose lowering in mice on a high-fat diet, suggesting a potential therapeutic strategy. These data reveal sIL13rα1 as a circulating human protein with an unexpected role in glucose metabolism.
可溶性白细胞介素-13受体α1（sIL-13rα1）是一种可溶性蛋白，可与白细胞介素-13（IL-13）结合，此前已在小鼠中有所描述。sIL13rα1的功能尚不清楚，但据推测它可作为IL-13的诱饵受体。最近的研究已确定IL-13在葡萄糖代谢中发挥作用，这表明IL-13的诱饵受体可能会提高循环血糖水平。在此，我们报告通过基因转移或重组蛋白将sIL13rα1递送至小鼠体内可降低血糖水平。令人惊讶的是，sIL13rα1的降糖作用在缺乏IL-13的小鼠中依然存在，这表明该作用并不需要IL-13。相反，在小鼠中敲除IL-4消除了sIL13rα1的降血糖作用。在人类中，尽管糖尿病患者和非糖尿病患者之间没有差异，但IL13rα1的内源性血液水平差异很大。正常人类志愿者中sIL13rα1没有昼夜变化。将与可结晶片段（Fc）结构域融合的sIL13rα1递送至高脂饮食小鼠体内可持续降低血糖，提示了一种潜在的治疗策略。这些数据揭示sIL13rα1是一种在葡萄糖代谢中具有意外作用的循环人类蛋白。
