Soluble interleukin-13rα1: a circulating regulator of glucose

Soluble IL-13 receptor-alpha 1, or sIL13r alpha 1, is a soluble protein that binds lo interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13r alpha 1 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 sIL13r alpha 1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13r alpha 1 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 sIL13r alpha 1. In humans, endogenous blood levels of IL13r alpha 1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13r alpha 1 in normal human volunteers. Delivery of sIL13r alpha 1 fused to a fragment crystal-lizable (He) domain provided sustained glucose lowering in mice on a high-fat diet, suggesting a potential therapeutic strategy. These data reveal sIL13r alpha 1 as a circulating human protein with an unexpected role in glucose metabolism.