Soluble interleukin-13ra1: a circulating regulator of glucose

Soluble IL-13 receptor-a1, or sIL13ra1, is a soluble protein that binds to interleukin-13 (IL-13) that has been previously described in mice. The function of sIL13ra1 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 sIL13ra1 to mice by either gene transfer or recombinant protein decreases blood glucose levels. Surprisingly, the glucose-lowering effect of sIL13ra1 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 sIL13ra1. In humans, endogenous blood levels of IL13ra1 varied substantially, although there were no differences between diabetic and nondiabetic patients. There was no circadian variation of sIL13ra1 in normal human volunteers. Delivery of sIL13ra1 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 sIL13ra1 as a circulating human protein with an unexpected role in glucose metabolism.