Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia

摘要

Insulin resistance and β cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormali- ties result from excessive flux of nutrients through the UDP- hexosamine biosynthetic pathway leading to "glucose toxicity." How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpres- sion of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia.