Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes Through Defects in Microtubule Polymerization and Glucose Transporter Localization

Recent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.