Provided herein are methods for increasing insulin sensitivity in a subject. A method may comprise administering to a subject in need of increased insulin sensitivity a therapeutically effective amount of a glypican-4 agent. Also provided herein are methods for determining whether a subject is or is likely to become insulin resistant. A method may comprise determining the level of glypican-4 in a subject, wherein an elevated level of glypican-4 indicates that a subject is or is likely to become insulin resistant.