The present invention discloses for the first time that the
insulin receptor (IR) is a target of Herstatin, which modulates IR and IR-mediated
intracellular signaling. In preferred aspects, Herstatin binds at nM concentrations to
cell-surface IR, up-regulates basal IR expression by several-fold, induces the accumulation of pro-IR, and stimulates
insulin activation of the ERK pathway. Moreover, these changes in
insulin signaling are accompanied by alterations in IGF-IR expression, IRS-2 levels, and the
serine phosphorylation state of both IRS-1 and IRS-2. Preferred aspects provide novel therapeutic methods and pharmaceutical compositions for treatment of conditions associated with altered IR expression or IR-mediated signaling, including but not limited to
insulin resistance syndrome, pre-diabetic conditions,
metabolic syndrome, type 1 and type 2 diabetes, cardiac
disease, diabetes-associated
vascular disease, atherosclerosis, hypertension, diabetes-associated
lipid metabolism disorders (
dyslipidemia),
obesity,
critical illness, neurodegenerative disorders, and combinations thereof, and
cancer.