Human diabetic polyneuropathy (DPN) is a progressive complication of chronic diabetes mellitus. Preliminary evidence has suggested that intranasal insulin, in doses insufficient to alter hyperglycemia, suppresses the development of DPN. In this work we confirm this finding, but demonstrate that its impact is modified by sex and deletion of RAGE, the receptor for advanced glycosylation endproducts. We serially evaluated experimental DPN in male and female wild type mice and male RAGE null (RN) mice, each with nondiabetic controls, during 16 weeks of diabetes, the final 8 weeks including groups given intranasal insulin. Age matched nondiabetic female mice had higher motor and sensory conduction velocities than their male counterparts and had lesser conduction slowing from chronic diabetes. Intranasal insulin improved slowing in both genders. In male RN mice, there was lesser conduction slowing with chronic diabetes and intranasal insulin provided limited benefits. Rotarod testing, and hindpaw grip power offered less consistent impacts . Mechanical sensitivity and thermal sensitivity were respectively but disparately changed and improved with insulin in wild type female and male mice but not RN male mice. These studies confirm that intranasal insulin improves indices of experimental DPN but indicates that females with DPN may differ in their underlying phenotype. RN mice had partial but incomplete protection from underlying DPN and lesser impacts from insulin. We also identify an important role for sex in the development of DPN and report evidence that insulin and AGE-RAGE pathways in its pathogenesis may overlap.