title: A model of chronic diabetic polyneuropathy: benefits from intranasal insulin are modified by sex and RAGE deletion.
abstract: 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 end products. We serially evaluated experimental DPN in male and female wild-type mice and male RAGE null (RN) mice, each with nondiabetic controls, during 16 wk of diabetes, the final 8 wk 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 sexes. In male RN mice, there was less 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 indexes 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.
authors.affiliation: Department of Clinical Neurosciences, the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Cristiane L
authors.initials: CL
authors.lastname: de la Hoz
authors.affiliation: Department of Clinical Neurosciences, the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Chu
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Division of Neurodegenerative Disorders, St Boniface Hospital Research Centre and Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
authors.affiliation: Division of Neurology, Department of Medicine, Neuroscience and Mental Health Institute, Alberta Diabetes Institute, University of Alberta, Alberta, Canada; zochodne@ualberta.ca.|Department of Clinical Neurosciences, the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; and.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Zochodne
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002908:Chronic Disease; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D016896:Treatment Outcome
chemical_list: C000593873:Ager protein, mouse; D007004:Hypoglycemic Agents; D007328:Insulin; D000067759:Receptor for Advanced Glycation End Products
keywords: advanced glycation end products; diabetes mellitus; insulin; peripheral neuropathy