title: Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes.
abstract: OBJECTIVE
  Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment.
  
  
  METHODS
  We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin.
  
  
  RESULTS
  β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin.
  
  
  CONCLUSIONS
  Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.
authors.affiliation: Autoimmunity and Transplantation Division, Walter and Eliza Hall, Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Spiros
authors.initials: S
authors.lastname: Fourlanos
authors.forename: Christine
authors.initials: C
authors.lastname: Perry
authors.forename: Shane A
authors.initials: SA
authors.lastname: Gellert
authors.forename: Emanuela
authors.initials: E
authors.lastname: Martinuzzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.forename: Jeanne
authors.initials: J
authors.lastname: Butler
authors.forename: Peter G
authors.initials: PG
authors.lastname: Colman
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D004311:Double-Blind Method; D005215:Fasting / Q000097:blood; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D007330:Insulin Antibodies / Q000097:blood; D008297:Male; D008875:Middle Aged; D010919:Placebos; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D007330:Insulin Antibodies; D010919:Placebos