Evidence That Nasal Insulin Induces Immune Tolerance to Insulin in Adults With Autoimmune Diabetes
- Spiros Fourlanos1,2,3,
- Christine Perry2,
- Shane A. Gellert3,
- Emanuela Martinuzzi4,5,
- Roberto Mallone4,5,
- Jeanne Butler1,
- Peter G. Colman3 and
- Leonard C. Harrison1,2
- 1Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- 2Burnet Clinical Research Unit, Royal Melbourne Hospital, Parkville, Australia
- 3Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville, Australia
- 4INSERM, U986, DeAR Laboratory Avenir, Saint Vincent de Paul Hospital, Paris, France
- 5Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France
- Corresponding author: Leonard C. Harrison, .
OBJECTIVE Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes (T1D). In the NOD mouse model of T1D, 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 T1D in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment.
RESEARCH DESIGN AND METHODS We randomized 52 adults with recent-onset, noninsulin-requiring T1D 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-g 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 T1D, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals.
- Received September 23, 2010.
- Accepted January 6, 2011.
- © 2011 by the American Diabetes Association.
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