Pancreatic β-Cell Function and Immune Responses to Insulin After Administration of Intranasal Insulin to Humans At Risk for Type 1 Diabetes

Abstract

OBJECTIVE -Mucosal administration of insulin retards development of autoimmune diabetes in the nonobese diabetic mouse model. We conducted a double-blind crossover study in humans at risk for type 1 diabetes to determine if intranasal insulin was safe, in particular did not accelerate ␤-cell destruction, and could induce immune effects consistent with mucosal tolerance. RESEARCH DESIGN AND METHODS-A total of 38 individuals, median age 10.8 years, with antibodies to one or more pancreatic islet antigens (insulin, GAD65, or tyrosine phosphatase-like insulinoma antigen 2) were randomized to treatment with intranasal insulin (1.6 mg) or a carrier solution, daily for 10 days and then 2 days a week for 6 months, before crossover. The primary outcome was ␤-cell function measured as first-phase insulin response (FPIR) to intravenous glucose at 0, 6, and 12 months and then yearly; the secondary outcome was immunity to islet antigens, measured monthly for 12 months.RESULTS -No local or systemic adverse effects were observed. Diabetes developed in 12 participants with negligible ␤-cell function at entry after a median of 1.1 year. Of the remaining 26, the majority had antibodies to two or three islet antigens and FPIR greater than the first percentile at entry, as well as ␤-cell function that generally remained stable over a median follow-up of 3.0 years. Intranasal insulin was associated with an increase in antibody and a decrease in T-cell responses to insulin. CONCLUSIONS -Results from this pilot study suggest that intranasal insulin does not accelerate loss of ␤-cell function in individuals at risk for type 1 diabetes and induces immune changes consistent with mucosal tolerance to insulin. These findings justify a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes. Diabetes Care 27:2348 -2355, 2004T ype 1 diabetes is an autoimmune disease in which T-cells mediate destruction of insulin-secreting ␤-cells in the pancreatic islets. Asymptomatic individuals with preclinical type 1 diabetes can be identified by the presence of circulating antibodies (Abs) to insulin, GAD 65-kDa isoform, and tyrosine phosphatase-like insulinoma antigen 2 (IA2) (1-3). Insulin is the only self-antigen specific for ␤-cells, and several lines of evidence indicate that it may play a major role in driving autoimmune ␤-cell destruction (4 -7). In experimental rodent models, administration of self-antigens to mucosa-associated lymphoid tissues can induce immune tolerance and prevent autoimmune disease (8,9). In the nonobese diabetic (NOD) mouse, a spontaneous model of autoimmune type 1 diabetes, oral (10) or naso-respiratory (11) insulin induces regulatory, diabetes-protective Tcells. After naso-respiratory insulin, there was a decrease in T-cell and an increase in Ab responses to insulin (11), conforming to the shift from T-helper (Th)-1 cellular immunity to Th2 humoral immunity that is associated with protection against diabetes in this rodent model (12). In human volunteers, oral (13)...

Mucosal Tolerance to Prevent Type 1 Diabetes: Can the Outcome Be Improved in Humans?

“…There is now evidence that intranasal (pro)insulin peptide administration induces pathogenic CTL [42]. The possibility of inducing pathogenic CTL should therefore be considered in ongoing trials with intranasal insulin, although a pilot study in children receiving intranasal insulin found a decline in humoral and proliferative T-cell responses to insulin [62], thus suggesting that intranasal insulin induces mucosal tolerance. We propose that in intranasal protocols, peptides rather than protein should be administered.…”

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

“…However, there has been some concern that induction of high autoantibody levels, following administration of autoantigens as immunomodulatory agents, could result in adverse events. In trials using either intranasal insulin in individuals at high risk for developing type 1 diabetes [22], or insulin B-chain given intramuscularly to patients with the disease [23], insulin antibodies were boosted without any adverse events. In LADA patients, GADA levels increased after injection of 500 µg GAD-alum but not after the lower dose, which yielded beneficial clinical effects [13].…”

Immune therapy in type 1 diabetes mellitus

“…In the Intranasal Insulin Trial (INIT), phase I and II trials, a double-blind, crossover design was used to study Australian IAA-positive subjects to first-degree relatives with T1D. INIT-I was completed 2004 with no significant effect on ß-cell function but it showed some indications of immune tolerance to insulin 35 . INIT-II (NCT00336674) is an ongoing randomized; double-blind, placebo-controlled trial using nasal insulin (1.6 or 16 mg) and aims at assessing the effects of nasal insulin on islet autoimmunity.…”