Long-Term Outcome of Individuals Treated With Oral Insulin

Abstract

OBJECTIVETo evaluate the long-term intervention effects of oral insulin on the development of type 1 diabetes and to assess the rate of progression to type 1 diabetes before and after oral insulin treatment was stopped in the Diabetes Prevention Trial–Type 1 (DPT-1).RESEARCH DESIGN AND METHODSThe follow-up included subjects who participated in the early intervention of oral insulin (1994–2003) to prevent or delay type 1 diabetes. A telephone survey was conducted in 2009 to determine whether diabetes had been diagnosed and, if not, an oral glucose tolerance test (OGTT), hemoglobin A1c (HbA1c), and autoantibody levels were obtained on all subjects who agreed to participate.RESULTSOf 372 subjects randomized, 97 developed type 1 diabetes before follow-up; 75% of the remaining 275 subjects were contacted. In the interim, 77 subjects had been diagnosed with type 1 diabetes and 54 of the remainder have had an OGTT; 10 of these were diagnosed with type 1 diabetes, subsequently. Among individuals meeting the original criteria for insulin autoantibodies (IAAs) (≥80 nU/mL), the overall benefit of oral insulin remained significant (P = 0.05). However, the hazard rate in this group increased (from 6.4% [95% CI 4.5–9.1] to 10.0% [7.1–14.1]) after cessation of therapy, which approximated the rate of individuals treated with placebo (10.2% [7.1–14.6]).CONCLUSIONSOverall, the oral insulin treatment effect in individuals with confirmed IAA ≥80 nU/mL appeared to be maintained with additional follow-up; however, once therapy stopped, the rate of developing diabetes in the oral insulin group increased to a rate similar to that in the placebo group.

Short‐term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

“…T1D prevention trials employing subcutaneous insulin administration have so far been uniformly unsuccessful [7,8,[16][17][18][19][20][21]. Given this failure in translating mouse studies to human trials, we took the opposite approach and tried to translate the strategy proposed for human trials into mouse, taking into account two key differences.…”

“…It was therefore not possible to track modifications induced in these pathogenic T-cell populations. In more recent years, insulin B [15][16][17][18][19][20][21][22][23] and isletspecific glucose-6-phophatase catalytic subunit-related protein (IGRP) 206-214 have emerged as major epitopes targeted by autoreactive CD8 + T cells [9]. Diabetes is induced when T-cell clones recognizing these sequences are transferred into healthy mice [10,11] or when transgenic T cells are primed by these epitopes in vivo [12,13].…”

Immune therapy in type 1 diabetes mellitus

“…A post hoc analysis revealed a subgroup of individuals with high titer IAA who experienced a significant delay in clinical onset 33 . Recent follow-up of the subjects with high titre IAA who took oral insulin suggest that the preservation of β-cell function was maintained as long as the oral insulin was taken (Figure 3) 34 . TrialNet is currently recruiting participants to continue to test whether oral insulin is effective to prevent diabetes in relatives at risk for T1D (http://www.diabetestrialnet.org/studies/oral-insulin.htm).…”

Antigen-based vs. systemic immunomodulation in type 1 diabetes

“…99 A follow-up study showed a prolongation of this effect which stopped as soon as therapy was discontinued. 117 However the data were suggestive enough to have led to a subsequent study in high Ab titer subjects which is still ongoing (http://www.clinicaltrials. gov; NCT00419562).…”