Toward Primary Prevention of Type 1 Diabetes

The incidence of type 1 diabetes has been progressively increasing during the past several decades, particularly among childrenyounger than5years.1At thesametime, therehasbeen substantialprogress inunderstanding the pathogenesis of the disease and identifying those at risk of progressing to type 1 diabetes.2 In children at genetic risk, diabetes-related autoantibodies appear, followed by the evolution of metabolic abnormalities and the eventual clinical appearance of the disease.2 If individuals identified by geneticmarkers subsequentlyundergo seroconversion anddevelop 2ormorediabetes-related autoantibodies, their risk of progression to type 1 diabetes is 75%over 10 years and appears to be almost inevitable over 20 years.3 However, attempts at both primary prevention, ie, before seroconversion, and secondary prevention, ie, in those with diabetes-related autoantibodies, have notbeensuccessful.4The interventionsevaluated todatehave been limited to those deemed extremely safe, because such interventions would be used in at-risk individuals who may or may not actually progress to type 1 diabetes. Onehopehasbeen that therapywithadiabetes-relatedantigen, administered in a manner that favors immune regulation rather than immune aggression (activation of effector T lymphocytes directed against beta cells), could achieveprotection without compromising general immune response— basically antigen-based vaccination. Oneway of approaching antigen-specific immunotherapy is to leverage the concept ofmucosal tolerance, inwhichantigenpresentedacross amucosal barrier preferentially induces a regulatory immune response. In type 1 diabetes, mucosal tolerance has been exploited insecondarypreventionstudiesusingnasal insulin5,6 and in secondary prevention and recent-onset type 1 diabetes studiesusingoral insulin.However, these studieshavenot been successful in altering the course of the disease. Yet in theDiabetes PreventionTrial–Type 1 (DPT-1) oral insulin trial, a study of oral insulin in secondary prevention, a subgroup with high levels of insulin autoantibodies at baseline had a projected 4.5to 5-year delay in the development of clinical type 1diabetes.7A subsequent analysis showedcontinued beneficial effects in the subgroup, even after oral insulin was discontinued.8 Because the subgroup was identified inaposthocanalysis and the findings therefore couldonly be considered hypothesis-generating, an ongoing trial is examiningoral insulin inparticipants similar to those in the subgroup with high-titer insulin autoantibodies. Participants in the interventiongroupof theDPT-1 oral insulin trial received 7.5 mg of oral insulin daily.7 The choice of dose was somewhat arbitrary, as previous studies of oral insulin hadonly been conducted in rodentmodels of type 1 diabetes. These animal studies had shown profound beneficial effects.9 At the same time as the DPT-1 trial, 3 studies with oral insulin were conducted in patients with recent-onset type 1 diabetes.10-12 These studies used various doses of oral insulin daily, ranging from 1 mg to 10 mg. The studies did not demonstrate an effect on beta cell function, except for one analysis that showed retention of endogenous beta cell function at adoseof 1mg,but theresponsewasdependenton initial stimulatedC-peptide response, age at diabetes onset, andnumbers of specific islet cell autoantibodies.12 Thecomplexanalysisdid not permit a clear conclusion to be drawn. The contrast between results in rodent models and those in humans has led to considerable debate as to appropriate dose, dosing schedule, need for an adjuvant, eligibility criteria, and stage of the disease to evaluate oral insulin. With this background, the Pre-POINT Study Group conducted a pilot dose-ranging study, reported in this issue of JAMA, to determine the immunologic effects of oral insulin given to children aged 2 to 7 years who had relatives with type 1 diabetes and who were at extremely high genetic risk for type 1 diabetes but did not have evidence of diabetes autoantibodies.13Thestudywassmall,withonly 15children receiving oral insulin and 10 children receiving placebo. No adverseeffects, signsof allergy tooral insulin, insulin-relatedadverse events, or evidence that oral insulin induced type 1 diabetes in genetically at-risk children were found. However, dailyoral administrationof67.5mgof insulin actively engaged the immune system, with features of immune regulation in 5 of 6 children (83.3%) receiving this dose,13 amuch higher dose than that used in the earlier clinical trials. It is clear from previousstudies that thedoseof insulin is critically important, and this study informs future research efforts. Previous studieswithoral insulinusedmetabolicoutcome measures, suchasC-peptidepreservation, as an indexof betacell function,10-12 or appearance of clinical type 1 diabetes.7 In contrast, the Pre-POINT study used extensive contemporary methods for assessing immune response and demonstrated findingsconsistentwith theconcept thatoral exposure to insulin can promote a protective regulatory T-cell response.13 Adefinitive studybasedon thePre-POINTStudywouldbe a primary prevention study involving relatives without diabetes autoantibodies butwith genetic risk. The Pre-POINT Study was limited to individuals with the highest genetic risk, principallythosewithHLAhaplotypesHLADR4-DQB1*0302orDR4DQB1*0304. Others with risk not quite as high would likely be included in adefinitive study. Twoprevious clinical trials have used a broader HLA definition for potential entry.6,14 A quesRelated article page 1541 Opinion