of diabetes‐associated autoantibodies, to identify those at high risk to develop clinical disease and to characterize the natural course of T1D; (3) to identify the environmental factors inducing the seroconversion to autoantibody‐positivity in children at increased genetic risk; and (4) to evaluate whether it is possible to delay or prevent progression to clinical T1D by daily administration of intranasal insulin. Whereas points 1–4 have been fulfilled and useful information has been obtained, the trial with intranasal insulin started soon after detection of autoantibodies, and did not show any beneficial effect of this treatment in preventing or delaying the disease [25].
In conclusion, since the failure of ENDIT and DPT1 trials (see secondary prevention) in preventing the onset of T1D in subjects who are β‐cell autoantibody positive, interest has switched to prevention trials starting before islet‐cell autoimmunity has developed. These primary prevention trials of T1D offer an exciting view of how our knowledge of the pathogenesis of this disease can lead to the possibility of intervening at birth. There is still a long way to go; however, the rationale is sound and the prospects seem good.
Secondary Prevention
Secondary prevention of T1D aims to reduce the incidence of the disease by stopping progression of β‐cell destruction in individuals with signs of such a process. This approach may represent a viable alternative to an actual cure by blocking the autoimmune response while β‐cell mass is still functional. For this reason, in the last few decades, prevention studies have started to focus on subjects at risk of developing the disease, in which the autoimmune process has begun but the β‐cell mass is still preserved. The most‐used approach at this stage of T1D is as an antigen‐specific therapy, based on insulin administration to establish tolerance. Generally, mechanistic long‐term effects of these treatments rely on effector T‐cell depletion with expansion of T regulatory cells (T‐reg) (Figure 2.2).
Three large multicenter trials of diabetes prevention in autoantibody‐positive relatives have been completed. The European Nicotinamide Diabetes Intervention Trial (ENDIT), the Diabetes Prevention Trial‐Type 1 (DPT‐1) and the Type 1 Diabetes Prediction and Prevention Study (DIPP). However, no significant benefits of these treatments on the prevention of clinical onset of T1D were found (Table 2.1).
European Nicotinamide Diabetes Intervention Trial (ENDIT)
The ENDIT study, conducted predominantly in Europe, examined whether nicotinamide could lead to a reduction in the rate of progression to T1D in at risk relatives of T1D probands. Over 40,000 first‐degree relatives aged 5–40 years were screened in centers in Europe and North America. The study was designed to recruit at least 422 subjects with ICA titers ≥ 20 JDF units to be randomized to either a nicotinamide‐ or a placebo‐treated group. With an expected rate of progression to diabetes of 40% in the placebo arm, the proposed 5‐year observation period should have allowed a 90% power to observe a 35% reduction in the incidence of disease [26, 27].
Nicotinamide treatment at the doses used did not show any significant effect on the primary outcome – progression to T1D. A total of 159 participants developed the disease within 5 years of randomization to treatment, 82 (30%) in the active treatment group and 77 (28%) in the placebo group. The unadjusted Cox proportional hazard estimate showed no difference between the placebo and nicotinamide groups on an intention to treat basis. Nor was any difference was found between groups after adjustment for age at baseline, glucose concentrations at 2‐h glucose in the OGTT, and number of islet autoantibodies. The proportion of relatives who developed diabetes within 5 years was almost identical in those treated with nicotinamide and those treated with placebo, and there was no suggestion of a treatment effect in any of the subgroups defined by well established markers of additional risk.
A useful message of this trial has been that large‐scale collaborations were essential to move things forward and that the place for single‐center trials was limited.
DPT‐1 Trials
The Diabetes Prevention Trial ‐Type 1 (DPT‐1) consisted of two clinical trials that sought to delay or prevent T1D. Nine medical centers and more than 350 clinics in the United States and Canada took part in the two trials of the DPT‐1 [28].
Individuals who were eligible for testing were identified as follows: age 3 to 45 years, with a brother or sister, child or parent with T1D; age 3 to 20 years, with a cousin, uncle or aunt, nephew or niece, grandparent, or half‐sibling with T1D. Those who met these criteria had ICA antibodies measured. To be eligible, a subject had to be positive for ICAs.
Animal research and small studies indicated that small, regular doses of insulin could prevent or delay T1D in subjects at risk. One DPT‐1 trial tested whether low‐dose insulin injections could prevent or delay the development of T1D in people at high risk for developing T1D within 5 years.
First‐degree relatives, 3 to 45 years of age, and second‐degree relatives, 3 to 20 years of age, of patients with T1D were screened for islet‐cell antibodies. Those with an islet‐cell antibody titer of 10 JDF units or higher were offered staging evaluations.
Subjects identified as having a high risk of T1D were eligible for random assignment to the experimental intervention (parenteral insulin therapy) or to a control group that underwent close observation.
The results demonstrated that insulin, in small doses, can indeed be administered safely to persons who are at risk for T1D. The increase in presumed and definite hypoglycemia among the subjects in the intervention group did not adversely affect cognitive function.
In high‐risk relatives of patients with diabetes, the insulin regimen did not delay or prevent the development of T1D [27]. There are several potential explanations for the lack of effect observed so far. One is that the intervention took place too late in the disease process to slow down the progression of disease. Studies conducted earlier in the disease process may be more successful. Moreover, the low dose insulin used in the trial may have failed to achieve such an effect on β‐cells, but the dose was limited by the risk of hypoglycemia. With a different dosing scheme or a different regimen, insulin or insulin‐like peptides might alter the course of development of diabetes.
The other study was an oral insulin trial that sought to prevent T1D in subjects with a moderate risk for developing diabetes [28].
First‐degree (ages 3–45 years) and second‐degree (ages 3–20 years) relatives of patients with T1D were screened for ICAs. Those with ICA titer ≥10 JDF units were invited to undergo staging evaluations.
Staging confirmed ICA positivity, measured insulin autoantibody (IAA) status, assessed first‐phase insulin response (FPIR) to intravenous glucose, assessed oral glucose tolerance (OGT), and determined presence or absence of HLADQA1* 0102/DQB1*0602 (a protective haplotype that excluded subjects from participation).
The study was a double‐masked, placebo‐controlled, randomized clinical trial, in which participants were assigned to receive capsules of either oral insulin, 7.5 mg of recombinant human insulin crystals (Eli Lilly, Indianapolis, IN), or matched placebo. Subjects consumed the capsule (insulin or placebo) as a single daily dose before breakfast each day, either by taking the capsule or, if the subject could not swallow capsules, sprinkling its contents in juice or on food.
In the primary analysis of relatives selected and randomized in DPT‐1, oral insulin did not delay or prevent development of diabetes. There was greater variability in the IAA assay for values
