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 39–79 nU/ml than for values ≥80 nU/ml, particularly in confirmation of a positive result (98.7% overall confirmation for values ≥80 nU/ml compared with 70.6% for values 39–79 nU/ml). This prompted comparison of the rate of evolution of diabetes by entry IAA level. The cohort with confirmed IAA ≥80 nU/ml (the original entry IAA criterion) progressed to diabetes at a faster rate than those subjects who did not have confirmed IAA ≥80 nU/ml. In addition, those with confirmed IAA ≥ 80 nU/ml had other risk characteristics that suggested more rapid evolution to diabetes, including younger age, greater likelihood of having other antibodies, and greater loss of β‐cell function [28].
The effect of intervention in each of these two subgroups was further evaluated.
The group with confirmed IAA ≥ 80 nU/ml showed a beneficial effect of oral insulin, whereas the group who did not have confirmed IAA ≥ 80 nU/ml showed a trend suggesting a detrimental effect of oral insulin [28]. This group also had a much lower overall rate of development of diabetes.
Furthermore, the rate of progression seemed to increase when oral insulin therapy was stopped, suggesting that the therapy was probably effective but required ongoing administration [29]. This observation has prompted a larger and justified follow‐up study with oral insulin to confirm these preliminary studies (Clinical trial NCT00419562; www.clinicaltrials.gov).
In conclusion, neither low‐dose insulin injections in subjects at high risk for developing T1D nor insulin capsules taken orally by those at moderate risk for T1D were successful at preventing or delaying the disease.
Type 1 Diabetes Prediction and Prevention Study (DIPP)
The DIPP study was a randomized double‐blind trial investigating whether nasal insulin could reduce the incidence of T1D in children with HLA genotypes and autoantibodies conferring increased risk of disease [25]. Daily doses of intranasal insulin were administered; however, after 1.8 years of observation, no differences were found in the rate of progression to T1D.
Similar results have been obtained in the Intranasal Insulin Trial (INIT I). This pilot study, based in Australia and New Zealand, treated autoantibody‐positive subjects with intranasal insulin, showing that intranasal insulin did not prevent T1D onset. However, investigators found that intranasal insulin administration induced immune changes consistent with mucosal tolerance to insulin, justifying a formal trial to determine if intranasal insulin is immunotherapeutic and retards progression to clinical diabetes [30]. The INIT II study is still ongoing and will expand the number of enrolled subjects. Thus, clinical trials evaluating insulin administration for disease prevention have demonstrated to date limited success in preventing the disease's progression.
Tertiary Prevention
Tertiary prevention is aimed at delaying or preventing the development of complications in subjects who already have T1D. A landmark trial investigating patients with T1D showed that good glycemic control [31] as well as low glycemic variability [32] can reduce the likelihood of microvascular complications leading to blindness or kidney disease, but the trend toward a decrease in macrovascular disease was not statistically significant. Diabetes education of health care professionals and those affected by diabetes plays a key role in the tertiary prevention of the disease. Tertiary prevention is identified by the maintenance of the residual β‐cell function present at disease onset and can be realized by immune suppression or immune modulation since the time of clinical diagnosis of T1D (Figure 2.2).
The best results in this field were obtained 30 years ago with the use of cyclosporine, subsequently abandoned because of transient benefits and undesired adverse effects [33].
In the following years none of the several treatments that have been proposed has obtained appreciable results but for nicotinamide [34] (Table 2.1).
Over the last few decades, there has been growing interest in vitamin D and its active metabolites in relation to T1D and its immune pathogenesis. Vitamin D metabolites have been shown to exert several immunomodulatory effects and 1,25‐dihydroxyvitamin D3 [1,25‐(OH)2D3] can either prevent or suppress autoimmune encephalomyelitis, inflammatory bowel disease, and other autoimmune diseases. Based on this rationale, several interventional and randomized controlled trials