(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 evaluated the role for vitamin D in the treatment of T1D, with mixed results.
Previous data in humans have demonstrated that reduction in vitamin D supplementation is associated with a higher risk of the disease, whereas its supplementation is associated with a decreased frequency of T1D [35]. Other authors observed a significant increase in T‐reg cells in T1D patients supplemented with cholecalciferol at different dosages [36, 37]. Similar effects were reported by Treiber et al., who administrated 70 IU/Kg of cholecalciferol daily for 12 months, demonstrating not only the enhancement of the T‐reg cells, but also an increased T‐reg cell suppressive capacity among the supplemented group [38].
Different trials showed a better preservation of residual pancreatic β‐cell function in T1D patients supplemented with different forms of vitamin D (cholecalciferol, alfacalcidiol or calcitriol), as proven by the significantly higher level of fasting C‐peptide and/or lower needed daily insulin dose observed in supplemented groups [37, 39]. However, there are also studies that indicate no significant role for vitamin D in the treatment of T1D. The IMDIAB XI trial was an open‐label randomized trial designed to determine whether supplementation with the active form of vitamin D (calcitriol) at diagnosis of T1D could improve parameters of glycemic control [40]. The secretion of C‐peptide as an index of residual pancreatic β‐cell function was the primary end point, with HbA1c and insulin requirement as secondary end points. The aim of this study was to investigate whether supplementation with the active form of vitamin D (calcitriol) in subjects with recent‐onset T1D, protects residual pancreatic β‐cell function and improves glycemic control (HbA1c and insulin requirement). In this open‐label randomized trial, 70 subjects with recent‐onset T1D, mean age 13.6 ± 7.6 years, were randomized to calcitriol (0.25 microg on alternate days) or nicotinamide (25 mg/kg daily) and were followed up for 1 year. Intensive insulin therapy was implemented with three daily injections of regular insulin + NPH insulin at bedtime. No significant differences were observed between calcitriol and nicotinamide groups in respect of baseline/stimulated C‐peptide or HbA1c 1 year after diagnosis, but the insulin dose at 3 and 6 months was significantly reduced in the calcitriol group. In conclusion, at the dosage used, calcitriol had a modest effect on residual pancreatic β‐cell function and only temporarily reduced the insulin dose [40]. These results were confirmed later by the same group (IMDIAB XIII Trial), who found no effect of calcitriol in protecting β‐cell function in subjects with recent‐onset T1D and high C‐peptide at diagnosis followed‐up for 2 years [41]. Currently, a pilot study (POSEIDON) is investigating the safety and efficacy of a regimen that combines Omega‐3 fatty acids and cholecalciferol in subjects at T1D onset (NCT03406897). Thus, omega‐3 fatty acids have effects on several immunotypes and are known to increase T‐reg cell differentiation. The recruitment is still open.
Immune Intervention Therapies at Diagnosis of T1D
Other strategies for prevention of β‐cells damage with immune intervention at onset of the disease are based on immunotolerance (monoclonal antibodies, antigen‐based treatments, pro‐inflammatory cytokine‐based treatments) (Figure 2.3, Tables 2.2 and 2.3).
In the last decades, experience obtained with the use of
