Prevention of loss of b cells in type 1 diabetes is a major goal of current research. Knowledge of the genetic susceptibility, increasing ability to predict who may be at risk, recognition of the potential clinical impact of residual insulin secretion after diagnosis, and development of new immunomodulatory agents have supported an increasing number of clinical trials to prevent b-cell loss. Interventions can be targeted at 3 stages: before the development of autoimmunity (primary prevention), after autoimmunity is recognized (secondary prevention), or after diagnosis when significant numbers of b cells remain (tertiary prevention). Thus far, several agents show promise when given shortly after diagnosis, but no interventions before diagnosis have shown benefit. Knowledge in this area has grown quickly in recent years and will continue to grow rapidly with several international collaborative efforts underway.
Type 1 diabetes (T1D) is an autoimmune disease in which the β cells of the pancreatic islets are destroyed, rendering the individual increasingly incapable of mounting a normal insulin response to ingested nutrients. In the early 1980s, Eisenbarth enunciated the main phases in the pathogenesis of T1D ( Fig. 1 ), a framework which continues to be useful in considering approaches to the prevention or cure of this disorder:
- 1.
Susceptibility to T1D is inherited through a series of genes, the most important of which relate to the HLA class II locus on chromosome 6, with lesser contribution from several others, including the insulin gene, CTLA4 and others (see later discussion). Susceptibility genes are essential, but insufficient in explaining the immune pathogenesis of T1D, that is, most individuals with these susceptibility genes never develop the disorder.
- 2.
Exposure to 1 or more environmental triggers alters the immune system in such a way that susceptibility is converted to pathophysiology and destruction of β cells begins. Despite intensive searches for environmental triggers, the number of candidates being assessed in clinical trials remains small, for example, cow’s milk proteins, relative lack of vitamin D, and supplementation with omega-3 fatty acids.
- 3.
Although attack on the β cells is mediated in large part by T cells, it is the presence of humoral (B-cell) markers that punctuates the next phase: normal glucose homeostasis in the presence of 1 or more T1D-specific autoantibodies; ICA512/IA-2, insulin autoantibody (IAA) and glutamic acid decarboxylase (GAD) are the main ones available for measurement. The progression to clinical T1D is highly predictable based on the number of antibodies present.
- 4.
The earliest metabolic abnormality detected is loss of first phase insulin secretion in response to an intravenous glucose load. Glucose levels remain normal in response to meal challenges at this stage. Later, impaired glucose tolerance develops. This leads inexorably to the next phases of clinical diabetes.
- 5.
When β-cell mass is significantly decreased, insulin secretory capacity is damaged to such a degree that it is no longer sufficient to maintain normoglycemia and clinical diabetes supervenes. This phase includes the honeymoon or remission period of T1D when some β-cell function is retained, also called the C-peptide–positive phase of clinical diabetes.
- 6.
Finally, in most, but not all, individuals with T1D, β cell function is eventually completely lost and C-peptide levels become undetectable. There is a relationship between the presence of diabetic ketoacidosis at disease onset and the rapidity of loss of β cells, and between the presence of residual β-cell function and the ability to achieve and maintain better metabolic control.
A few additional facts are important in considering targets for prevention or early intervention in the pathogenesis of T1D : Firstly, the incidence of this condition is increasing by 2% to 5% per year worldwide, especially in the youngest age group (<5 years of age). Secondly, there is enormous variability in incidence of T1D around the world, from less than 4 per 100,000 in a population younger than 14 years in much of Africa and Asia to more than 20, in Canada, Australia, and parts of Europe, with the highest incidence being in Finland (>50 per 100,000 in the population reported in 2008). Thirdly, migrating populations take on the increased incidence of their new countries fairly rapidly, for example, Asian immigrants to the United Kingdom, immigrants from the Horn of Africa (Somalia, Eritrea, and Ethiopia) to North America. Fourthly, there is evidence that genetically similar populations may have enormously dissimilar incidence rates, for example, Finland and Russian Karelia. These factors strongly indicate an important role for environmental factors in the cause of T1D, because genetic drift cannot explain the rapidity of these changes. Furthermore, where incidence is increasing most rapidly, the contribution of genetic susceptibility seems to be less.
Genetics of T1D
T1D is 15 times more common in siblings of those with T1D, with the general population prevalence of approximately 0.4% and the sibling prevalence of approximately 6%. Genes located within the HLA class II region on chromosome 6p21 account for approximately 50% of genetic risk of T1D. Haplotypes associated with T1D include DQ2 (DQB1∗0201–DQA1∗0501–DRB1∗03) and DQ8 (DQB1∗0302–DQA1∗0301–DRB1∗04). Other HLA alleles, DQA1∗0102, DQB1∗0602 confer protection from T1D. A region in the regulatory region of the insulin gene (INS) locus has also been shown to provide approximately 10% of the genetic susceptibility to T1D. A polymorphism in the PTPN22 (protein tyrosine phosphatase non-receptor type 22) gene has been found to be associated with several autoimmune diseases, including T1D and autoimmune thyroid disease. The gene product, a lymphoid tyrosine phosphatase, inhibits the T-cell receptor signaling pathway. Polymorphisms in the cytotoxic T-lymphocyte–associated gene (CTLA4) are also associated with T1D and several other autoimmune diseases. Signaling through CTLA4 is critical in the down-regulation of T-cell responses. Association has also been found with the interleukin-2 receptor alpha subunit gene region. This region codes for the CD25 portion of the receptor which has a significant role in controlling T cell proliferation. Over 40 genes/regions have been confirmed to be associated with T1D. Identification of these genes provides investigative targets for new understanding of disease pathogenesis.
Although there have been important discoveries in the genetics of T1D and the autoimmune processes involved, little progress has been made in identifying highly specific environmental factors pivotal in triggering this disorder. Two hypotheses remain prominent in this respect: (1) the hygiene hypothesis suggests that in modern society, the lack of exposure to pathogens early in life prevents the genetically predisposed immune system from protecting itself from autoimmune phenomena, (2) the accelerator hypothesis suggests that increasing worldwide obesity stresses the susceptible β-cell, thereby triggering its early demise. The only environmental trigger undergoing active investigation is early exposure to cow’s milk proteins, which may be important in T1D pathogenesis; conversely, breast milk may protect against triggering of the autoimmune attack. The effort to better identify environmental factors is currently being led by The Environmental Determinants of Diabetes in the Young study. This study is scheduled to enroll 7800 infants by the end of 2009 with high-risk HLA genotypes for serial assessment of islet autoimmunity and environmental exposures, such as diet, infectious diseases, and immunizations.
Targets for prevention or early intervention
Prevention of T1D would require interventions aimed at (1) avoiding exposure to environmental triggers early in life—primary prevention; (2) interfering with the autoimmune cascade that occurs during β-cell destruction—secondary prevention or intervention; or (3) halting or reversing β-cell loss after clinical presentation of T1D—tertiary intervention. Once full-blown clinical T1D has developed, the only approach to disease reversal would be physiologic insulin replacement using either an artificial pancreas or β-cell replacement with islet or pancreatic transplantation. T1D is seen as one of the disorders most likely to be amenable to stem cell therapy in the future.
Targets for prevention or early intervention
Prevention of T1D would require interventions aimed at (1) avoiding exposure to environmental triggers early in life—primary prevention; (2) interfering with the autoimmune cascade that occurs during β-cell destruction—secondary prevention or intervention; or (3) halting or reversing β-cell loss after clinical presentation of T1D—tertiary intervention. Once full-blown clinical T1D has developed, the only approach to disease reversal would be physiologic insulin replacement using either an artificial pancreas or β-cell replacement with islet or pancreatic transplantation. T1D is seen as one of the disorders most likely to be amenable to stem cell therapy in the future.
Primary prevention
An environmental role in the pathophysiology of T1D is supported by a number of factors: low concordance rate of the disorder in identical twins (20%–50%); different incidence rates in populations of similar genetic makeup but significantly different socioeconomic status (eg, Finland and Russian Karelia); and rapid shifts in incidence in different areas of the world and with population migration. The specific environmental factors involved remain largely unproven, although epidemiologic and animal-model data suggest a potential role for dietary factors, more specifically, early exposure to cow’s milk and low vitamin D concentrations, with much more data pointing to a role for cow’s milk proteins.
There are good data to indicate that the pathogenetic processes leading to T1D may begin very early in life. This data, with animal-model and epidemiologic data, has provided the impetus to evaluate carefully the role of weaning diets on the evolution of T1D, especially the role of early exposure to cow’s milk proteins. A more detailed description of the supporting data is beyond the scope of this article but can be found in references.
The Trial to Reduce IDDM (insulin-dependent diabetes mellitus) in the Genetically at Risk (TRIGR) is a double-blind, randomized placebo-controlled trial that is intended for definitively testing the hypothesis that weaning to a hydrolyzed diet, thereby avoiding early cow’s milk protein exposure, protects high-risk newborns from initiation of the β-cell–specific autoimmune response, and therefore prevents T1D. This international multicenter study is powered to meet these objectives. The recruitment of high-risk neonates allows for concentration of subjects more likely to develop T1D, the criterion being that their mother, father, or sibling has T1D. They are screened for high-risk HLA haplotypes. If results are positive, the neonates are randomly assigned to 1 of 2 groups: feeding up to 6 to 8 months of age with a regular cow’s milk-based formula, or an extensively hydrolyzed cow’s milk formula. Breast feeding is encouraged and noted as a potential confounder in the study. The study design is shown in Fig. 2 and inclusion and exclusion criteria are listed below:
Neonates with a first-degree relative (ie, mother/father/sibling) with T1D are eligible.
Inclusion criteria
- 1.
The infant has one of the following genotypes:
- a.
HLA-DQB1∗0302/DQA1∗05-DQB1∗02
- b.
HLA-DQB1∗0302/x (ie, excluding DQB1∗02, DQB1∗0301, DQB1∗0602)
- c.
HLA-DQA1∗05–DQB1∗02/y (ie, excluding DQA1∗0201-DQB1∗02, DQB1∗001, DQB1∗0602/3)
- d.
HLA-DQA1∗03–DQB1∗02/y (ie, excluding the same ones as in [c]. above)
- a.
- 2.
Family able to provide written informed consent.
Exclusion criteria
- 1.
An older sibling in TRIGR intervention
- 2.
Multiple gestation
- 3.
Parents unwilling or unable to give study formula
- 4.
Newborn has recognizable severe illness
- 5.
Inability of family to participate in the study
- 6.
Infant received any formula other than Nutramigen before randomization
- 7.
Infant older than 7 days at randomization
- 8.
No HLA sample before 8 days of age.
The major outcome for the first phase of TRIGR is the frequency of T1D-associated autoantibodies and/or development of diabetes by age 6 years. The outcome of the second phase is the manifestation of diabetes by age 10 years according to standard criteria, obviously the more definitive outcome, although the intervention may delay rather than prevent the manifestation of T1D. This latter outcome would be masked by the final outcome being measured at age 10 years. Screening for TRIGR began in May 2002, with final enrollment completed by September 2006. The antibody data will be available in 2012 and the T1D outcomes in 2016.
Knip and colleagues reported results of the Finnish pilot study of TRIGR, documenting the rates of development of beta-cell autoimmunity (measured by autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8) in this randomized, double-blind trial of 230 infants with HLA-conferred susceptibility to T1DM. Their data show that over a median observation period of 10 years, infants receiving the study (casein hydrolysate) formula were about half as likely to develop positivity for one or more autoantibodies compared to the infants receiving conventional, cow’s-milk-based formula. Further observation is required to see whether this translates to differences in the incidence of clinical T1DM.
A double-blind placebo-controlled pilot study of omega-3 fatty acid supplementation with docosahexaenoic acid (DHA) to prevent islet autoimmunity is being performed by the Type 1 Diabetes TrialNet study group. Diets higher in omega-3 fatty acids have been associated with lower risk of islet autoimmunity and diabetes. DHA is known to have an anti-inflammatory effect. Entry to the study was during the third trimester for pregnant mothers or during the first 5 months of life for infants with a first-degree relative with T1D. At birth, HLA typing was done on cord blood and those with high risk alleles were eligible. Enrollment of 97 infants is complete with results of compliance, levels of whole blood DHA, and inflammatory markers expected in late 2009.
A feasibility study, BABYDIET, of delay of introduction of gluten to prevent islet autoimmunity in infants with a first-degree relative with T1D and high-risk HLA genotypes did not show a reduced risk of islet autoimmunity. The timing of introduction of cereals to infants has been associated with diabetes. Infants were randomized to introduction of gluten at age 6 or 12 months with follow-up every 3 months up to 36 months of age.
Vitamin D is increasingly recognized as an immunomodulator. Its effects on the immune system are multifold:
- 1.
In acquired immunity, Vitamin D induces an inhibitory response through reduction of T-cell proliferation, interleukin-2 and interferon-γ production, and CD8-mediated cytotoxicity. This results in a reduction of T-helper 1 responses and a promotion of T-helper 2 responses. In this way, it improves T-regulatory forces and provides for a more balanced and tolerogenic milieu ;
- 2.
In the innate immune system, Vitamin D inhibits dendritic cell function at multiple levels and mediates antibacterial actions through cathelicidin and the toll-like receptor 4 pathway.
Animal models show that treatment with 1,25(OH) 2 Vitamin D 3 or its analogs can prevent T1D and other immune-modulated disorders. Furthermore, there are data on humans that suggest that Vitamin D may also play a role. For example, the incidence of T1D increases with increasing distance from the equator suggesting a role for sun exposure. A published meta-analysis examined the association between vitamin D supplementation and the development of T1D. It found a significantly reduced risk of developing T1D in those supplemented with vitamin D (OR 0.71). A definitive prospective study on the effect of vitamin D supplementation on the development of diabetes remains to be performed.
Secondary prevention
The goal of secondary prevention studies is to prevent the progression of islet destruction that will lead to overt T1D. To carry out these studies, reliable prediction models are required. Current prediction models use combinations of autoantibodies and measures of glucose tolerance to stratify risk. It is known that autoantibodies typically develop years before onset of diabetes. These antibodies include ICA, IAA, and antibodies to GAD, tyrosine phosphatase (IA-2/ICA512), and zinc transporter 8 (ZnT8). The presence of 2 or more antibodies indicates a significantly increased risk of developing diabetes, with some studies reporting increasing risk with increasing number of antibodies. One study showed that relatives with 1 or more antibodies had a 25% risk of disease development over a 5-year period, 2 or more antibodies had a 39% risk of developing T1D within 3 years, and those with 3 or more antibodies had a 75% risk of disease development over a 5-year period. As β-cell destruction progresses, subclinical glucose abnormalities develop. Evidence from the Diabetes Prevention Trial – Type 1 (DPT-1), showed that fasting and 2-hour glucose levels rise gradually, as stimulated C-peptide levels slowly decline in the 30 months before diagnosis. Type 1 Diabetes TrialNet, an international study group performing research in the prevention and early treatment of T1D, is running a large longitudinal observational study of relatives of those with T1D to further improve prediction.
Three large multi-center trials of diabetes prevention in autoantibody-positive subjects have been completed. The European Nicotinamide Diabetes Intervention Trial used nicotinamide as a secondary preventative agent. Despite promising animal data and evidence from a previous study, nicotinamide administration in ICA-positive relatives did not delay the onset of T1D when compared with placebo. In DPT-1, insulin was given orally or parenterally to alter the immune response toward insulin. Subjects at high risk (>50% over 5 years with ICA positive and low first-phase insulin response) of developing T1D received parenteral insulin. Those at moderate risk (25%–50% over 5 years with ICA and IAA but normal first-phase insulin secretion) received insulin orally. The primary analysis of both arms of DPT-1 did not show an effect on the development of T1D. Post hoc analysis of DPT-1 oral insulin arm, however, suggested a beneficial effect in the subgroup with high titers of insulin autoantibodies. The results of the T1D Prediction and Prevention Study were recently published. In this study, newborns from the general population and siblings of those with diabetes had HLA genotyping done at birth. Those with 2 or more islet antibodies and high-risk HLA alleles were treated with nasal insulin or placebo. The study was stopped early as the treatment had no effect. The results of these studies, though disappointing, demonstrate that large scale prevention studies are feasible and provide significant insight into planning for future studies.
There are currently 3 diabetes prevention trials underway. The first is the Type 1 Diabetes TrialNet study, “Oral Insulin For Prevention of Diabetes In Relatives at Risk for Type 1 Diabetes Mellitus.” This study is further investigating the suggestion of oral insulin benefit as seen in the DPT-1 subjects with high IAA titers. Subjects have insulin autoantibodies and one of ICA, GAD antibodies, or ICA512 antibodies. The study intervention is oral insulin 7.5 mg/d or placebo for the study’s duration with the endpoint, the development of diabetes. Recruitment began in 2007. The Pre-POINT trial is an international multicenter study that is examining intervention with nasal and oral insulin in children aged 18 months to 7 years who have a sibling or 2 or more relatives with T1D. These children also have high-risk HLA alleles but no islet autoantibodies. The effects of 4 doses of oral and nasal insulin are being studied to determine whether autoimmunity will be affected. If the study is successful, a larger trial is planned.
The Intranasal Insulin Trial is based in Australia and New Zealand and is assessing the effect of intranasal insulin in first- and second-degree relatives aged 4 to 30 years who are at increased risk of diabetes based on data from an earlier pilot study. Treatment continues for one year with follow-up for the development of diabetes for 4 years.
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