In the past 15 years, multiple clinical trials have attempted to find prevention for type 1 diabetes. The accompanying article by Bresson and von Herrath (1) reviews basic mechanisms underlying immunoprevention and immunotherapy of type 1 diabetes as well as selected human trials in the context of data from animal models. The second part of this mini-symposium provides an overview of the recent or ongoing human trials. Immunotherapy for prevention of type 1 diabetes or to ameliorate the course of the disease after clinical diagnosis is currently restricted to research studies. References are provided to the clinical.trials.gov database or other sources where the reader can find additional information.
Type 1 diabetes is an autoimmune disease caused by interplay of genetic and environmental factors. Figure 1 summarizes the main stages in the development of type 1 diabetes and examples of prevention trials at these stages. The initial step—development of islet autoimmunity marked by the presence of autoantibodies to insulin, GAD (GAD65), insulinoma-associated protein 2 (IA-2), and tyrosine phosphatase or zinc transporter (ZnT8)—is believed to be driven by environmental trigger(s) (2). Over the past 40 years, the incidence of childhood type 1 diabetes worldwide has increased by 3–5% annually (3–6). Elimination of the environmental trigger(s) responsible for this epidemic would be the most efficient approach to primary prevention. However, there is lack of consensus regarding which environmental factor(s) initiates islet autoimmunity. The National Institutes of Health have established The Environmental Determinants of type 1 Diabetes in the Young (TEDDY) consortium to evaluate the leading candidates (7,8).
After initiation of islet autoimmunity, most patients have a long preclinical period (9–12) that offers opportunity for secondary prevention—halting progression to clinical diabetes (Fig. 1). Large randomized trials initiated in the 1990s, including the Diabetes Prevention Trial Type 1 (DPT-1), the European Nicotinamide Diabetes Intervention Trial (ENDIT), and the Diabetes Prediction and Prevention (DIPP) project (13–16), have targeted this stage of pre–type 1 diabetes. The trials (17,18) and a cohort study (19) have shown that mild asymptomatic hyperglycemia, detected by oral glucose tolerance test (OGTT) or A1C, may precede by months or years overt insulin dependence among individuals with islet autoantibodies. Intervention at this “dysglycemic” stage of pre–type 1 diabetes may theoretically preserve endogenous insulin secretion and prevent acute and long-term complications of type 1 diabetes (20–22).
For the same reasons, preservation or restoration of insulin secretion after diagnosis of diabetes continues to be an attractive goal. Such tertiary prevention trials have used a number of immunomodulatory agents. These agents are often considered first in patients with established diabetes and, when proven safe, may be applied to patients with dysglycemic pre–type 1 diabetes and eventually those with normoglycemic pre–type 1 diabetes. However, efficacy in preserving C-peptide after diagnosis of type 1 diabetes should not be a precondition to applying an intervention to patients with pre–type 1 diabetes, as there may be a “point of no return” in the autoimmune destruction of the islets, rendering some interventions effective only at the earlier stages of the process.
Current approaches to prevent type 1 diabetes include:
- Avoidance of environmental triggers of islet autoimmunity such as cow's milk or gluten. Celiac disease provides an encouraging example of autoimmune disease that can be prevented in this way. Alternatively, diet is supplemented with nutrients for which deficiency presumably promotes islet autoimmunity, e.g., n-3 fatty acids or vitamin D.
- Antigen-specific “vaccination” using islet autoantigens, e.g., intact insulin, altered insulin or proinsulin peptides, GAD65, or heat shock protein 60 (HSP60) peptide. The goal is to induce autoantigen-specific tolerance by induction of regulatory T-cells that downregulate immunity to a specific autoantigen as well as promote tolerance to additional autoantigens.
- Non–antigen-specific systemic therapies that range from mild modulation with oral nicotinamide or bacille Calmette–Guerin (BCG) vaccination to immunosuppression and cellular therapies.
- Stimulation of β-cell regeneration in conjunction with suppression of apoptosis that is increased in islet autoimmunity to overcome the relapsing-remitting course of pre-diabetes.
- Metabolic modifications, such as weight loss and maintenance, increased physical activity, and β-cell rest.