Prevention of Type 1 Diabetes

Type 1 diabetes is one of the most common chronic childhood illnesses. Each year nearly 15,000 Americans are diagnosed with type 1 diabetes.[1] Type 1 diabetes currently requires lifelong insulin therapy, and intensive control is associated with increased risks for hypoglycemia. Until there is a cure, it is critical that research continues to focus on potential therapies to prevent type 1 diabetes.

Type 1 prevention trials

Numerous different treatments have been attempted, but, to date, no treatment has been shown to prevent type 1 diabetes in human beings, although many promising therapies are currently being tested. In the United States, the Diabetes Prevention Trial (DPT-1)was conducted with the aim of determining whether antigen-based treatment with oral or injected insulin would prevent or delay diabetes in antibody-positive relatives. These treatments did not demonstrate the ability to slow the progression to diabetes.[2]

Currently, the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) is underway.[3] The goal of this trial is to examine the influence of environmental factors among people who are genetically susceptible. Specifically, this study aims to investigate whether longer duration of breastfeeding or weaning to casein hydrolysate formula (as opposed to cow’s milk formula) is associated with a reduced risk of diabetes among genetically susceptible newborns.

Intervention targets

The long prodromal phase preceding the onset of type 1 diabetes has given researchers the opportunity to begin to evaluate earlier intervention and possible prevention of type 1 diabetes. The genetic component of type 1 diabetes allows for the evaluation of relatives of patients with type 1 diabetes. Detection of 2 or more islet-related autoantibodies to glutamic acid decarboxylase (GADA) islet cells (IA-2) or insulin autoantibodies in relatives of patients with type 1 diabetes has a positive predictive value exceeding 90%.[4]

Another potential group to target in type 1 diabetes prevention efforts is patients with reduced β-cell mass, as identified by an intravenous glucose tolerance test (IVGTT). A majority of people with reduced β-cell mass will go on to develop type 1 diabetes within 5 years.[5] Although this group may seem like an ideal intervention target based on the high likelihood of development of type 1 diabetes and the time frame in which it is usually developed, the IVGTT is not a practical screening tool. Thus, this approach has been used only for small studies and has not been incorporated into any large-scale prevention efforts.[5]

Finally, a third group that has been targeted in type 1 diabetes prevention efforts is newly diagnosed patients.[5] Although this approach may seem counterintuitive, the honeymoon phase in the early stages following diagnosis represents an optimal period in which to attempt to slow or halt the autoimmune destruction of β cells. However, this group may have disease that is too far advanced to warrant intervention. A possible alternative is patients with latent autoimmune diabetes of adulthood (LADA), a more slowly progressing form of autoimmune diabetes.

Type 1 diabetes prevention strategies

Type 1 diabetes prevention strategies generally fall into 3 categories: strategies to protect β cells from autoimmune destruction, strategies to promote β-cell regeneration, and β-cell replacement efforts.[5] Most prevention efforts have focused on β-cell protection and β-cell replacement.

Strategies to prevent β-cell loss include nonspecific immunosuppressive therapy, immunomodulation, targeted immune intervention, and β-cell protection.[5] A summary of approaches appears in Table 1.

Table 1. Immune strategies to prevent type 1 (insulin-dependent) diabetes mellitus[5]

In terms of β-cell regeneration, research has been conducted on a number of β-cell growth factors, including vascular endothelial growth factor, hepatocyte growth factor, regenerating gene-1, transforming growth factor (TGF) α, and islet neogenesis-associated protein.

In terms of β-cell replacement, both pancreas transplants and islet cell transplants have been performed.[6] Currently, approximately 1500 whole-pancreas transplants are done annually, although the risks of this procedure are great.6 In terms of islet-cell transplants, the Edmonton Protocol, adopted in 2000, greatly improved the efficacy of islet-cell transplants, making all patients who receive them insulin independent at the time of transplant, with 85% remaining insulin independent at 1-year follow-up.[6] Although this procedure is promising, it is still quite labor intensive, requires posttransplant immunosuppressive therapy, and is limited by the availability of islets.

The future of prevention may be the cure

The potential for the development of targeted monoclonal antibodies to fend off the autoimmune attack is very promising and has been shown in children and adults studied to delay the progression of newly diagnosed type 1 patients.[7] Targeted monoclonal antibodies along with the new incretin hormones, such as glucagon-like peptide-1, which shows promise for islet neogenesis, may hold the key to preventing type 1 diabetes.

References

1. Laporte RE, Matsushima M, Chang YF. Prevalence and incidence of insulin-dependent diabetes. Available at: http://diabetes.niddk.nih.gov/dm/pubs/america/pdf/chapter3.pdf. Accessed May 2004.
2. National Institutes of Diabetes and Digestive and Kidney Diseases. Diabetes Prevention Trial- type 1. Available at http://www.niddk.nih.gov/patient/dpt_1/dpt_1.htm. Accessed May 2004.
3. Trial to Reduce IDDM in the Genetically at Risk. About TRIGR. Available at http://www.trigr.org/about.html.
4. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45: 926-33.
5. Petrovsky N, Silva D, Schatz DA. Prospects for the prevention and reversal of type 1 diabetes. Drugs. 2002; 62:2617-2635.
6. Shapiro AMJ, Ryan EA, Paty BW, Lakey JRT. Pancreas and islet transplantation. In Pickup JC, Williams G, eds. Textbook of Diabetes 2. Malden, MA; 2003:42.1-42.15.
7. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1A diabetes mellitus. N Engl J Med. 2002; 346:1692-1698.