Type 1 Diabetes Prevention

Type 1 diabetes mellitus is an autoimmune disease. Although the process of pancreatic cell destruction is not well understood, several known risk factors and immune-related markers accurately identify many first-degree relatives who will develop the disease. As development of type 1 diabetes can now be predicted in some people, intervention therapy to halt or even prevent cell destruction in such individuals is under investigation.

An inherited defect causes an alteration in immunologic integrity, placing the islet beta-cell at increased risk of inflammatory damage. The mechanism of damage is autoimmune, however other factors may be involved, including viruses and environmental factors:

• Viruses, e.g. mumps virus, coxsackie virus, cytomegalovirus, and hepatitis viruses
• Dietary factors: diets high in dairy products are associated with increased risk; possible risk in diets high in nitrosamines
• Environmental toxins
• Emotional and physical stress

Rare causes

• Autoimmune polyendocrine syndrome type I (APS-I)
• X-linked polyendocrinopathy, immune dysfunction, and diarrhoea

Contributory or predisposing factors

• There is a positive family history in 10% of patients.
• Strong association with histocompatibility (HLA) alleles DR3 and DR4.
• Presence of autoantibodies.
• Early cessation of breast-feeding has also been linked to increased risk of developing type 1 diabetes, but the association is unproven and controversial.

Race

• The most at-risk population for type 1 diabetes is Caucasian of northern European ancestry.
• Incidence is high in Scandinavian people.
• Hispanic or Latin American people have been shown to have lower incidence of type 1 diabetes when compared with Caucasians.
• Incidence is low in Asian people, especially those from Korea, China, and Japan, and in Mexico.

Genetics

• There is 30-50% concordance in identical twins and a positive family history in 10% of patients.
• The HLA locus on chromosome 6p appears to be the major susceptibility locus for type 1 diabetes. Specific DR3 and DR4 genotypes appear to increase risk of type 1 diabetes up to15- fold above that of low-risk genotypes; 95% of type 1 patients have both DR3 and DR4.
• Several genotypes appear to be protective against type 1 diabetes.
• Non-HLA genes also appear to play a role, including the insulin gene.

• Routine screening of children for diabetes is not warranted. Screening for the diagnosis of diabetes in first-degree relatives of patients with type 1 is reasonable, keeping in mind that the absolute risk is quite low.
• Screening of first-degree relatives for the diagnosis of diabetes should be encouraged.
• Screening by determining HLA type is not currently warranted outside the context of defined research studies.
• Screening for genetic markers predisposing to diabetes should be done in the context of ongoing research studies.

To date no treatment has been shown to prevent type 1 diabetes in humans. More than 100 different treatments prevent type 1 diabetes in the NOD mouse model, and this may indicate that disease prevention in this model is "too" easy.¹ Early cessation of breast feeding has been linked to increased risk of developing type 1 diabetes, but this association is controversial.

• A National Institutes of Health (NIH) workshop (1990) discussed the many factors related to immunomodulation to prevent type 1 diabetes. General consensus was that there is methodology that can identify, with near certainty among first-degree relatives, those who will develop diabetes, and that immune intervention therapy before the onset of symptoms might prevent the disease from occurring.
• An NIH-sponsored multicenter study, Diabetes Prevention Trial 1 (DPT-1), designed to determine whether the development of type 1 diabetes can be prevented or delayed, showed no benefit in preventing type 1 diabetes in at-risk individuals. The diabetes prevention trial (DPT-1) was started in 1994 with the aim of determining whether antigen based treatment with insulin (oral and parenteral insulin treatment in relatives at high and moderate risk) would prevent or delay diabetes. These treatments did not overall slow the progression to diabetes.
• A European study, European Nicotinamide Diabetes Intervention Trial (ENDIT), that randomized relatives of patients with type 1 diabetes to either nicotinamide or placebo also showed no benefit in preventing type 1 diabetes.²
• A large multicenter co-operative group, TrialNet,³ currently proposes to undertake multiple pilot studies aimed at type 1 diabetes prevention, genetic studies to determine at-risk populations, and novel treatment regimens at different stages of disease.

Vaccination⁴

• Primary prevention by traditional 'positive' vaccination awaits evidence that infectious agents trigger type 1 diabetes.
• The pre-clinical phase of type 1 diabetes, in which at-risk individuals can be infected by the presence of autoantibodies to islet antigens, is a window for secondary prevention.
• A major area for research is 'negative' vaccination to induce immune tolerance against disease-specific autoantigens that drive immune-mediated pathology:
  • This can be achieved by administering autoantigen via a 'tolergenic' (e.g., mucosal, intradermal) route, cell (e.g., resting dendritic cell), mode (e.g. with blockade of c0-stimulation molecules) or form (as an 'altered peptide ligand').
  • Although effective in rodent models of autoimmune disease, these strategies have so far been disappointing in humans. This review discusses the prospects of vaccination to prevent type 1 diabetes, focusing on autoantigen-specific mucosal tolerance.