Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part of the body which helps fight infections) mistakenly attacks and destroys the cells that produce insulin (islet cells found in the pancreas). As these cells are destroyed, the body's ability to produce insulin decreases. There is evidence suggesting that repeated oral administration of an autoantigen (the same protein that the immune system is reacting to) may introduce a protective immunity and cause the immune system to stop its attack. An earlier, large scale study was done to see if oral insulin could delay or prevent the development of T1D in relatives at risk for developing T1D. The overall results showed that for the entire study population, oral insulin did not delay or prevent T1D.

However, an analysis that was done after the conclusion of the trial suggested a potential beneficial effect in a subgroup of participants. The participants who seemed to benefit from oral insulin had higher levels of insulin autoantibodies which were directed against insulin itself (called mIAA). Eligible participants were randomized to receive either oral insulin (7.5 mg of recombinant human insulin crystals) or placebo daily.

All participants randomized into TrialNet 07 were seen at a study site for a follow-up evaluation, three and six months after randomization, and every six months thereafter. Participants were contacted by phone between six monthly clinic visits to assess changes in diabetes status, medication compliance, and adverse events. These phone contacts occurred approximately three months from the date of the previous clinic visit. At the study visits, participants underwent assessments of their insulin production, immunologic status, and overall health.

To assess the efficacy of oral insulin in the prevention or delay of the development of type 1 diabetes mellitus in subjects with mIAA and other autoantibodies and a proband with type 1 diabetes.

Primary outcome measure:

• Rate of T1D per year among individuals in the primary stratum when treated with oral insulin versus placebo (Time frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years)

• Rate of T1D per year in secondary stratum (Stratum 2) when treated with oral insulin versus placebo (Time Frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years)
• Rate of T1D in secondary stratum (Stratum 3 and 4) when treated with oral insulin versus placebo (Time frame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years)

Inclusion criteria:

• Have a proband with type 1 diabetes mellitus (T1DM). A proband is an individual diagnosed with diabetes before age 40 and started on insulin therapy within 1-year of diagnosis. Probands considered to have type 1 diabetes by their physician who do not meet this definition will be referred to the TrialNet Eligibility Committee.
• If the proband is a parent, sibling, or a child, the study participant must be 3-45 years of age. If the proband is a second or third degree relative (i.e., niece, nephew, aunt, uncle, grandparent, cousin, or half-sibling), the study participant must be 3-20 years of age.
• Willing to sign informed consent form.
• Oral glucose tolerance test (OGTT) performed within 7 weeks prior to randomization in which:
  • Fasting plasma glucose < 110 mg/dL (6.1 mmol/l), and
  • 2-hour plasma glucose < 140 mg/dL (7.8 mmol/l)
• mIAA confirmed positive within the previous six months.
• Two samples with at least one autoantibody other than mIAA positive within the previous six months.

• Does not satisfy the above inclusion criteria. Subjects with mIAA positive but no other autoantibodies positive are not eligible for randomization.
• Has severe active disease (e.g., chronic active hepatitis, severe cardiac, pulmonary, renal, hepatic, immune deficiency, and/or disease that is likely to limit life expectancy or lead to therapies such as immunosuppression during the time of the study).
• Prior participation in a trial for prevention of T1DM (e.g., nicotinamide, insulin, immunosuppressive drugs).
• History of treatment with insulin or oral hypoglycemic agent.
• History of therapy with immunosuppressive drugs or glucocorticoids within the past two years for a period of more than three months.
• Ongoing use of medications known to influence glucose (i.e., sulfonylureas, growth hormone, metformin, anticonvulsants, thiazide or potassium depleting diuretics, beta adrenergic blockers, niacin). Subjects on such medications would be changed to a suitable alternative, if available, and would become eligible one month after medication was discontinued.
• Pregnant or intend to become pregnant while on study or lactating.
• Deemed unlikely or unable to comply with the protocol.
• OGTT that reveals diabetes, impaired glucose tolerance (IGT), or impaired fasting glucose (IFG).
• Diabetes is defined by fasting plasma glucose ≥ 126 mg/dL (7 mmol/l), or 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/l)
• IGT is defined by fasting plasma glucose < 126 mg/dL (7 mmol/l), and 2-hour plasma glucose 140-199 mg/dL (7.8-11 mmol/l)
• IFG is defined by fasting plasma glucose 110-125 mg/dL (6.1-6.9 mmol/l), and 2-hour plasma glucose < 140 mg/dL (7.8 mmol/l)
• Subject has HLA DQA1*0102, DQB1*0602 haplotype.

Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings did not support oral insulin as used in this study for diabetes prevention.