• To describe the effects of oral insulin in other subjects defined using different combinations of autoantibodies and metabolic status
• To assess the effects of oral insulin on immunologic and metabolic markers

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 Type 1 diabetes in relatives at risk for developing Type 1 diabetes. The overall results showed that for the entire study population, oral insulin did not delay or prevent Type 1 diabetes. 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 are directed against insulin itself ( called mIAA).

The Type 1 Diabetes TrialNet study group will further explore the potential role of oral insulin to delay or prevent Type 1 diabetes in a similar group of people. The study will also include a secondary group of individuals at different levels of risk than those in the primary cohort to gather information for future studies.

Eligible participants will be randomized to receive either oral insulin (7.5 mg of recombinant human insulin crystals) or placebo daily.

All participants randomized into this study will be seen at a study site for a follow-up evaluation, three and six months after randomization, and every six months thereafter. Participants will be contacted by phone between 6-monthly clinic visits to assess changes in diabetes status, medication compliance and adverse events. These phone contacts will occur approximately 3 months from the date of the participants previous clinic visit.

At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. As the primary outcome measure, subjects will be followed until development of type 1 diabetes or the conclusion of the study. The trial is expected to last approximately 7-8 years or until the required amount of information is gathered.

• Bergerot I, Fabien N, Maguer V, Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. J Autoimmun. 1994 Oct;7(5):655-63.
• Muir A, Schatz D, Maclaren N. Antigen-specific immunotherapy: oral tolerance and subcutaneous immunization in the treatment of insulin-dependent diabetes. Diabetes Metab Rev. 1993 Dec;9(4):279-87. Review. No abstract available.
• Muir A, Peck A, Clare-Salzler M, Song YH, Cornelius J, Luchetta R, Krischer J, Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest. 1995 Feb;95(2):628-34.
• Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252-6.
• Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1. Diabetes Care. 2005 May;28(5):1068-76.
• Lachin JM. Maximum information designs. Clin Trials. 2005;2(5):453-64.

Inclusion Criteria:

1. Have a proband with 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.
2. 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.
3. Willing to sign Informed Consent Form.

4. 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)
5. mIAA confirmed positive within the previous six months.
6. Two samples with at least one autoantibody other than mIAA positive within the previous six months.

Exclusion Criteria:

1. Does not satisfy the above inclusion criteria. Subjects with mIAA positive but no other autoantibodies positive are not eligible for randomization.
2. 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.
3. Prior participation in a trial for prevention of T1DM, e.g. nicotinamide, insulin, immunosuppressive drugs.
4. History of treatment with insulin or oral hypoglycemic agent.
5. History of therapy with immunosuppressive drugs or glucocorticoids within the past two years for a period of more than three months.
6. 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 should be changed to a suitable alternative, if available, and will become eligible one month after medication is discontinued.
7. Pregnant or intends to become pregnant while on study or lactating.
8. Deemed unlikely or unable to comply with the protocol.

9. OGTT that reveals Diabetes, Impaired Glucose Tolerance (IGT), or Impaired Fasting Glucose (IFG).

   Diabetes is defined by:

   • fasting plasma glucose ³ 126 mg/dL (7 mmol/l), OR
   • 2 hour plasma glucose ³ 200 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 - 11mmol/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)
10. Subject has HLA DQA1*0102, DQB1*0602 haplotype.

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• National Institute of Allergy and Infectious Diseases (NIAID)
• National Center for Research Resources (NCRR)
• American Diabetes Association
• Juvenile Diabetes Research Foundation