Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice

J Clin Invest. 1996 Sep 15;98(6):1324-31. doi: 10.1172/JCI118919.


Oral administration of self-antigens has been proposed as a therapy to prevent and treat autoimmune diseases. Here we report that oral treatment with insulin prevents virus-induced insulin-dependent diabetes mellitus (IDDM) in a transgenic (tg) mouse model. Such mice express the viral nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under control of the rat insulin promoter in their pancreatic beta cells and < 2% spontaneously develop diabetes. However, 2 mo after challenge with LCMV, IDDM occurs in > 95% of tg mice but not in controls. Oral treatment with 1 mg of insulin twice per week for 2 mo starting either 1 wk before or 10 d after initiating LCMV infection prevents IDDM in > 50% of the tg mice (observation time 8 mo). Thus, insulin therapy is effective in preventing progression to overt IDDM in prediabetic tg mice with ongoing islet infiltration. Oral administration of insulin does not affect the generation of LCMV-NP-specific anti-self cytotoxic T lymphocytes nor the infiltration of lymphocytes into the pancreas. However, less beta cells are destroyed in insulin-treated mice, upregulation of MHC class I and II molecules does not occur, and antiviral (self) cytotoxic T lymphocytes are not found in the islets, events present in tg mice developing IDDM. The majority of lymphocytes in the islets of insulin-treated tg mice without IDDM produces IL-4, IL-10, and TGF-beta. In contrast, lymphocytes from islets of tg mice developing IDDM mainly make gamma-IFN.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Autoimmunity
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / pathology
  • Cell Movement
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / virology
  • Histocompatibility Antigens Class I / biosynthesis
  • Histocompatibility Antigens Class II / biosynthesis
  • Hypoglycemic Agents / therapeutic use*
  • Immunohistochemistry
  • Insulin / therapeutic use*
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / biosynthesis
  • Interleukin-4 / biosynthesis
  • Islets of Langerhans / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Transgenic
  • Nucleoproteins / immunology
  • Pancreas / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • Transforming Growth Factor beta / biosynthesis


  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II
  • Hypoglycemic Agents
  • Insulin
  • Nucleoproteins
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interleukin-4
  • Interferon-gamma