Abstract
We have studied the effects of longterm treatment with azathioprine (AZA) vs cyclosporin A (CSA) vs placebo (PL), in three groups of 10 week old, prediabetic NOD mice. One of 8 AZA, none of 8 CSA and 7 of 11 PL treated mice developed overt diabetes (IDDM). Quantitative morphometry analysis conducted on mouse pancreatic histologic sections documented that extent and degree of islet beta-cell damage were incomparably less severe in the mice that received AZA or CSA compared to those treated with PL. Since early and prolonged treatment with AZA seems to prevent the onset of DM in NOD mice as nearly effectively as CSA, AZA, which is significantly safer than CSA, could replace the latter as a potential approach for the immunotherapy of IDDM.
Similar content being viewed by others
References
Bottazzo G.F., Florin-Christensen A., Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiences. Lancet 2: 1274, 1974.
Lernmark Å., Freedman Z.R., Hofmann C., Rubenstein A.H., Steiner D.F., Jackson R.L., Winter R.J., Traisman H.S. Islet-cell surface antibodies in juvenile diabetes mellitus. N. Engl. J. Med. 299: 375, 1978.
Palmer J.P., Asplin C.M., Clemons P., Lyen K., Tatpati O., Raghu P.K., Paguette T.L. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222: 1337, 1983.
Bohmer K., Keilacher H., Kuglin B., Hubinger A., Bertrams J., Gries F.A., Kolb H. Proinsulin autoantibodies are more closely associated with type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies. Diabetologia 34: 830, 1991.
Karlsen A.E., Michelsen B.K., Petersen J.S., Hagopian W.A., Grubin C.E., Boel E., Madsen O.D., Stenger D.P., Lernmark A. Glutamic acid decarboxylase, an autoantigen in insulin-dependent diabetes mellitus. Diab. Nutr. Metab. 5 (Suppl. 1): 97, 1992.
Bonifacio E., Bingley P.J., Shattock M., Dean B.M., Dunger D., Gale E.A.M., Bottazzo G.F. Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes. Lancet 335: 147, 1990.
Ziegler A.G., Herskowitz R.D., Jackson R.A., Soeldner J.S., Eisenbarth G.S. Predicting type I diabetes. Diabetes Care 13: 762, 1990.
Barmeier H., McCulloch D.K., Neifing J.L., Warnock G., Rajotte R.V., Palmer J.P., Lernmark A. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 34: 727, 1991.
Stiller C.R., Dupre J., Gent M., Jenner R., Koewn P.A., Laupacis A., Martell R., Rodrer N.W., Graffenried B.V., Wolfe B.M.J. Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset. Science 223: 1362, 1984.
Assan R., Feutren G., Sirmai J., Laborie C., Boitard C., Vexiau P., Du Rostu H., Rodier M., Figoni M., Vague P., Hors J., Bach J.F. Plasma C-Peptide levels and clinical remissions in recent-onset type 1 diabetic patients treated with Cyclosporin A and insulin. Diabetes 39: 768, 1990.
Harrison L.C., Colman P.G., Dean B.M., Baxter R., Barton F.I.R. Increase in remission rate in newly diagnosed Type I diabetic subjects treated with azathioprine. Diabetes 34: 130, 1985.
Silverstein J., Maclaren N., Riley W., Spillar R., Radjenovic D., Johnson S. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N. Engl. J. Med. 319: 599, 1988.
Kolb H. Mouse models of insulin-dependent diabetes: lowdose streptozotocin-induced diabetes and nonobese (NOD) mice. Diabetes Metab. Rev. 3: 751, 1987.
Chalmers A.H., Knight P.R., Atkinson M.R. Conversion of azathioprine into mercaptopurine and mercaptoimidazole derivatives in vitro and during immunosuppressive therapy. Aust. J. Exp. Biol. Med. Sci. 47: 263, 1969.
Van Wanghe P., Dequeker J. Compliance and long-term, effect of azathioprine in 65 rheumatoid arthritis cases. Ann. Rheum. Dis. 41 (Suppl. 1): 40, 1982.
Triger D.R. Autoimmune chronic active hepatitits and primary biliary cirrhosis. Baillieres. Clin. Gastroenterol. 3: 21, 1989.
Havard C.W., Fonseca V. New treatment approaches to myasthenia gravis. Drugs 39: 66, 1990.
Mori Y., Suko M., Okudaira H., Matsuba I., Tsurnoka A., Sasaki A., Yokoyama H., Tanase T., Shida T., Nishimura M., Terada E., Ikeda Y. Preventive effects of cyclosporin on diabetes in NOD mice. Diabetologia 29: 244, 1986.
Calafiore R., Pietropaolo M., Basta G., Falorni A., Picchio M.L., Brunetti P. Mechanisms of pancreatic islet beta-cell destruction in NOD mice. Metabolism, in press.
Palmer J.P., McCulloch D.K. Prediction and prevention of IDDM-1991. Diabetes 40: 943, 1991.
Mordes J.P., Desemone J., Rossini A.A. The BB rat. Diabetes. Metab. Rev. 3: 725, 1987.
American Diabetes Association Position statement: prevention of type I diabetes mellitus. Diabetes 39: 1151, 1990.
Murase N., Lieberman I., Nalesnik M.A., Mintz D.H., Todo S., Drash A.L., Starzl T.E. Effect of FK506 on spontaneous diabetes in BB rats. Diabetes 39: 1584, 1990.
Yazici H., Pazarli H., Barnes C.G., Tuzun Y., Ozyagan Y., Silman A., Serdaroglu S., Oguz V., Yurdakul S., Lovatt G.E. A controlled trial of azathioprine in Behcet’s syndrome. N.Engl. J. Med. 322: 32, 1990.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Calafiore, R., Basta, G., Falorni, A. et al. Preventive effects of azathioprine (AZA) on the onset of diabetes mellitus in NOD mice. J Endocrinol Invest 16, 869–873 (1993). https://doi.org/10.1007/BF03348947
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF03348947