Apoptosis and remodelling of beta cells by paracrine interferon-γ without insulitis in transgenic mice

• Published in: Diabetologia 1999-05, Vol.42 (5), p.566-573
• Main Authors: YAMAOKA, T, YANO, M, IDEHARA, C, YAMADA, T, TOMONARI, S, MORITANI, M, LI, S, YOSHIMOTO, K, HATA, J, ITAKURA, M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gene Expression; Glucagon - genetics; Glucose - pharmacology; Glucose Tolerance Test; In Situ Nick-End Labeling; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Interferon-gamma - blood; Interferon-gamma - genetics; Interferon-gamma - pharmacology; Islets of Langerhans - cytology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Promoter Regions, Genetic; Rats; Tumor Necrosis Factor-alpha - analysis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s001250051196

To examine whether interferon-gamma destroys islet beta cells directly or indirectly through lymphocyte activation, or whether direct action of interferon-gamma on beta cells by itself induces diabetes without insulitis. To avoid possible nonspecific breakdown of beta cells by transgenic overexpression of interferon-gamma by the insulin promoter, we generated transgenic mice expressing interferon-gamma under the control of rat glucagon promoter (RGP-IFN-gamma-Tg mice). The absence of insulitis in RGP-IFN-gamma-Tg mice enabled us to investigate the direct effects of paracrine interferon-gamma. In RGP-IFN-gamma-Tg mice, serum concentrations of interferon-gamma and tumour necrosis factor-alpha (TNF-alpha) were 50 and 6 times higher than those in their littermates, respectively, and glucose-responsive insulin secretion decreased to one-half the level of that in the littermates. Transgenic interferon-gamma induced remodelling of beta cells where apoptosis of many beta cells was compensated by their vigorous regeneration and diabetes did not occur in most of the RGP-IFN-gamma-Tg mice. Interferon-gamma alone is insufficient for the complete destruction of beta cells in vivo, and factors other than interferon-gamma including activated lymphocytes or other cytokines, are necessary in addition to interferon-gamma for the development of Type I (insulin-dependent) diabetes mellitus.