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

Aims/hypothesis. To examine whether interferon-gamma destroys islet beta ce lls directly or indirectly through lymphocyte activation, or whether direct action of interferon-gamma on beta cells by itself induces diabetes withou t insulitis. Methods. To avoid possible nonspecific breakdown of beta cells by transgeni c overexpression of interferon-gamma by the insulin promoter, we generated transgenic mice expressing interferon-gamma under the control of rat glucag on promoter (RGP-IFN-gamma-Tg mice). Results. The absence of insulitis in RGP-IFN-y-Tg mice enabled us to invest igate the direct effects of paracrine interferon-gamma. In RCP-IFN-gamma-Tg mice, se rum concentrations of interferon-gamma and tumour necrosis factor -alpha (TNF-alpha) were 50 and 6 times higher than those in their littermat es, respectively, and glucose-responsive insulin secretion decreased to one -half the level of that in the littermates. Transgenic interferon-gamma ind uced remodelling of beta cells where apoptosis of many beta cells was compe nsated by their vigorous regeneration and diabetes did not occur in most of the RG-IFN-gamma-Tg mice. Conclusion/interpretation. Interferon-gamma alone is insufficient for the c omplete destruction of beta cells in vivo, and factors other than interfero n-gamma including activated lymphocytes or other cytokines, are necessary i n addition to interferon-gamma for the development of Type I (insulin-depen dent) diabetes mellitus.