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


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Yamaoka
T
T
Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, Japan.
Yano
M
M
Idehara
C
C
Yamada
T
T
Tomonari
S
S
Moritani
M
M
Ii
S
S
Yoshimoto
K
K
Hata
J
J
Itakura
M
M
D000818:Animals; D017209:Apoptosis; D005260:Female; D015870:Gene Expression; D005934:Glucagon / Q000235:genetics; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000097:blood / Q000235:genetics* / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D005934:Glucagon; D005947:Glucose