Nicotinamide prevents the development of diabetes in the cyclophosphamide-induced NOD mouse model by reducing beta-cell apoptosis

The development of diabetes in non-obese diabetic (NOD) mice, which normall y takes between 3 and 7 months, can be accelerated by cyclophosphamide (CY) injections,,vith rapid progression to diabetes within only 2-3 weeks. This insulin-dependent diabetes mellitus (IDDM) can be prevented or delayed in CY-treated NOD mice by nicotinamide (NA). The present study was undertaken to determine the mode of cell death responsible for the development of IDDM in CY-treated male NOD mice and to investigate the effect of NA on beta-ce ll death. Apoptotic beta cells were present within the islets of Langerhans in haematoxylin and eosin-stained sections of the pancreata harvested from 3- and 12-week-old male NOD mice, from 8 h until 14 days after a single in traperitoneal injection of CY (150 mg/kg body weight). The maximum amount o f beta-cell apoptosis in 3-week-old animals occurred 1-2 days after CY trea tment (20 apoptotic cells per 100 islets), after which time levels of apopt osis declined steadily throughout the 14-day period studied. The incidence of beta-cell apoptosis in 12-week-old male NOD mice occurred in two peaks; the first was recorded 8-24 h after CY treatment (30 apoptotic cells/100 is lets), while the second, at 7 days (36 apoptotic cells per 100 islets), coi ncided with increased insulitis, Administration of NA 15 min before CY trea tment, and thereafter daily, substantially reduced the amount of apoptosis and effectively eliminated (4 apoptotic cells per 100 islets) the second wa ve of beta-cell apoptosis seen at day 7 in 12-week-old animals given CY alo ne. These results show that apoptosis is the mode of beta-cell death respon sible for the development of CY-induced IDDM and that prevention of IDDM by NA is associated with a reduction in beta-cell apoptosis. Copyright (C) 20 00 John Wiley & Sons, Ltd.