Apoptosis and beta-cell destruction in pancreatic islets of NOD mice with spontaneous and cyclophosphamide-accelerated diabetes
- Author(s)
- Augstein, P; Elefanty, AG; Allison, J; Harrison, LC;
- Details
- Publication Year 1998-11,Volume 41,Issue #11,Page 1381-1388
- Journal Title
- DIABETOLOGIA
- Publication Type
- Journal Article
- Abstract
- Autoimmune-mediated destruction of pancreatic islet beta cells leads to insulin-dependent diabetes in non-obese diabetic (NOD) mice. Although both direct cytotoxic T cell- and indirect cytokine-, nitric oxide- or free radical-mediated mechanisms induce beta-cell apoptosis in vitro, beta-cell death in vivo in spontaneous autoimmune diabetes is not well-characterized. Furthermore, whether beta cells die gradually, or rapidly in the late pre-clinical stage, is a question of current interest. To investigate beta-cell death in vivo, we measured the frequency and intra-islet localisation of apoptosis, defined as DNA strand breaks by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) technique, during spontaneous and cyclophosphamide-accelerated diabetes in NOD mice. In spontaneous diabetes, the frequency of apoptosis in islets correlated with the progression of beta-cell destruction with age. Although apoptosis was detected at low frequency within the reduced insulin-positive islet area of pre-diabetic mice at 90 days of age, it was rarely co-localised to beta cells. After acceleration of beta-cell destruction with cyclophosphamide, the frequency of apoptosis reached maximum at 12 days, at which time 3.2 % of apoptotic cells were beta cells. Apoptosis was most frequent in the insulin-negative islet area comprised of mononuclear cell infiltrate and was localized to CD8(+) T cells. The rarity of detectable apoptotic beta cells in spontaneous prediabetic mice with pronounced insulitis and reduced insulin-positive islet areas most likely reflects the rapid clearance of apoptotic beta cells. Our findings are more consistent with gradual destruction of non-renewable beta-cells in spontaneous diabetes, than with their rapid, accelerated destruction (as after cyclophosphamide) in the late pre-clinical stage.
- Publisher
- SPRINGER VERLAG
- Keywords
- DNA FRAGMENTATION; T-CELLS; DEATH; MOUSE; IDENTIFICATION; CYTOKINES; INSULITIS; MODEL; BCL-2; ONSET
- Publisher's Version
- https://doi.org/10.1007/s001250051080
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 1998-11-01 12:00:00