Insulin-like growth factors prevent cytokine-mediated cell death in isolated islets of Langerhans from pre-diabetic non-obese diabetic mice

Interleukin-1‚ (IL-1‚), tumour necrosis factor-AE (TNF-AE) and interferon-a (IFN-a) contribute to the initial stages of the autoimmune destruction of pancreatic ‚ cells. IL-1‚ is released by activated macrophages resident within islets, and its cytotoxic actions include a stimulation of nitric oxide (NO) production and the initiation of apoptosis. Insulin-like growth factors (IGFs)-I and -II prevent apoptosis in non-islet tissues. This study investigated whether IGFs are cytoprotective for isolated islets of Langerhans from non-obese diabetic mice (NOD) mice exposed to cytokines. Pancreatic islets isolated from 5‐6week-old, pre-diabetic female NOD mice were cultured for 48 h before exposure to IL-1‚ (1 ng/ml), TNF-AE (5 ng/ml), IFN-a (5 ng/ml) or IGF-I or -II (100 ng/ml) for a further 48 h. The incidence of islet cell apoptosis was increased in the presence of each cytokine, but this was significantly reversed in the presence of IGF-I or -II (IL-1‚ control 3·5&1·6%, IL-1‚ 1 ng/ml 27·1& 5·8%, IL-1‚+IGF-I 100 ng/ml 4·4&2·3%, P<0·05). The majority of apoptotic cells demonstrated immunoreactive glucose transporter 2 (GLUT-2), suggesting that they were ‚ cells. Islet cell viability was also assessed by trypan blue exclusion. Results suggested that apoptosis was the predominant cause of cell death following exposure to each of the cytokines. Co-incubation with either IGF-I or -II was protective against the cytotoxic eVects of IL-1‚ and TNF-AE, but less so against the eVect of IFN-a. Exposure to cytokines also reduced insulin release, and this was not reversed by incubation with IGFs. Immunohistochemistry showed that IGF-I was present in vivo in islets from pre-diabetic NOD mice which did not demonstrate insulitis, but not in islets with extensive immune infiltration. Similar results were seen for IGF-binding proteins (IGFBPs). These results suggest that IGFs protect prediabetic NOD mouse islets from the cytotoxic actions of IL-1‚, TNF-AE and IFN-a by mechanisms which include a reduction in apoptosis.