Transgenic mice were generated that expressed the inhibitor of apoptosis and mitotic regulator survivin in pancreatic islet beta cells. Control non-transgenic or transgenic islets were then used in a model of islet transplantation in diabetic recipient mice and tested for their ability to correct hyperglycemia and allow long-term engraftment of tranplanted islets in vivo. Control or transgenic islets were analyzed by chip microarray for potential transcriptional changes associated with transgenic expression of survivin, in vivo.

Study the impact of survivin (Birc5), a gene implicated in the inhibition of apoptosis, on the survival of transgenic islets expressing survivin in beta cells when transplanted into diabetic recipients.

Two transgenic mouse lines were generated with RIP (rat insulin promoter)-driven survivin cDNA. Transgenic islets stained strongly for survivin and had normal beta-cell function, glucose tolerance, and insulin secretion (non-transgenic islets were negative for survivin). Islet RNA was prepared from transgenic and control mice and were hybridized on the Affymetrix GeneChip Mouse Genome 430 2.0 array. For transplant studies, C57Bl/6 mice were made diabetic by streptozotocin injection and transplanted with islets from RIP-survivin transgenic mice or non-transgenic litter mates. Islets for transplantation were also generated by adenoviral transduction of haemagglutinin-tagged survivin or GFP.

Islet size and number were the same between survivin transgenics and non-transgenic litter mates. Staurosporine caused caspase-associated apoptosis in non-transgenic islets but not in survivin transgenics. Survivin trangenic islets but not non-transgenic islets were able to confer normoglycemia at suboptimal numbers (150) in diabetic recipients and were negative for apoptosis marker staining after 1 month. Based on a single fold-change comparison (> 2.2x), upregulation of cellular stress response genes (Hsp70), inhibitors of multiple apoptotic pathways (BTG2, TIA1, DUSP1 and DUSP6/MKP3), antagonists of cytokine signalling (SOCS-3 and SOCS-6) and promoters of angiogenesis (VEGF, Egr1 and Siah-1) was found. Upregulation was confirmed for HSP70, Egr-1, and SOCS-3 genes with semi-quantitative RT-PCR and Western blotting).

The inhibition of apoptosis and the cytoprotective gene signature provided by survivin (Birc5) in transgenic beta-cells might be beneficial for gene therapy of diabetes.

• stress and apoptosis in islets/ beta cells: 751, 2000, 2001, 2020, 2021, 2301, 2904, 3244, 3650, 3975, 3977, 3979, 3980,