It is well accepted that compromised ß-cell function is an integral part of diabetes development. Several recent studies, mostly using complex genetic mouse models, have supported the notion that a change in the ß-cell state or identity due to varying insults causes diabetes in the absence of ß-cell death. Our work has focused on the involvement of the von Hippel Lindau/Hypoxia Inducible Factor (VHL/HIF) pathway, a master regulator of cellular response to diminished oxygen (hypoxia). In a mouse model that stabilizes the HIF pathway despite normal oxygen levels within the ß-cell, we observe the development of diabetes which correlates strongly with a) a loss of the ß-cell differentiation state as determined by markers such as Pdx-1, Nkx6.1, MafA, Glut-2, and Insulin, and b) inappropriate activation of embryonic signaling pathways and genes. Immunofluorescence analyses on islets from diabetic animals displayed strikingly reduced level of insulin as compared to control, normoglycemic littermates, which indicate the cause of diabetes to be insulin insufficiency. The broad disruption of gene expression observed in diabetic mice suggests a loss of ß-cell identity (or dedifferentiation) as the underlying cause. We have also shown that ectopic expression of a key transcription factor Sox9 (normally expressed during embryogenesis) in the ß-cell causes dedifferentiation and diabetes. Our goal is to translate our findings from the mouse models of diabetes into the human condition. It is becoming apparent that diabetic patients can be stratified into distinct cohorts (based on onset of disease, age, weight, race) and it is critical to identify what sub-population of patients develops the disease due to ß-cell dedifferentiation. To this end, samples available from the nPOD provide an invaluable resource to a) identify patients who have compromised ß-cell identity, and b) correlate the findings from mouse models into human patients by identifying what signaling pathways or genes are erroneously regulated in these samples. Mouse tissue allows us to conduct genome wide expression analyses that can lead to identification of important regulators to be tested in the human samples. Our focus is on the maintenance of identity of the ß-cell, and discovering important regulators of this process may enable the development of intervention therapies that could block or delay the onset of ß-cell damage.