Erythropoietin Signaling in Pancreatic Beta Cells in Homeostasis and in Models of Type 1 and Type 2 Diabetes

Diabetes mellitus is a complex disorder characterized by chronic hyperglycemia and vascular complications leading to significant morbidity and mortality. The common feature in all forms of diabetes is the insufficient functional β-cell mass to maintain euglycemia; therefore, the promotion of β-cell survival and growth is a fundamental goal for diabetes prevention and treatment. Evidence has suggested that erythropoietin (EPO) exerts cytoprotective effects on non-erythroid cells. However, the in vivo role of EPO on the pancreatic β cells has not been evaluated to date. We hypothesized that EPO would have direct cytoprotective effects on the pancreatic β cells and provide protection against experimental models of diabetes. In Chapter IV, we report that recombinant human erythropoietin (rHuEPO) administration provided protection against diabetes development in the streptozotocin (STZ)-induced and db/db mice, models of type 1 and type 2 diabetes, respectively, through anti-apoptotic, proliferative and angiogenic effects within the islets. Next, we show in Chapter V, using β cell-specific EPO-R and JAK2 knockout (KO) mice, that these cytoprotective effects of EPO resulted from direct biological effects on the β cells, and that JAK2 is its essential intracellular mediator. We also show that endogenous EPO or JAK2 in β cells had no essential role in determining β-cell development or homeostasis. Given that epo is a target gene of the hypoxia inducible factor (HIF) pathway, we hypothesized that deletion of von Hippel Lindau (VHL), a negative regulator of this pathway, in the β cells would lead to enhanced transcription of HIF-target genes, which are largely pro-survival, and lead to enhanced β-cell mass and function. Contrary to our hypothesis, in Chapter VI, our results show that the epo gene is not expressed in islets. Furthermore, β cell-specific VHL KO mice were glucose intolerant due to impaired β-cell function and mass, which we were able to rescue with rHuEPO treatment. Our results demonstrate that EPO exerts direct biological effects on the pancreatic β cells. Further understanding of the biology of EPO may hold promise for the development of a potential novel strategy for diabetes prevention and treatment.Ph