Erythropoietin Provides Diabetes Protection through Direct Effects on Pancreatic β Cells
From ENDO 2010 The Endocrine Society Annual Meeting, San Diego, June 19-22, 2010
Diabetes mellitus is a chronic disorder of insulin insufficiency, resulting in poor glycemic control and vascular complications. The feature common to all forms of diabetes is the insufficient functional pancreatic β-cell mass that is required to maintain euglycemia. Emerging evidence has suggested that erythropoietin (EPO) may exert cytoprotective effects on non-erythroid cells. Interestingly, the EPO receptor (EPO-R) has been found on the pancreatic β cells; however, the biological effects of EPO on the β cells are not well understood.
The effect of recombinant human erythropoietin (rHuEPO) administration was assessed on models of type 1 and type 2 diabetes, using multiple low doses (MLDS) of streptozotocin (STZ) and db/db mice. Mice were given i.p. injections of rHuEPO (50μg/kg) or saline 3 times per week for 4 weeks. In both diabetes models, it was observed that the rHuEPO-treated mice had reduced blood glucose levels compared to controls. The improved glycemic control in the rHuEPO-treated groups was not due to enhanced peripheral insulin sensitivity, but rather enhanced β-cell mass, which was attributed to increased islet proliferation and decreased apoptosis. Treatment with rHuEPO also resulted in enhanced islet angiogenesis. Western blots of isolated islets from rHuEPO-treated C57BL/6 mice demonstrated activation of the JAK2/STAT5 pathway. Bcl-xL, c-Myc, c-kit, and vegf expression levels were upregulated in the rHuEPO-treated mice. To test for the direct biological effects of EPO on the β cells, β cell-specific EPO-R knockout mice were generated. Treatment with rHuEPO failed to provide diabetes protection in these mutant mice following STZ; this supports the direct role of EPO in pancreatic β cells. To assess for essential downstream signaling, β cell-specific JAK2 knockout mice were also tested. These mice also failed to be protected from STZ-induced diabetes development following rHuEPO treatment. Furthermore, enhancement of β-cell mass and angiogenesis were also abolished in rHuEPO-treated knockout mice. These results show that rHuEPO directly inhibits apoptosis, and enhances proliferation and angiogenesis by activating EPO-R and JAK2 specifically in the β cells.
This study demonstrated that rHuEPO can exert beneficial effects directly on the pancreatic β cells. These results may lead to further elucidation of mechanisms of EPO biology relevant to β cells, which may result in novel therapeutic strategies for diabetes.
Choi D, Schroer SA, Wang L, Wu X, Woo M. University of Toronto, Toronto, Canada; St Michael's Hospital Toronto, Canada
The role of rHuEPO in pancreatic cells may bear potential benefits to diabetic patients. Other investigators also found that rHuEPO had no effect on cell apoptosis but it significantly inhibited apoptosis induced by cytokines. It also had no effect on cell insulin secretion, but significantly improved insulin secretion inhibited by cytokines. From these findings, it was concluded that EPO was expressed in NIT-1 cells and EPO could protect NIT-1 cells from apoptosis induced by cytokines.1 More research is needed before a therapeutic role is considered.
Fima Lifshitz, MD
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