Erythropoietin Treatment Leads to Reduced Blood Glucose Levels and Body Mass: Insights From Murine Models.

Abstract 4557

Erythropoietin (EPO) regulates proliferation and differentiation of erythroid precursor cells into erythrocytes. The last decade has revealed non-renal sites of EPO production and extrahematopoietic expression of the EPO-receptor (EPO-R), suggesting that EPO has pleiotropic functions. We have previously shown anti-cancer and immunomodulating effects of the hormone in humans and mice. Here we addressed the interplay among EPO, glucose metabolism, and body weight by employing a panel of relevant experimental murine models. The models focused on situations of increased EPO levels, including EPO-injected C57BL/6 and BALB/c mice, as well as transgenic mice (tg6) constitutively overexpressing human EPO and thus exposed to constantly high EPO serum levels. As experimental models for diabetes and obesity we employed protein Tyr phosphatase 1B (PTP1B) knockout mice associated with resistance to diabetes (PTP1B^-/-), and ob/ob mice susceptible to diabetes and obesity. Our data demonstrated an EPO-associated decrease in blood glucose levels in all mice models tested. The tg6 mice, continuously exposed to EPO, were hypoglycemic even under non-fasting conditions. Blood glucose reduction in the experimental models tested was evident already one week following EPO administration in all models, including the PTP1B^-/- and ob/ob mice. This conclusion gained further support by the glucose tolerence test (GTT). EPO overexpression or administration led to improved glucose clearance in all the tested murine models. Notably, in the ob/ob mice we observed EPO-associated attenuation of body weight gain and reduction of hemoglobin A1C. Preliminary clinical observations with several diabetic patients support these data and will be discussed further. Taken together our data bear significant clinical implications for EPO treatment in the management of a wide range of metabolic diseases and add an important novel therapeutic potential to this pleiotropic hormone.