Effects of Erythropoietin on Glucose Metabolism

Abstract

We purposed to determine the impact of erythropoietin on altering glucose metabolism in the settings of in vitro and in vivo experiments. The acute effect of erythropoietin on lowering blood glucose levels was studied in animal experiments. In [³H]-deoxy-D-glucose isotope studies we measured glucose uptake with insulin and erythropoietin using 3T3-L1 cells cultured under normal or high glucose conditions. Altered activation of Akt and ERK pathways was evaluated in immunoblot analyses. Immunocytochemistry was conducted to determine the glucose transporter 4 translocation to the plasma membrane. Addition of erythropoietin significantly lowered blood glucose levels in vivo in rats. The glucose uptake was markedly increased by erythropoietin treatment (at concentrations 0.15, 0.3, and 0.625 ng/ml) in adipocytes grown in high glucose medium (p<0.05), but it remained unaltered in cells under normal glucose conditions. Significant increase of phosphorylation of ERK and Akt was detected due to erythropoietin (p<0.05). Co-administration of erythropoietin and insulin resulted in higher phosphorylation of Akt and [³H]-deoxy-D-glucose uptake in adipocytes than insulin treatment alone. We found that erythropoietin induced the trafficking of glucose transporter 4 to the plasma membrane. Our data showed that erythropoietin significantly decreased blood glucose levels both in vivo and in vitro, in part, by increasing glucose uptake via the activation of Akt pathway. Preliminary data revealed that adipocytes most likely exhibit a specific receptor for erythropoietin.

Chronic erythropoietin treatment improves diet-induced glucose intolerance in rats

“…A single injection of a high dose of EPO induced transient phosphorylation of AKT without altering systemic levels of glucose, indicating that EPO-induced phosphorylation of AKT in skeletal muscle has a limited role in acute glucose control in animals with normal blood glucose levels. In contrast, results described in a previous report indicated that acute EPO injection in streptozotocin-induced diabetic rats with elevated blood glucose levels (approximately 22 mM) led to a small (6%) but significant decrease in blood glucose levels; however, the tissues involved have not been identified (Mikolás et al 2012). Initial blood glucose levels may thus be critical in the acute effect of EPO, consistent with the study reporting that hyperglycemia is necessary for stimulation of EPO-induced glucose uptake in adipocytes (Mikolás et al 2012).…”

“…In contrast, results described in a previous report indicated that acute EPO injection in streptozotocin-induced diabetic rats with elevated blood glucose levels (approximately 22 mM) led to a small (6%) but significant decrease in blood glucose levels; however, the tissues involved have not been identified (Mikolás et al 2012). Initial blood glucose levels may thus be critical in the acute effect of EPO, consistent with the study reporting that hyperglycemia is necessary for stimulation of EPO-induced glucose uptake in adipocytes (Mikolás et al 2012). As we have also shown that rat soleus muscle did not express EPOR, AKT activation in our model is likely to be indirect via a still unknown mechanism (Wang et al 2014).…”

“…As EPOR mRNA was undetectable in soleus or EDL, we conclude that any effect of EPO treatment on muscle AKT phosphorylation is indirect and results from lower systemic inflammation, reduced muscle oxidative stress, or increased HSP72 expression, all known to positively influence insulin signaling. On the other hand, other metabolic tissues, such as liver (Meng et al 2013) or adipose tissue (Mikolás et al 2012, which have been shown to express EPOR and respond to EPO, can also participate in improved glucose control in our model. Our results from cultured cells confirm that EPO can stimulate AKT activation in synergy with insulin in 3T3L1 adipocytes and demonstrate the lack of direct action of EPO on muscle cells.…”

“…6B and C). Given the previous results indicating that EPO activates the PI3K/AKT pathway in metabolic cells (Mikolás et al 2012), we investigated the effect of EPO on AKT phosphorylation in differentiated rat muscle cell lines and human primary cells. We then first confirmed the existence of a synergy between EPO and insulin towards AKT phosphorylation using 3T3-L1 adipocytes treated with insulin and EPO (P!0.05; Fig.…”

“…Acute treatment with EPO protects pancreatic cells against the combined action of pro-apoptotic cytokines interleukin 1 (IL1b) tumor nexcosis factor alpha (TNFa), and interferon gamma (IFNg), suggesting indicative of its cytoprotective role (Maiese et al 2005). In cultured adipocytes, EPO prevented dexamethasone-induced decrease in glucose uptake (Mikolás et al 2012, Pan et al 2013.…”