Effects of Erythropoietin on Glucose Metabolism

2nd Department of Medicine and Nephrological Center, University of Pécs, Pécs, Hungary.
Hormone and Metabolic Research (Impact Factor: 2.12). 02/2012; 44(4):279-85. DOI: 10.1055/s-0032-1301901
Source: PubMed


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.

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    • "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). "
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    ABSTRACT: Erythropoietin (EPO) ameliorates glucose metabolism through mechanisms not fully understood. Here, we investigated the effect of EPO on glucose metabolism and insulin signaling in skeletal muscle. A two-week EPO treatment of rats fed with a high fat diet (HFD) improved fasting glucose levels and glucose tolerance, without altering total body weight or retroperitoneal fat mass. Concomitantly, EPO partially rescued insulin-stimulated Akt activation, reduced markers of oxidative stress and restored heat shock protein 72 expression in soleus muscles from HFD-fed rats. EPO incubation on skeletal muscle cell cultures failed to induce Akt phosphorylation and had no effect on glucose uptake or glycogen synthesis. We found the EPO receptor gene expressed in myotubes while undetectable in soleus. Together, our data demonstrate that EPO treatment improves glucose tolerance but does not directly activate the phosphorylation of Akt in muscle cells. We propose that the reduced systemic inflammation or oxidative stress that we observe after treatment with EPO could contribute in the improvement of whole body glucose metabolism.
    Journal of Endocrinology 03/2015; 225(2). DOI:10.1530/JOE-15-0010 · 3.72 Impact Factor
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    ABSTRACT: Recombinant human erythropoietin (rHuEPO) reduces serum insulin levels, increases insulin sensitivity, and reduces insulin resistance (IR). However, the mechanisms behind these effects are unclear. This study aimed to investigate the mechanism by which rHuEPO effects IR in 3T3L1 adipocytes. After treatment with different concentrations of rHuEPO, glucose consumption, and tumor necrosis factor (TNF-α), adiponectin, and leptin levels were assayed with a commercial enzyme-linked immunosorbent assays. Endogenous erythropoietin receptor (EPOR) expression was inhibited using small interfering RNA (siRNA). EPOR protein and mRNA expression was detected via immunofluorescence and real-time PCR analyses, respectively. The expression of pAKT/AKT and p-STAT5/STAT5 was determined via Western blot analysis. rHuEPO treatment improved glucose uptake, increased adiponectin levels, and reduced TNF-α and leptin levels in 3T3L1 adipocytes with dexamethasone-induced IR. Whereas EPOR protein and gene expression was absent in preadipocytes, it was observed in mature 3T3L1 adipocytes. However, the expression of EPOR in insulin resistant 3T3L1 adipocytes was significantly decreased (p<0.05). rHuEPO increased the expression of EPOR, and upregulated the expression of pAKT/AKT and pSTAT5/STAT5 in 3T3L1 adipocytes (p<0.05), which was blocked by siEPOR, the phosphatidylinositol-3-kinase (PI3K) inhibitor, LY294002, and a STAT5 inhibitor, respectively. In summary, rHuEPO reduced IR in adipocytes by increasing glucose uptake and improving the adipokine profile. rHuEPO-induced EPOR protein expression and subsequent induction of pAKT and pSTAT5 suggest that the EPO-EPOR system may play a role in glucose metabolism within adipocytes.
    Molecular and Cellular Endocrinology 01/2013; 367(1-2). DOI:10.1016/j.mce.2012.12.027 · 4.41 Impact Factor
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    ABSTRACT: The growing prevalence of obesity and diabetes necessitate a better understanding of the role of adipocyte biology in metabolism. Increasingly, erythropoietin (EPO) has been shown to have extra-erythropoietic and cytoprotective roles. Exogenous administration has recently been shown to have beneficial effects on obesity and diabetes in mouse models and EPO can modulate adipogenesis and insulin signalling in 3T3-L1 adipocytes. However, its physiological role in adipocytes has not been identified. Using male and female mice with adipose tissue-specific knockdown of the erythropoietin receptor (EpoR), we determine that adipocyte EPO signalling is not essential for maintenance of energy homeostasis, or glucose metabolism. Adipose tissue-specific disruption of EpoR did not alter adipose tissue expansion, adipocyte morphology, insulin resistance, inflammation or angiogenesis in vivo. In contrast to the pharmacological effects of EPO, we demonstrate that EPO signalling at physiological levels is not essential for adipose tissue regulation of metabolism.
    Endocrinology 07/2013; 154(10). DOI:10.1210/en.2013-1113 · 4.50 Impact Factor
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