epoetin-alfa and Insulin-Resistance

Erythropoietin (EPO) contributes to insulin resistance in fat and muscle. In the present study, the role and mechanism of EPO in hepatic insulin resistance were investigated in HepG2 cells. Hepatic insulin resistance was induced by palmitic acid (PA) in the HepG2 cells, which were then treated with EPO (5 or 10 U/ml) or specific phosphoinositide 3‑kinase (PI3K) inhibitors, wortmannin or LY294002. EPO treatment significantly increased glycogen levels and reduced the protein expression of phosphoenolpyruvate carboxykinase in the PA‑induced HepG2 cells. EPO also inhibited the serine phosphorylation of insulin receptor substrate (IRS)‑1 (Ser307) and IRS‑2 (Ser473), and increased the protein expression levels of PI3K, phosphorylated (p)‑protein kinase B (AKT), p‑forkhead box O1 (FOXO1) and p‑glycogen synthase kinase 3 (GSK‑3) β. In agreement with these result, the expression of p‑FOXO1 (Ser256) and p‑GSK‑3β (Ser9), downstream molecules of AKT, were enhanced by EPO treatment (P<0.05). The specific PI3K inhibitors, LY294002 and wortmannin, markedly inhibited the EPO‑mediated increases in p‑AKT (Ser473), p‑FOXO1 (Ser256) and p‑GSK‑3β (Ser9) in the PA‑induced HepG2 cells (P<0.05). The gene expression levels of tumor necrosis factor‑α, interleukin‑1β and monocyte chemoattractant protein‑1, and the p‑c‑Jun N‑terminal kinase (JNK)/total‑JNK ratio were markedly suppressed by EPO treatment. These findings suggested that EPO treatment improved hepatic glucose metabolism, potentially through the IRS/AKT/FOXO1 and GSK‑3β signaling pathway, which may be associated with its inhibitory effect on the inflammation-associated response.

Topics: Androstadienes; Chemokine CCL2; Chromones; Epoetin Alfa; Forkhead Box Protein O1; Glucose; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Morpholines; Palmitic Acid; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Tumor Necrosis Factor-alpha; Wortmannin

Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of (14)C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.

Topics: Animals; Darbepoetin alfa; Diabetes Mellitus, Experimental; Dietary Fats; Disease Models, Animal; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Glucose; Glucose Clamp Technique; Glucose Tolerance Test; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Obesity; Receptors, Erythropoietin; Recombinant Fusion Proteins; Recombinant Proteins; Time Factors