LAUSR

Cancer‐bearing often exhibits hypoinsulinemia, insulin (INS) resistance and glutamine depletion associated with cachexia. However, INS and glutamine effects on cachexia metabolic abnormalities, particularly on tumor‐affected proteins related to INS resistance, are poorly known. The main purpose of this study was to investigate the effects of INS and glutamine dipeptide (GDP) treatments on phospho‐protein kinase B (p‐Akt), and phospho‐hormone sensitive lipase (p‐HSL) in Walker‐256 tumor‐bearing rats. INS (NPH, 40 UI/kg, subcutaneous), GDP (1.5 g/kg, oral), INS+GDP or vehicle (control rats) were administered for 13 days, once a day, starting at the day of inoculation of tumor cells. The experiments were performed 4 hours after the last treatment to evaluate acute effects of INS and GDP, besides the chronic effects. INS and/or INS+GDP treatments, which markedly increased the insulinemia, increased the p‐Akt: total Akt ratio and prevented the increased p‐HSLSer552: total HSL ratio in the retroperitoneal fat of tumor‐bearing rats, without changing the INS resistance and increased expression of factor tumor necrosis‐α (TNF‐α) in this tissue. INS and INS+GDP also increased the p‐Akt: total Akt ratio, whereas GDP and INS+GDP increased the GLUT4 glucose transporter gene expression, in the gastrocnemius muscle of the tumor‐bearing rats. Accordingly, treatments with INS and INS+GDP markedly reduced glycemia, increased retroperitoneal fat and attenuated the body mass loss of tumor‐bearing rats. In conclusion, hyperinsulinemia induced by high‐dose INS treatments increased Akt phosphorylation and prevented increased p‐HSLSer552: total HSL ratio, overlapping INS resistance. These effects are consistent with increased fat mass gain and weight loss (cachexia) attenuation of tumor‐bearing rats, evidencing that Akt activation is a potential strategy to prevent loss of fat mass in cancer cachexia.