Insulin, not glutamine dipeptide, reduces lipases expression and prevents fat wasting and weight loss in Walker 256 tumor-bearing rats

Morais, Hely de; Silva, Flaviane de Fatima; Silva, Francemilson Goulart da; Silva, Milene Ortiz; Graciano, Maria Fernanda Rodrigues; Martins, Maria Isabel Lovo; Carpinelli, Ângelo Rafael; Mazucco, Tânia Longo; Bazotte, Roberto Barbosa; Souza, Helenir Medri de

doi:10.1016/j.ejphar.2017.03.010

Cited by 6 publications

(11 citation statements)

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“…44 Although 50 UI/kg INS improved cachexia in this previous study, 7 it reduced tumor growth, impairing the evaluation of the effects of INS, since reduction in tumor size decreases the metabolic changes induced by the tumor. Confirming our previous study, 27 treatment with 40 IU/kg INS, which induced accentuated hypoglycemia, as well as GDP supplementation, did not influence the tumor growth (Table 1), although glucose 45 and glutamine 46 are highly utilized as a source of energy by tumor cells. GDP supplementation also did not influence the AH109A hepatoma growth in rats.…”

Section: Discussionsupporting

confidence: 89%

“…Reduction in Akt activity also results in increased lipolysis and proteolysis and decreased lipogenesis and protein synthesis, which corroborates with the loss of adipose and muscle mass (cachexia) of tumor-bearing rats found here (Table 1) and in other studies. 23,26,27 Accordingly, tumor-bearing rats showed increased activity of HSL (p-HSLSer 552 :total HSL ratio; Figure 5), a lipolytic enzyme, in retroperitoneal fat.…”

Section: Discussionmentioning

confidence: 99%

“…We used high-dose of INS (40 UI/kg) because 40 27 and 50 UI/kg 7 INS NPH improved Walker-256 tumor-induced cachexia and because high-dose of INS can overcome INS resistance. 44 Although 50 UI/kg INS improved cachexia in this previous study, 7 it reduced tumor growth, impairing the evaluation of the effects of INS, since reduction in tumor size decreases the metabolic changes induced by the tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Walker-256 carcinosarcoma cells (8 × 10 7 tumor cells) were inoculated subcutaneously in the right flank of rats (tumor-bearing rats), as previously described. 27,35 Healthy rats were injected with vehicle (phosphate buffered saline) in the same place.…”

Section: Animals and Inoculation Of Walker-256 Tumor Cellsmentioning

confidence: 99%

“…INS and GDP doses were based on previous studies. 7,27,36,37 The GDP is a synthetic dipeptide, composed of alanine and glutamine, 38 and shows lower extraction by splanchnic bed than glutamine, which increases its bioavailability. 39 The treatments were done for 13 days, once a day, starting on the day of tumor cell inoculation.…”

Section: Treatmentsmentioning

confidence: 99%

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Akt activation by insulin treatment attenuates cachexia in Walker‐256 tumor‐bearing rats

Silva

Morais

Silva

et al. 2020

J of Cellular Biochemistry

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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.

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