Insulin in combination with pioglitazone prevents advanced cachexia in 256-Walker tumor-bearing rats: effect is greater than treatment alone and is associated with improved insulin sensitivity.

Autor: Miksza DR; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Biazi GR; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Frasson IG; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., de Souza Galia WB; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Ferraz LS; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Diaz BF; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Kurauti MA; Department of Physiological Sciences, State University of Maringá, Maringá, PR, 87020-900, Brazil., Marmentini C; Department of Structural and Functional Biology, Campinas State University, Campinas, SP, 13083-862, Brazil., Mareze-Costa CE; Department of Physiological Sciences, State University of Maringá, Maringá, PR, 87020-900, Brazil., Peres SB; Department of Physiological Sciences, State University of Maringá, Maringá, PR, 87020-900, Brazil., Cassolla P; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Bertolini GL; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil., Bazotte RB; Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, PR, 87020-900, Brazil., de Souza HM; Department of Physiological Sciences, State University of Londrina, Londrina, PR, 86051-990, Brazil. hmedri@uel.br.
Jazyk: angličtina
Zdroj: Pharmacological reports : PR [Pharmacol Rep] 2023 Dec; Vol. 75 (6), pp. 1571-1587. Date of Electronic Publication: 2023 Oct 07.
DOI: 10.1007/s43440-023-00533-w
Abstrakt: Background: Insulin (INS) resistance and hypoinsulinemia commonly observed in cancer-carrying, can contribute to cachexia. However, the effects of INS and INS sensitizers, such as pioglitazone (PIO), particularly when used in combination therapy, on cancer cachexia have not been evaluated sufficiently. We investigated the effects of INS and PIO, at various doses, either isolated or combined, on cachexia in Walker-256 tumor-bearing rats (TB rats).
Methods: INS or INS + PIO were administered in TB rats, for 6 or 12 days, starting from the day of tumor cells inoculation.
Results: INS at 18 or 27 U/kg (12-days treatment), but not 9 U/kg, reduced fat loss and slightly prevented weight loss. However, INS 18 U/kg + PIO 5, 10, 20, or 40 mg/kg (6 or 12-day treatment) reduced fat loss and markedly prevented weight loss but did not affect muscle wasting. While TB rats lost weight (37.9% in 12 days), TB rats treated with INS 18 U/kg + PIO 5 mg/kg showed pronounced weight gain (73.7%), which was greater than the sum (synergism) of the weight gains promoted by isolated treatments with INS 18 U/kg (14.7%) or PIO 5 mg/kg (13.1%). The beneficial effect of the INS 18 U/kg + PIO 5 mg/kg on weight loss was associated with improved INS sensitivity, as indicated by the higher blood glucose clearance constant (kITT), decreased levels of free fatty acids and triacylglycerols (INS resistance-inducing factors) in the blood, and increased expression of p-Akt (INS signaling pathway protein) in adipose tissue.
Conclusions: The combined treatment with INS 18 U/kg + PIO 5 mg/kg was more effective in preventing advanced cachexia in TB rats than each treatment alone, emerging as the best approach, considering the lower dosage and higher efficacy. This combination completely preserved adipose mass and markedly reduced weight loss through a synergistic mechanism linked to improved insulin sensitivity. These findings provide new insights into the importance of drug combinations in effectively combating fat loss in advanced cachexia.
(© 2023. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)
Databáze: MEDLINE
Externí odkaz: