Evidence for the involvement of early insulin resistance in the development of cachexia in mice bearing colon‐26 tumors

Abstract

Cachexia occurs in ~30% of cancer patients, resulting in severe muscle and adipose atrophy, and poor prognosis. As resistance to insulin has been associated with cachexia, we sought to determine if this occurs prior to weight loss and whether sensitization to insulin attenuates cachexia in CD2F1 mice bearing colon‐26 (C26) tumors. Insulin sensitivity, measured by insulin tolerance test area under the curve, worsened in mice with tumors (T) compared to those without tumors (NT) ≥ 2 days before body weight differences were detected. Decreased quadriceps Akt activation corroborated these findings. Treatment of T mice with the insulin sensitizer rosiglitazone (ROSI, 20mg/kg/d) improved insulin resistance, evidenced by a larger blood glucose response to insulin 60 minutes after insulin administration compared to T mice without ROSI. Treatment with ROSI also prevented tumor‐induced depletion of adiponectin, an insulin‐sensitizing adipokine, and resulted in higher body weight at the end of the study. In conclusion insulin resistance occurred before weight loss, and sensitization to insulin by ROSI prevented weight loss in tumor‐induced cachexia. These data suggest a role for early insulin resistance in the pathology of cancer cachexia and sensitization to insulin in decreased severity of this disorder. Supported by Cognis Corporation and Ohio Agricultural Research and Development Center.