Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice
Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice
复制标题
DOI：
10.1002/ijc.24784
复制
发表时间：
2010-02-01
影响因子：
6.4
通讯作者：
Belury, Martha A.
中科院分区：
文献类型：
--
作者：
Asp, Michelle L.;Tian, Min;Belury, Martha A.
癌症恶病质是一种以骨骼肌和脂肪组织消耗为特征的意外体重减轻综合征。葡萄糖耐受不良和胰岛素抵抗与癌症恶病质有关。然而，目前尚不清楚胰岛素抵抗是否在恶病质的发展中起作用。在本研究中，患有结肠-26腺癌肿瘤的交配CD 2F 1小鼠在体重减轻开始前进行胰岛素耐受性试验。与没有肿瘤的小鼠相比，有肿瘤的小鼠对胰岛素的血糖反应明显减弱。证实这些发现，在研究结束时，患有肿瘤的小鼠的四头肌和附睾脂肪组织中Akt的磷酸化降低。Akt调节基因Atrogin-1、MuRF-1和Bnip 3在肌肉中的表达增加，表明胰岛素信号传导在恶病质肌肉中蛋白酶体蛋白水解和自噬的诱导中的作用降低。罗格列酮治疗增加血清脂联素、胰岛素敏感性和体重，并降低Atrogin-1和MuRF-1在荷瘤小鼠骨骼肌中的表达。总之，胰岛素抵抗是结肠26肿瘤诱导的恶病质小鼠的早期事件。罗格列酮改善胰岛素敏感性，降低恶病质的早期标志物。这些数据提供了证据，胰岛素抵抗不仅存在于恶病质中，而且在恶病质发病机制中具有作用。纠正胰岛素抵抗可能是治疗癌症恶病质的新靶点。
Cancer cachexia is a syndrome of unintentional weight loss that is characterized by wasting of both skeletal muscle and adipose tissue. Glucose intolerance and insulin resistance have been associated with cancer cachexia. However, it is unknown whether resistance to insulin has a role in the development of cachexia. In the present study, mate CD2F1 mice with colon-26 adenocarcinoma tumors underwent an insulin tolerance test before the onset of weight loss. Compared to mice without tumors, mice with tumors had a profoundly blunted blood glucose response to insulin. Corroborating these findings, mice with tumors had decreased phosphorylation of Akt in quadriceps muscle and epididymal adipose tissue at the end of the study. Expression of Akt-regulated genes Atrogin-1, MuRF-1, and Bnip3 was increased in muscle, suggesting a role for decreased insulin signaling in the induction of both proteasomal proteolysis and autophagy in cachectic muscle. Rosiglitazone treatment increased serum adiponectin, insulin sensitivity, and body weight, and decreased Atrogin-1 and MuRF-1 expression in the skeletal muscle of tumor-bearing mice. In conclusion, insulin resistance is an early event in mice with cachexia induced by colon-26 tumors. Rosiglitazone improves insulin sensitivity and decreases early markers of cachexia. These data provide evidence that insulin resistance is not only present in cachexia, but also has a role in cachexia pathogenesis. Correction of insulin resistance may be a novel therapeutic target for the treatment of cancer cachexia.