Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner
Skeletal muscle insulin resistance in zebrafish induces alterations in β-cell number and glucose tolerance in an age- and diet-dependent manner
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DOI：
10.1152/ajpendo.00441.2014
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发表时间：
2015-04-15
影响因子：
5.1
通讯作者：
Chen, Wenbiao
中科院分区：
文献类型：
--
作者：
Maddison, Lisette A.;Joest, Kaitlin E.;Chen, Wenbiao
胰岛素抵抗创造了一个环境，促进了β细胞衰竭和糖尿病的发展。了解从胰岛素抵抗到糖尿病的事件对于开发有效的预防和干预策略是必要的，而反映疾病进展的病理生理学的模型系统是实现这一目标的重要组成部分。我们已经证实，胰岛素增强了斑马鱼骨骼肌对葡萄糖的摄取，并利用显性负IGF-IR建立了斑马鱼骨骼肌胰岛素抵抗的模型。这些斑马鱼表现出钝化的胰岛素信号和骨骼肌对葡萄糖的摄取，证实了胰岛素抵抗。在年轻的动物中，我们观察到β细胞数量的增加和正常的糖耐量，这表明对胰岛素抵抗的补偿。在年长的动物中，β细胞量减少到对照组的水平，表现为葡萄糖清除受损，但空腹血糖没有升高。再加上营养过剩，与对照组相比，胰岛素抵抗组动物的空腹血糖升高，说明胰岛素抵抗鱼体内的β细胞处于脆弱状态。在这个模型系统中，从胰岛素抵抗到葡萄糖耐受的进展相对缓慢，未来有可能测试合作基因或代谢状况，这些基因或代谢条件可能会加速糖尿病的发展，并提供新的治疗靶点。
Insulin resistance creates an environment that promotes beta-cell failure and development of diabetes. Understanding the events that lead from insulin resistance to diabetes is necessary for development of effective preventional and interventional strategies, and model systems that reflect the pathophysiology of disease progression are an important component toward this end. We have confirmed that insulin enhances glucose uptake in zebrafish skeletal muscle and have developed a zebrafish model of skeletal muscle insulin resistance using a dominant-negative IGF-IR. These zebrafish exhibit blunted insulin signaling and glucose uptake in the skeletal muscle, confirming insulin resistance. In young animals, we observed an increase in the number of beta-cells and normal glucose tolerance that was indicative of compensation for insulin resistance. In older animals, the beta-cell mass was reduced to that of control with the appearance of impaired glucose clearance but no elevation in fasting blood glucose. Combined with overnutrition, the insulin-resistant animals have an increased fasting blood glucose compared with the control animals, demonstrating that the beta-cells in the insulin-resistant fish are in a vulnerable state. The relatively slow progression from insulin resistance to glucose intolerance in this model system has the potential in the future to test cooperating genes or metabolic conditions that may accelerate the development of diabetes and provide new therapeutic targets.