Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene
Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene
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DOI：
10.2337/diabetes.51.8.2450
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发表时间：
2002-08-01
期刊：
影响因子：
7.7
通讯作者：
Grunberger, G
中科院分区：
文献类型：
--
作者：
Mathews, ST;Singh, GP;Grunberger, G
胎球蛋白抑制胰岛素诱导的胰岛素受体（IR）自磷酸化和酪氨酸激酶活性在体外，在完整的细胞，和在体内。胎球蛋白基因（AHSG）位于人类染色体3q 27上，最近被确定为2型糖尿病和代谢综合征的易感基因。在这里，我们探讨胰岛素信号，葡萄糖稳态，以及高脂肪饮食对体重增加，体脂组成和葡萄糖处置携带两个空等位基因的基因编码胎球蛋白，Ahsg（136，129-Ahsg（tm 1 Mbl））的小鼠的影响。胎球蛋白敲除（KO）小鼠表现出增加的基础和胰岛素刺激的磷酸化的IR和下游信号分子丝裂原活化蛋白激酶（MAPK）和Akt在肝脏和骨骼肌。胎球蛋白基因敲除小鼠的葡萄糖和胰岛素耐量试验表明葡萄糖清除率和胰岛素敏感性显著增强。胎球蛋白基因敲除小鼠进行正常血糖-高胰岛素钳夹试验后，对胰岛素的敏感性增强，表现为葡萄糖输注速率增加（P = 0.077）和骨骼肌糖原含量显著增加（P < 0.05）。当喂食高脂饮食时，胎球蛋白KO小鼠对体重增加有抵抗力，表现出显著降低的体脂，并保持胰岛素敏感性。这些数据表明，胎球蛋白可能在调节餐后葡萄糖处置、胰岛素敏感性、体重增加和脂肪积累方面发挥重要作用，并且可能是治疗2型糖尿病、肥胖和其他胰岛素抵抗疾病的新的治疗靶点。
Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (136, 129-Ahsg(tm1Mbl)). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.