Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene
Peripheral but not hepatic insulin resistance in mice with one disrupted allele of the glucose transporter type 4 (GLUT4) gene
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DOI：
10.1172/jci119711
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发表时间：
1997-10-01
影响因子：
15.9
通讯作者：
Charron, MJ
中科院分区：
文献类型：
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作者：
Rossetti, L;Stenbit, AE;Charron, MJ
葡萄糖转运蛋白4(GLUT4)是一种胰岛素反应性基因，在横纹肌和脂肪组织中表达，为了研究GLUT4水平的部分不足对体内胰岛素作用的影响，我们研究了4-5个月龄清醒小鼠[GLUT4(+/-)]与野生型对照小鼠[GLUT4(+/-)]相比，高血糖发作前血糖水平正常，空腹(6小时)胰岛素浓度增加50%的高胰岛素钳夹试验中的葡萄糖处置和肝脏葡萄糖产生(HGP)。GLUT4(+/-)组肌肉中的GLUT4蛋白比WT(+/+)组少45%，结合[3-H-3]葡萄糖测定葡萄糖和HGP的出现率，用[U-C-14]-2-脱氧葡萄糖测定肌肉葡萄糖在体内的转运，用[U-C-14]乳酸测定肝脏葡萄糖的转运。在钳夹试验中，GLUT4(+/-)、GLUT4(与WT(+/+)小鼠相比，GLUT4(+/-)和WT(+/+)小鼠体内糖原合成速率降低是由于葡萄糖转运刺激减少所致，胰岛素对肌糖原合成酶的激活与WT(+/+)小鼠相似，而GLUT4(+/-)小鼠的高胰岛素抑制HGP的能力不受影响。GLUT4(+/-)小鼠肝脏葡萄糖代谢的正常调节得到了通过葡萄糖循环、糖异生和糖原分解的相似的肝脏葡萄糖流量分布的进一步支持。我们得出结论：GLUT4基因的一个等位基因的破坏导致严重的外周胰岛素抵抗，而不是肝脏胰岛素抵抗，因此，横纹肌和脂肪组织中不同水平的GLUT4蛋白可以显著改变全身葡萄糖的处置，这些差异很可能是外周胰岛素作用的个体差异的原因。
Glucose transporter type 4 (GLUT4) is insulin responsive and is expressed in striated muscle and adipose tissue, To investigate the impact of a partial deficiency in the level of GLUT4 on in vivo insulin action, we examined glucose disposal and hepatic glucose production (HGP) during hyperinsulinemic clamp studies in 4-5-mo-old conscious mice with one disrupted GLUT4 allele [GLUT4 (+/-)], compared with wild-type control mice [WT (+/+)], GLUT4 (+/-) mice were studied before the onset of hyperglycemia and had normal plasma glucose levels and a 50% increase in the fasting (6 h) plasma insulin concentrations, GLUT4 protein in muscle was similar to 45% less in GLUT4 (+/-) than in WT (+/+), Euglycemic hyperinsulinemic clamp studies were performed in combination with [3-H-3]glucose to measure the rate of appearance of glucose and HGP, with [U-C-14]-2-deoxyglucose to estimate muscle glucose transport in vivo, and with [U-C-14]lactate to assess hepatic glucose fluxes.During the clamp studies, the rates of glucose infusion, glucose disappearance, glycolysis, glycogen synthesis, and muscle glucose uptake were similar to 55% decreased in GLUT4 (+/-), compared with WT (+/+) mice, The decreased rate of in vivo glycogen synthesis was due to decreased stimulation of glucose transport since insulin's activation of muscle glycogen synthase was similar in GLUT4 (+/-) and in WT (+/+) mice, By contrast, the ability of hyperinsulinemia to inhibit HGP was unaffected in GLUT4 (+/-). The normal regulation of hepatic glucose metabolism in GLUT4 (+/-) mice was further supported by the similar intrahepatic distribution of liver glucose fluxes through glucose cycling, gluconeogenesis, and glycogenolysis.We conclude that the disruption of one allele of the GLUT4 gene leads to severe peripheral but not hepatic insulin resistance, Thus, varying levels of GLUT4 protein in striated muscle and adipose tissue can markedly alter whole body glucose disposal, These differences most likely account for the interindividual variations in peripheral insulin action.