GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization
GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization
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DOI：
10.1172/jci200421341
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发表时间：
2004-12-01
影响因子：
15.9
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Kotani, K;Peroni, OD;Kahn, BB
2型糖尿病的一个关键缺陷是胰岛素刺激的葡萄糖转运和肌肉和脂肪细胞代谢受损。为了了解这引发的代谢适应，我们产生了脂肪细胞和肌肉中GLUT4葡萄糖转运蛋白（AMG4KO）靶向破坏的小鼠。与全身glut4缺失的小鼠相比，AMG4KO小鼠表现出正常的生长、发育、脂肪量和寿命。它们会出现空腹高血糖和葡萄糖耐受不良，并且比仅在一个组织中缺乏GLUT4的小鼠有更大的胰岛素抵抗风险。高胰岛素-正糖钳夹研究显示葡萄糖输注率降低75%，骨骼肌（85-90%）和白色脂肪组织（65%）对2-脱氧葡萄糖的摄取明显减少。然而，AMG4KO小鼠通过优先利用脂质燃料来适应，这可以通过口服脂质灌胃后较低的呼吸商和血清中脂质清除率的增加来证明。当胰岛素对肝脏葡萄糖生成和糖异生酶的作用受损时，肝脏葡萄糖激酶表达、c -14-葡萄糖与脂质结合以及肝脏vldl -甘油三酯释放增加。脂肪生成活性可能是通过肝脏中SREBP-1c和乙酰辅酶a羧化酶的表达增加介导的。因此，组织间通讯导致肌肉和脂肪细胞对葡萄糖转运受损的适应，这涉及到肝脏葡萄糖摄取和脂质合成的增加，而肌肉通过优先利用脂质燃料来适应。限制这种“代谢灵活性”的遗传决定因素可能导致人类胰岛素抵抗和2型糖尿病。
A critical defect in type 2 diabetes is impaired insulin-stimulated glucose transport and metabolism in muscle and adipocytes. To understand the metabolic adaptations this elicits, we generated mice with targeted disruption of the GLUT4 glucose transporter in both adipocytes and muscle (AMG4KO). In contrast to total body GLUT4-null mice, AMG4KO mice exhibit normal growth, development, adipose mass, and longevity. They develop fasting hyperglycemia and glucose intolerance and are at risk for greater insulin resistance than mice lacking GLUT4 in only one tissue. Hyperinsulinemic-euglycemic clamp studies showed a 75% decrease in glucose infusion rate and markedly reduced 2-deoxyglucose uptake into skeletal muscle (85-90%) and white adipose tissue (65%). However, AMG4KO mice adapt by preferentially utilizing lipid fuels, as evidenced by a lower respiratory quotient and increased clearance of lipids from serum after oral lipid gavage. While insulin action on hepatic glucose production and gluconeogenic enzymes is impaired, hepatic glucokinase expression, incorporation of C-14-glucose into lipids, and hepatic VLDL-triglyceride release are increased. The lipogenic activity may be mediated by increased hepatic expression of SREBP-1c and acetyl-CoA carboxylase. Thus, inter-tissue communication results in adaptations to impaired glucose transport in muscle and adipocytes that involve increased hepatic glucose uptake and lipid synthesis, while muscle adapts by preferentially utilizing lipid fuels. Genetic determinants limiting this "metabolic flexibility" may contribute to insulin resistance and type 2 diabetes in humans.