Hexokinase II-deficient mice -: Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes
Hexokinase II-deficient mice -: Prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes
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DOI：
10.1074/jbc.274.32.22517
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发表时间：
1999-08-06
影响因子：
4.8
通讯作者：
Laakso, M
中科院分区：
文献类型：
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作者：
Heikkinen, S;Pietilä, M;Laakso, M
2型糖尿病的特征在于胰岛素刺激的葡萄糖摄取和利用率降低，己糖激酶II mRNA和酶产生减少，以及胰岛素敏感性骨骼肌和脂肪组织中葡萄糖6-磷酸的基础水平低。己糖激酶II主要在肌肉和脂肪组织中表达，在那里它催化葡萄糖磷酸化为葡萄糖6-磷酸，这是葡萄糖处置的可能限速步骤。为了研究己糖激酶II在胰岛素作用和葡萄糖稳态以及小鼠发育中的作用，我们产生了己糖激酶II敲除小鼠。己糖激酶II缺乏症（HXII-/-）纯合子小鼠在受精后约7.5天死亡，表明己糖激酶II对着床后和器官形成前的小鼠胚胎形成至关重要，HKII+/-小鼠存活、可生育且生长正常。令人惊讶的是，即使HKII+/-小鼠在骨骼肌、心脏和脂肪组织中的己糖激酶II mRNA和活性水平显著降低（50%），即使在高脂饮食的挑战下，它们也没有表现出胰岛素作用或葡萄糖耐量受损。
Type 2 diabetes is characterized by decreased rates of insulin-stimulated glucose uptake and utilization, reduced hexokinase II mRNA and enzyme production, and low basal levels of glucose 6-phosphate in insulin-sensitive skeletal muscle and adipose tissues. Hexokinase II is primarily expressed in muscle and adipose tissues where it catalyzes the phosphorylation of glucose to glucose 6-phosphate, a possible rate-limiting step for glucose disposal, To investigate the role of hexokinase II in insulin action and in glucose homeostasis as well as in mouse development, we generated a hexokinase II knock-out mouse. Mice homozygous for hexokinase II deficiency (HXII-/-) died at approximately 7.5 days post-fertilization, indicating that hexokinase II is vital for mouse embryogenesis after implantation and before organogenesis, HKII+/- mice were viable, fertile, and grew normally. Surprisingly, even though HKII+/- mice had significantly reduced (by 50%) hexokinase II mRNA and activity levels in skeletal muscle, heart, and adipose tissue, they did not exhibit impaired insulin action or glucose tolerance even when challenged with a high-fat diet.