HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use
HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use
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DOI：
10.1210/en.2016-1288
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发表时间：
2016-09-01
期刊：
影响因子：
4.8
通讯作者：
Layden, Brian T.
中科院分区：
文献类型：
--
作者：
Ludvik, Anton E.;Pusec, Carolina M.;Layden, Brian T.
在最近的一项全基因组关联研究中，在怀孕28周的2小时葡萄糖耐量测试中，发现己糖激酶域包含蛋白1，或HKDC1，与妊娠血糖水平有关。由于我们对妊娠期血糖稳态调节因子的了解还不完全，我们建立了第一个转基因小鼠模型，开始了解HKDC1在全身血糖稳态中的作用。有趣的是，这两个HKDC1等位基因的缺失会导致子宫胚胎死亡。因此，在这项研究中，我们使用杂合子缺失的HKDC1小鼠模型(HKDC1(+/-))与匹配的野生型小鼠比较，报道了HKDC1在体内对全身血糖动态平衡的作用。首先，在雄性和雌性HKDC1(+/-)小鼠中，我们没有观察到体重、空腹或随机血糖或空腹胰岛素随年龄增长的异常。然而，在葡萄糖耐量测试中，雌性和雄性HKDC1(+/-)小鼠在15、30和120分钟后(28周龄)的血糖水平都受到了损害。这些糖耐量差异也存在于较早年龄的雌性HKDC1(+/-)小鼠中，但仅在妊娠期。最后，HKDC1(+/-)小鼠的糖耐量受损可能是由于全身葡萄糖使用量减少所致，HKDC1(+/-)小鼠的肝脏能量储存减少和外周组织对葡萄糖的摄取减少表明。总而言之，这些数据强调了HKDC1在怀孕期间维持全身葡萄糖动态平衡所必需的，但在衰老过程中也是如此，可能是通过其在葡萄糖利用中的作用。
In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2-hour glucose tolerance tests at 28 weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous-deleted HKDC1 mouse model (HKDC1(+/-)) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1(+/-) mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1(+/-) mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1(+/-) mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1(+/-) mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1(+/-) mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use.