The function and regulation of the novel pregnancy-specific hexokinase HKDC1

妊娠期高血糖和妊娠期糖尿病(GDM)与母亲和新生儿的不良妊娠结局有关。此外，特别是妊娠期糖尿病，也可能对晚年的新陈代谢结果有害。一项名为“高血糖和不良妊娠结局(HAPO)研究”的大型遗传学研究先前发现己糖激酶域成分-1(HKDC1)与妊娠期高血糖之间存在独特的遗传关联。这项研究已经得到了其他人的证实，也被证明与妊娠期糖尿病有关。此次资助续期意在继续我们对妊娠糖代谢这一重要环节的研究。这项建议的重点是基于我们的数据，即HKDC1与肝细胞中的线粒体外膜蛋白VDAC相互作用，当HKDC1的氨基末端缺失时，这种相互作用被破坏。进一步的数据显示，HKDC1在肝脏中的过表达改善了小鼠怀孕期间的葡萄糖耐量，我们的数据表明，这导致碳流的代谢转向合成代谢途径。现在，研究HKDC1与线粒体相互作用的分子基础以及这种相互作用对线粒体形态和功能的影响是非常重要的。此外，我们预计遗传变异通过HKDC1的表达增加GDM的风险，尽管具体的因果变异仍然难以捉摸。综上所述，这项建议将从机制上探讨HKDC1在妊娠期血糖动态平衡中的作用以及驱动其在人类中表达的遗传变异。

Gestational hyperglycemia and gestational diabetes (GDM) are associated with adverse pregnancy outcomes for mothers and newborns. Additionally, GDM, in particular, can also be detrimental to metabolic outcomes later in life. A large genetic study, ‘The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study’ previously identified a unique genetic association near hexokinase domain component-1 (HKDC1) to gestational hyperglycemia. This study has been confirmed by others and also shown to be associated with GDM. This grant renewal intends to continue our investigation of this important link to gestational glucose metabolism. The focus of this proposal is based on our data that HKDC1 interacts with the mitochondrial outer membrane protein, VDAC, in hepatocytes, where this interaction is disrupted when the amino terminus of HKDC1 is deleted. Further data shows that overexpression of HKDC1 in the liver improved glucose tolerance during pregnancy in mice and our data suggests that this results in a metabolic shift in the carbon flux toward anabolic pathways. Now, it is important to investigate the molecular basis of HKDC1 interaction with mitochondria and the impact of such interactions on mitochondrial morphology and function. Further, we expect that genetic variants contribute to GDM risk via HKDC1 expression, though the specific causal variants remain elusive. In sum, this proposal will mechanistically explore the role of HKDC1 in gestational glucose homeostasis and the genetic variants driving its expression in humans.