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相关。此外，尤其是GDM，也可能对晚年的代谢结果有害。一项大型遗传学研究，“高血糖和不良妊娠结局（HAPO）研究”先前发现了一种独特的遗传关联，即靠近己糖激酶结构域组分-1（HKDC 1）与妊娠高血糖症。这项研究已得到其他人的证实，并且也表明与GDM有关。这项资助的更新旨在继续我们对妊娠期葡萄糖代谢这一重要联系的研究。该建议的重点是基于我们的数据，即HKDC 1与肝细胞中的线粒体外膜蛋白VDAC相互作用，当HKDC 1的氨基末端缺失时，这种相互作用被破坏。进一步的数据表明，肝脏中HKDC 1的过表达改善了小鼠妊娠期间的葡萄糖耐量，我们的数据表明，这导致碳通量向合成代谢途径的代谢转变。现在，重要的是研究HKDC 1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。此外，我们预计遗传变异通过HKDC 1表达导致GDM风险，尽管特定的致病变异仍然难以捉摸。总之，该提案将从机制上探索HKDC 1在妊娠期葡萄糖稳态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.