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

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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.