Studies conducted in our laboratory thus far

Studies conducted in our laboratory, thus far, have shown that HKDC1 is broadly expressed [28]. Using the first developed HKDC1 mouse model, we found that complete loss of HKDC1 function is embryonic lethal, similar to other HKs [29,30]. Further studies using HKDC1 heterozygous knockout mice showed normal insulin production, insulin sensitivity, gluconeogenesis and glucose homeostasis, although there was a mild impairment of glucose tolerance in aged mice [28]. We also did observe impaired glucose tolerance in pregnant mice, which supports the GWAS-derived observation that HKDC1 is associated with maternal 2-h glucose levels after an oral glucose challenge at 28 weeks' gestation in humans [20]. Therefore, in our initial report, we concluded that only under conditions of metabolic stress (i.e., pregnancy or aging) does reduced HKDC1 ABT-737 affect glucose homeostasis. The liver plays important roles in nutrient management, including glucose production, ketone synthesis, and lipid handling that are important for maternal health and fetal growth [31]. As HKDC1 is expressed in the liver [32], in this study we have examined the role of hepatic HKDC1 in late term pregnancy. To do this, we have developed mouse models to delete or over-express HKDC1 in the liver and used them to understand the role of HKDC1 in the control of nutrient metabolism, in particular glucose, during pregnancy.
Materials and methods
Results
Discussion Pregnancy is characterized by a plethora of biochemical changes that work together to allocate nutrients between the growing fetus and the mother. These finely tuned mechanisms are tightly regulated, and a more complete understanding is required to develop better treatment avenues for pregnancy in pathophysiological conditions such as diabetes and obesity. For reasons noted above, this study focused on the role of hepatic specific gain of function and loss of function of HKDC1 during the later stages of pregnancy. Collectively, these data reveal that HKDC1 plays previously unidentified roles in gestational glucose metabolism through its action in the liver. Moreover, its hepatic expression influences not only maternal glucose but also other nutrients balance (fatty acids and ketone levels), through its modulation of whole-body insulin resistance, hepatic gluconeogenesis and ketoneogenesis. In humans, regulatory regions influence HKDC1 expression, and through the large human population studies, was associated with maternal glucose levels [20]. Our new data provide insight into the influence of the expression of this gene on maternal glucose levels and its downstream effects on maternal nutrients, a fundamental important balance for the health of the mother and fetus. It has been well known that in late pregnancy, maternal IR develops thereby shifting the nutrient balance, which supports the rapidly growing fetus [3,11,12,33]. However, the molecular basis of IR during late pregnancy is still incompletely understood, where a number of maternal and fetal variables influence this. While insulin resistance was evident in our pregnant control dams by the insulin tolerance test, this effect was reversed in pregnant aHepHKDC1-OE mice. In contrast, aHepHKDC1-KO mice had evidence of further impaired insulin tolerance. Therefore, we found that in addition to modulating glucose disposal, hepatic expressed HKDC1 was altering whole body insulin sensitivity. Strengthening these findings, the phosphorylation state of protein kinase B confirmed these findings, not only in the liver, but in adipose and skeletal muscle. Future directions need to explore how hepatic HKDC1 expression influences whole body insulin sensitivity during pregnancy. Basal glucose levels undergo gradual changes over the entire course of pregnancy to meet the nutritional and anabolic demands of the mother and fetus. Fasting plasma glucose levels significantly decline despite increased hepatic glucose production over the course of pregnancy by complex mechanisms that are still poorly understood [13]. We found that in line with enhanced insulin sensitivity in the hepatic aHepHKDC1-OE mice, significantly less glucose production after an overnight fast in a pyruvate challenge was observed. Moreover, aHepHKDC1-KO mice produced more glucose when challenged with pyruvate. Complimenting this, we found that genes involved in de novo gluconeogenesis were down-regulated in aHepHKDC1-OE and up-regulated in aHepHKDC1-KO liver. Next steps will be to explore how HKDC1 influences hepatic glucose production.