Maternal hyperglycemia during pregnancy impacts both maternal and fetal health and is linked to adverse metabolic outcomes like heart disease for both the mother and the newborn later in life. In a recent genome wide association study using the Hyperglycemia and Adverse Pregnancy Outcomes cohort, our group identified novel genetic variants associated with maternal glycemic traits during pregnancy. One of the most strongly associated genes, HKDC1 (hexokinase domain containing 1) has not been characterized. Thus, the major goal of the current proposal is to understand the function and biology of HKDC1. Previous reports have shown that HKDC1 shares sequence similarity with other hexokinases. Our preliminary data also demonstrates that HKDC1 has hexokinase activity. We further show that HKDC1 genetic mouse models develop glucose intolerance. An analysis of tissue expression patterns revealed that HKDC1 is expressed in tissues which are key mediators of glucose sensing and homeostasis like liver and pancreatic beta cells. These observations have lead us to hypothesize that, HKDC1 is a novel fifth vertebrate hexokinase that controls glucose homeostasis during pregnancy. Addressing this hypothesis, firstly, the kinetics and properties of hexokinase activity of HKDC1 will be extensively characterized and compared and contrasted with other hexokinases. The structural components (critical amino acid residues and subunit conformation) responsible for its functional integrity will also be analyzed. A significant outcome of the proposal will be characterization of HKDC1 as a novel hexokinase. As hexokinases are fundamental to metabolism, the discovery of a 5th hexokinase is a substantial advance that will challenge the contention that only 4 hexokinase enzymes exist in humans. This will also have broad reaching impact on understanding of vertebrate glucose metabolism and will open new research avenues. Secondly, using the global gene ablation mouse models the in vivo role of HKDC1 in glucose homeostasis during pregnancy will be assessed. Another significant outcome will be that a new mechanism of glucose homeostasis during pregnancy mediated by HKDC1 will be revealed. This may provide new points of therapeutic, preventive or prognostic interventions for gestational diabetes, a growing global health concern for both the mother and the newborn.
|Effective start/end date||1/1/15 → 8/31/16|
- American Heart Association Midwest Affiliate (15POST22410016)