br Acknowledgements br Introduction Pregnancy brings forth
Introduction Pregnancy brings forth significant metabolic reprogramming that induces a number of metabolic changes to ensure that the nutrient requirements of the mother and fetus are met [, , ]. These adaptations change radically over the period of pregnancy depending on the anabolic or catabolic demand [, , ]. The overall focus of the maternal metabolic response is focused on conserving and storing nutrients to sustain the demands of continuous supply of nutrients to the fetus even during periods of food unavailability to preserve fetal development and maternal survival [4,5]. Understanding these shifts of nutrients is integral to the health of the mother and developing fetus. Glucose is the major source of energy and macromolecular building blocks during pregnancy, and thus, understanding its regulation and flux during pregnancy under physiological and pathophysiological conditions is important. Overall, insulin controls glucose homeostasis by lowering plasma glucose by increasing cellular uptake and inhibiting hepatic glucose production. In contrast, reduced insulin action promotes lipolysis, fatty rho kinase inhibitors oxidation and gluconeogenesis. A balance between insulin production by the pancreas and its subsequent action on maternal muscle, liver and fat tissues mediates the regulation of gestational glucose levels with unique differences from this balance in the non-pregnant state . Early pregnancy is characterized by heightened insulin sensitivity that leads to maternal lipid accumulation; whereas, later stages of pregnancy show increased resistance to insulin with increased mobilization of the stored lipid depots [2,3,, , , , , , , , ]. In early gestation, progressive accumulation of maternal adipose tissue lipids is due to enhanced food intake, extrahepatic tissue lipoprotein lipase (LPL) activity, and adipose tissue lipogenesis . During the later stages of pregnancy, insulin resistance is characterized by reduced maternal glucose utilization, increased lipolysis and increased levels of hepatic glucose production [, , , , , , , , ]. In late gestation, there is increasing insulin resistance contributing to maternal hypertriglyceridemia and also decreased fat synthesis accompanied by enhanced adipose tissue lipolytic activity, which depletes maternal fat depots [, , , , , , , , ,, , ]. Additionally, in late gestation, the maternal-fetal glucose transfer results in a lowering of the maternal glucose set point especially during fasting and/or starvation which further activates maternal gluconeogenesis [4,5]. Recently, in a genome-wide association (GWA) study that focused on human gestational glucose metabolism, we discovered that HKDC1 (hexokinase domain containing 1), a novel fifth hexokinase, is associated with glucose tolerance in pregnant mothers at 24–28 weeks of gestation , through polymorphisms in regulatory variants . These data suggest that HKDC1 may play a specific role during pregnancy [, , , , ]. HKDC1, based on sequence, was suggested to be a novel hexokinase, and has since been shown to have hexokinase activity . The primary function of a hexokinase is to phosphorylate and thus trap glucose in the cell for further processing . Previously, the hexokinase (HK) family was comprised of four known members, each having distinct expression patterns and enzyme activities [25,26]. HK 1–3 have a high enzymatic activity in phosphorylating glucose (represented by low Km values) and are responsible for glucose metabolism and energy production. In contrast, HK 4, known as glucokinase (GCK), has a high Km value and is considered the glucose sensor of the body due to its expression being restricted to tissues that participate in whole-body glucose sensing (pancreas and liver) . These four HKs have been thought to be the only HKs in humans to mediate this pivotal step of glucose metabolism, until the discovery of HKDC1. Our data, and others, have now confirmed that HKDC1 is a 5th hexokinase; however, its enzymatic properties have yet to be fully reported [20,21,28].