Our knowledge of nutritional management of very low birth weight (VLBW) infants has lagged significantly behind the advancements in cardio-respiratory therapy. VLBW infants have higher energy demands and higher glucose requirements on a body weight basis when compared to more mature infants and adults, because their brain (the principal glucose consumer) accounts for a larger proportion of the body weight. Since VLBW infants are born before fetal fat stores and hepatic glycogen are accumulated, and their gluconeogenic capacities may be limited by substrate availability (glycerol and amino acids), immature gluconeogenic enzyme activities, compromised hormone secretion and decreased hormone signaling, they are at a high risk for hypoglycemia, which may have severe neurodevelopmental consequences. To prevent hypoglycemia and to provide sufficient calorie intake for normal growth, VLBW infants are depending on TPN during their first week(s) of life. However, these infants have a diminished tolerance for parenteral glucose resulting in a frequent occurrence of hyperglycemia, which might have significant short and long-term impact on their outcome. Thus, it is crucial to define a composition of preterm TPN solutions that maintains euglycemia, while providing sufficient nutrients for normal growth. The purpose of this research project is to investigate the ability of VLBW infants to utilize their gluconeogenic pathways for production of glucose from the components of standard parenteral nutrition solutions.

Overall hypothesis: By selection of the correct composition of TPN constituents in VLBW infants, endogenous synthesis of glucose (i.e. gluconeogenesis) can be utilized to minimize the risk of hypo and hyperglycemia, while providing appropriate substrates to meet each infant’s need of energy and essential nutrients.

The project includes 6 protocols. In each of those, stable isotope tracers are administered according to the following scheme:

At study hour zero the following infusions will be started and continued at constant rates over 10 hrs: 1) [U-13C]glucose at 3 mg/kg min to measure glucose appearance rate and gluconeogenesis; 2) ([2-13C]glycerol at 0.03 mg/kg min to measure lipolysis; 3) [1-13C]leucine at 0.015 mg/kg min to measure proteolysis; and 4) [15N2]urea at 0.023 mg/kg min to measure protein oxidation. Since urea has a large mixing pool, this tracer will be primed (7 mg/kg) to ensure that steady state conditions are achieved. At start of the studies, the glucose infusion rate is reduced first to 6 mg/kg for 1 h and then to 3 mg/kg min for the remaining 9 h. The infants are receiving only glucose; or supplemental glycerol; Intralipid; TrophAmine; or glutamine and finally in one study we will administer both Intralipid and TrophAmine + glucagon. Blood glucose is checked hourly at the bedside. If blood glucose falls to 40 mg/dL, additional glucose is given. Using the compounds labelled with stable isotopes, we can determine how these babies produce glucose from various substrates and how protein and lipid metabolism are affected. All protocols except for the last two (glutamine and glucagon) are completed and published.

Blood samples are obtained at start of the studies, and then at study hors 4; 4.5; 5; 9; 9.5a and 10. The total amount of blood withdrawn is 3 mL, which is within the guidelines established by the IRB.

96 (I need 16 more infants to complete the project).

Birth weight 750-1250 g; gestational age £29 wks; clinically stable; both UAC and UVC; not fed.

We have demonstrated that VLBW infants receiving glucose at 3 mg/kg min (half their normal glucose turnover rate) maintain normoglycemia primarily from glucose produced via gluconeogenesis; that they can use both endogenous and exogenous substrate; that Intralipid is more important than TrophAmine in supporting gluconeogenesis; and that of the two components of Intralipid (glycerol and FFA) that can potentially support gluconeogenesis, glycerol is the most important. (Sunehag et al Diabetes 48, 1999; Sunehag Pediatr Res 53, 2003; Sunehag Pediatr Res 54, 2003)