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Glucose metabolism in very low birth weight infants
receiving parenteral nutrition
By Agneta Sunehag, M.D., Ph.D.
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Delivering appropriate nutrients to very low birth weight infants is problematic, since these infants also have a diminished tolerance for enteral feedings during the first several weeks of life, making them dependent on the parenteral route for energy supply. Consequently, it is crucial to define a composition of preterm TPN solutions that maintains euglycemia, while providing a sufficient nutrient intake for normal growth.
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As a result of improved
cardio-respiratory care, 75 to 80
percent of infants weighing less than 1,500 grams survive in the
U.S. today1. However, our knowledge of the
metabolic effects of current nutritional management of these
very low birth weight (VLBW) infants has lagged 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 weight2. Since VLBW
infants are born before hepatic glycogen and fetal fat stores
are accumulated3, 4, and their gluconeogenic capacities may
be limited by substrate availability (glycerol and amino acids),
immature gluconeogenic enzyme activities, compromised hormone
secretion and decreased hormone signaling5 they are at high
risk for hypoglycemia, which may have severe neuro-developmental
consequences6, 7.
Delivering nutrients to VLBW infants
To prevent hypoglycemia and to provide sufficient energy intake
for normal growth, VLBW infants are routinely receiving glucose
via total parenteral nutrition (TPN) at rates exceeding their
normal glucose turnover rate2,8. However, these infants have
a diminished tolerance for parenteral glucose, which might be a
result of limited amounts of insulin dependent tissues (muscle
and fat)4, glucose transporter systems that are not fully
developed9, 10, insufficient insulin secretion and/or insulin
resistance4, 9-11. This glucose intolerance leads to a
frequent occurrence of hyperglycemia12-15. Preliminary
results from a retrospective study in VLBW infants (≤ 30 weeks
with an average of 26.4 ± 2.3 weeks) admitted to the level 3
NICU at Texas Children’s Hospital between January 1 and December
31, 2001, show that during the first week of life, 71 percent of
the infants had blood glucose concentrations >150 mg/dL; of
these infants 13 percent had blood glucose between 150 and 200
mg/dL, 27 percent between 200 and 300 mg/dL and 61 percent above
300 mg/dL) (manuscript in preparation). Hyperglycemia could also
have significant short and long-term impact on the outcome of
these infants12. Recent studies in critically ill adults16
and children17 have demonstrated an association between
hyperglycemia and increased mortality. Although there are no
corresponding studies in VLBW infants, these small infants also
represent a high-risk population and, thus, preventing
hyperglycemia without compromising the energy intake may reduce
their risk of an adverse outcome.
Delivering appropriate nutrients to VLBW infants is problematic,
since these infants also have a diminished tolerance for enteral
feedings during the first several weeks of life, making them
dependent on the parenteral route for energy supply.
Consequently, it is crucial to define a composition of preterm
TPN solutions that maintains euglycemia, while providing a
sufficient nutrient intake for normal growth. TPN contains
important potential gluconeogenic substrates (glycerol and amino
acids) as well as factors that may support gluconeogenesis by
providing energy fuel (fatty acids). Therefore, to optimize the
composition of preterm TPN, it is necessary to determine the
ability of VLBW infants to utilize their gluconeogenic
capacities for production of glucose from the non-carbohydrate
sources included in parenteral nutrition solutions.
Studies focus on gluconeogenesis
Over the past several years we have conducted a number of
studies in VLBW infants addressing these issues using compounds
labeled with stable isotopes analyzed by Gas Chromatography-Mass
Spectrometry (GCMS).
Stable isotopes are non-radioactive, naturally occurring and
completely harmless. Compounds (glucose, glycerol, fatty acids,
amino acids and water) labeled with stable isotopes are
metabolically equivalent to the corresponding unlabeled
substrates allowing us to measure the dynamics of glucose, lipid
and protein metabolism. An important advantage of the stable
isotope- GCMS techniques is their high sensitivity and precision
and, therefore, only very small blood volumes (~50 µL of plasma)
are required for accurate measurements, which make this method
particularly suitable for studies of the metabolism of VLBW
infants.
Gluconeogenesis is one of the
primary outcome variables of our studies in VLBW infants. Since
gluconeogenesis is a complex process, which is not entirely easy
to measure, our first study had two primary goals: 1) to
validate three different stable isotope methods and adapt them
to measures of gluconeogenesis in VLBW infants; and 2) to
determine whether VLBW infants can utilize this pathway to
produce glucose to maintain normoglycemia while receiving total
parenteral nutrition providing glucose at a reduced rate. In
subsequent studies, we used these methods to determine whether
a) premature infants could utilize their own small substrate
stores for gluconeogenesis; b) which components of parenteral
lipid and amino acid solutions are most important in supporting
gluconeogenesis; and c) which factors are the primary
determinants of hyperglycemia in VLBW infants receiving TPN.
We demonstrated that:
1) Despite their immaturity these
small infants are capable of producing glucose from both their
own small substrate stores and the components provided via TPN
during their first days of life, although exogenous substrate is
important to sustain glucose production over time18,19. Since
glucose production and gluconeogenesis is non-existent in a
fetus of corresponding gestational age, these results imply that
it is the birth process rather than gestational age that
activates key gluconeogenic enzymes.
2) The lipid emulsion (Intralipid)
is more important than the amino acid solution (TrophAmine) in
supporting gluconeogenesis20.
3) The glycerol component of
Intralipid is more important than the fatty acids to sustain
gluconeogenesis19. Intravenous infusion of glycerol alone
did, in fact, increase gluconeogenesis, thereby, compensating
for time dependent decrease in glycogenolysis and sustaining
glucose production19.
4) The glucose infusion rate was the
primary determinant of hyperglycemia in VLBW infants receiving
routine TPN explaining ~50 percent of the variation in the blood
glucose concentration, although insufficient suppression of
glucose production also contributed but to a lesser extent.
Maintaining normoglycemia and energy
intake
A practical implication of these studies is that reducing the
glucose infusion rate to ~ 6 to 8 mg/kg min (i.e., normal
newborn glucose turnover rate) while infusing Intralipid at 3
g/kg d and TrophAmine at 3 g/kg d (according to standard
clinical routines) would be a potential approach to prevent
hyperglycemia, hypoglycemia and insufficient energy intake in
VLBW infants during their first week of life.
Another potential approach to treating hyperglycemia is
intravenous infusion of insulin. In a just started study, we are
exploring which factors regulate glucose metabolism in VLBW
infants, i.e., whether their glucose intolerance is due to
insufficient insulin secretion and/or insulin resistance or
small masses of insulin sensitive tissue or a combination of
these factors. We are also investigating the metabolic effects
of intravenous insulin in these infants. This information is
important in designing the most appropriate approach to
maintaining both normoglycemia and an adequate energy intake in
VLBW infants.
Agneta Sunehag, M.D., Ph.D., is associate professor of Pediatrics
and a faculty member at the Children’s Nutrition Research
Center.
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