ROLE OF ENTERAL GLUTAMATE IN SUPPORTING GLUCONEOGENESIS IN INFANTS

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Premature infants have high glucose demands on a per kg body weight basis but only small body fuel stores to be used for production of glucose. To prevent hypoglycemia and to provide a sufficient energy intake, these infants routinely receive glucose by vein from birth onwards together with parenteral lipids and amino acids. When the glucose infusion rate exceeds the normal glucose turnover rate, hyperglycemia is frequently occurring, particularly in the very premature infants (<29 weeks of gestation). Knowledge about the physiology of glucose metabolism is important to enable us to design a composition of glucose, lipids and amino acids that renders these infants normoglycemic yet providing a sufficient energy intake. Glutamate, the most abundant amino acid in breast milk, is an important substrate for glucose production via gluconeogenesis. Studies in pigs have demonstrated that the major part of enterally administered glutamate is utilized by the gut, i.e., the appearance of glutamate in the systemic circulation is minimal. It is not known whether this is the case also in premature infants, or whether the appearance of enterally administered glutamate is dose dependent. The purpose of this project is to determine the role of enterally administered glutamate in supporting gluconeogenesis in very premature infants. However, before this issue can be addressed, it is necessary to determine at which dose of enterally administered glutamate, a significant amount of glutamate appears in the systemic circulation, thus, being available for gluconeogenesis. The purpose of the proposed pilot study is to gain this information. HYPOTHESIS a) In premature infants, the appearance of enterally administered glutamate is dose dependent. b) An ingestion rate of glutamate corresponding to 4x that of breast milk (130 ml/kg d) is required to achieve a measurable increase in the concentrations of glutamate in plasma. SPECIFIC AIMS The purpose of the proposed study is to determine 1) whether a potential appearance of glutamate (administered via a gastric feeding tube) in plasma is dose dependent; and 2) if a portion of glutamate appears in plasma, does it support gluconeogenesis. The present application addresses only the first issue. The results from this "pilot study" will be used to design a second study addressing the role of enterally administered glutamate in supporting gluconeogenesis. BACKGROUND AND SIGNIFICANCE Very premature infants (gestational age <29 weeks) have a large brain to body weight ratio, i.e. in an infant, the brain accounts for 12% of total body weight as compared to only 2% in an adult. Thus, in an infant, 90% of total glucose utilization is by the brain as compared to 40% in an adult. As a consequence the infant has about 3 times the glucose turnover rate of an adult per kg body mass (6 vs. 3 mg/kg min). Since an infant, a premature infant in particular, has very small body fuel stores to meet these glucose demands, he/she is at high risk of hypoglycemia. To prevent hypoglycemia and provide energy, premature infants are routinely given parenteral glucose from birth. The infusion rates are rapidly increased over the first couple of days and parenteral lipids and amino acids are added. However, premature infants have a low tolerance for parenteral glucose resulting in a frequent occurrence of hyperglycemia which might be associated with urinary loss of glucose and water and an increased risk of dehydration. In an ongoing protocol (H7213), I am investigating how very premature infants utilize the components of regular TPN to produce glucose via the gluconeogenic pathway with the ultimate goal to define a composition of neonatal TPN that renders the infants normoglycemic i.e., preventing both hypo- and hyperglycemia while providing a sufficient energy intake. Glutamate is a very important gluconeogenic amino acid. It is the most abundant amino acid in breast milk. It has also been speculated (although not proven) that glutamate might reduce the risk of NEC. The proposed studies are not designed to address this latter issue.