ROLE OF ENTERAL GLUTAMATE IN SUPPORTING GLUCONEOGENESIS IN INFANTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。早产儿在每公斤体重的基础上有很高的葡萄糖需求，但只有少量的身体燃料储存用于生产葡萄糖。为了防止低血糖和提供足够的能量摄入，这些婴儿从出生起就常规地通过静脉注射葡萄糖，同时注射脂质和氨基酸。当葡萄糖输注速率超过正常葡萄糖周转率时，高血糖就会频繁发生，尤其是在极早产儿（妊娠<29周）。关于葡萄糖代谢的生理学知识对于我们设计葡萄糖、脂质和氨基酸的组成是很重要的，使这些婴儿血糖正常，同时提供足够的能量摄入。谷氨酸是母乳中最丰富的氨基酸，是通过糖异生产生葡萄糖的重要底物。对猪的研究表明，肠内给药的谷氨酸的主要部分是由肠道利用的，也就是说，谷氨酸在体循环中的出现是最小的。目前尚不清楚早产儿是否也会出现这种情况，或者肠内给药谷氨酸的出现是否与剂量有关。该项目的目的是确定肠内给药谷氨酸在支持极早产儿糖异生中的作用。然而，在解决这个问题之前，有必要确定在何种剂量的肠内给药谷氨酸，大量谷氨酸出现在体循环中，从而可用于糖异生。拟议的试点研究的目的是获得这些信息。假设a)在早产儿中，肠内给药谷氨酸的出现是剂量依赖性的。b)谷氨酸的摄取率需要相当于母乳的4倍（130 ml/kg d），才能实现血浆中谷氨酸浓度的可测量的增加。本研究的目的是确定1)血浆中谷氨酸（通过胃饲管给药）的潜在出现是否与剂量有关；2)如果一部分谷氨酸出现在血浆中，它是否支持糖异生？本申请仅解决第一个问题。这项“试点研究”的结果将用于设计第二项研究，探讨肠内给药谷氨酸在支持糖异生中的作用。背景和意义非常早产的婴儿（胎龄<29周）的大脑与体重的比例较大，即婴儿的大脑占总体重的12%，而成人的这一比例仅为2%。因此，在婴儿中，总葡萄糖的90%是由大脑利用的，而成人只有40%。因此，婴儿每公斤体重的葡萄糖周转率约为成人的3倍（6对3毫克/公斤分钟）。由于婴儿，尤其是早产儿，体内能满足这些葡萄糖需求的能量储存非常少，他/她低血糖的风险很高。为了防止低血糖和提供能量，早产儿从出生起就常规地给予肠外葡萄糖。在最初几天内，输液速度迅速增加，并添加了肠外脂质和氨基酸。然而，早产儿对肠道外葡萄糖的耐受性较低，导致高血糖的频繁发生，这可能与尿中葡萄糖和水的丢失以及脱水的风险增加有关。在一项正在进行的方案（H7213）中，我正在研究早产儿如何利用常规TPN的成分通过糖异生途径产生葡萄糖，最终目标是确定新生儿TPN的成分，使婴儿血糖正常，即防止低血糖和高血糖，同时提供足够的能量摄入。谷氨酸是一种非常重要的糖异生氨基酸。它是母乳中含量最多的氨基酸。也有人推测（尽管没有得到证实）谷氨酸可能会降低NEC的风险。拟议的研究并非旨在解决后一个问题。

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.