CARBOHYDRATE AND LIPID METABOLIC PATHWAYS

碳水化合物和脂质代谢途径

• 批准号: 2414766
• 负责人: BERNARD R LANDAU
• 金额: $ 34.14万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1999-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2414766
• 关键词: carbohydrate metabolism; clinical research; deuterium; deuterium oxide; dosage; enzyme activity; fasting; formaldehyde; glucokinase; gluconeogenesis; glucose metabolism; glycogen; glycogenolysis; human subject; lipid metabolism; liver metabolism; magnetic resonance imaging; method development; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; obesity; pathologic process; radiotracer

The long term objective is to develop and apply methods for quantitating pathways of carbohydrate and lipid metabolism. The specific aim is to develop a method for estimating rates of gluconeogenesis which is safe, reliable, definitive, easily performed, and broadly applicable, an apply it to the testing of hypotheses with regard to carbohydrate metabolism in physiological and pathological conditions with emphasis on the diabetic state. D2O is administered at a safe, well tolerated dose. In the fasted state hexamethylenetetramine, formed from 6 equivalents of formaldehyde, is used to measure the enrichment of the deuteriums bound to carbons 2,5 and 6 of glucose. Formaldehyde containing the deuterium bound to carbon 6 is formed on periodic acid oxidation of blood glucose. Formaldehyde containing deuterium bound to carbon 5 is formed on oxidation of xylose formed from the glucose. Formaldehyde containing deuterium at carbon 2 is formed by oxidation of ribitol-5-P formed from the glucose. In the fed state, the D2O is given with acetaminophen. Deuterium bound to carbon 2 and 5 of glucose formed from the glucuronic acid moiety of the excreted glucuronide is determined. The fraction of glucose output formed by gluconeogenesis in the fasted state and the fraction of glycogen formation by gluconeogenesis in the fed state, also to the ratio of the enrichment at carbon 5 to that in body water. The carbon 5 to carbon 6 ratio is a measure of the contribution of glycerol to gluconeogenesis and the extend of equilibration of the hydrogens of pyruvate with those in water. Absolute rates of gluconeogenesis in the fasted state are estimated by multiplying the fraction via gluconeogenesis by glucose output measured using tritiated glucose or (6,6-D2) glucose. In the fed state the quantity of glycogen formed is measured using MRI to estimate liver volume and 13CNMR glycogen concentration. In the fasted state MRI and NMR are used to relate estimates of rates of gluconeogenesis to rates of glycogenolysis. Measurements will be made in normal subjects, in subjects who are obese and in NIDDM and MODY subjects. The findings should bear on the role of the liver in producing hyperglycemia in the diabetic. This in turn bears on the design of therapeutic agents and the adequacy of insulin given systemically in returning metabolism, not just blood glucose concentration, to normal. The approach for the first time allows the giving of D2O in safe and convenient doses to obtain adequate labeling in glucose for measurements of the pathways of its formation and conversion to glycogen. Because of the small dose of deuterated water that has to be given and the small amount of glucose that is required for analysis, the approach should be useful in pediatric as well s adult clinical studies.

长期目标是开发和应用定量方法， 碳水化合物和脂质代谢途径。 具体目标是 开发一种安全的估计胚胎发生率的方法， 可靠，明确，易于执行，广泛适用，并应用它 关于碳水化合物代谢的假设的测试， 生理和病理条件，重点是糖尿病 状态 D2O以安全、耐受性良好的剂量给药。 在禁食 所述六亚甲基四胺由6当量甲醛形成， 用于测量与碳2，5结合的氘的富集， 6葡萄糖 含有与碳6键合的氘的甲醛是 高碘酸氧化血糖形成的。 甲醛 含有与碳5键合的氘，在木糖氧化时形成 由葡萄糖形成。 在碳2上含有氘的甲醛是 通过氧化由葡萄糖形成的核糖醇-5-P而形成。 美联储 在美国，D2O与对乙酰氨基酚一起使用。 氘与碳2结合 和5的葡萄糖形成的葡萄糖醛酸部分的排泄物 葡糖苷酸测定。 葡萄糖输出的分数由 空腹状态下的糖原生成和糖原形成分数 通过在进食状态下的异生作用，也与在 碳5在体内的含量。 碳5与碳6的比例是 甘油对植物异生作用的影响及其延伸 丙酮酸的氢与水的氢平衡。 通过以下公式估计禁食状态下新生儿的绝对速率： 将通过葡萄糖生成的分数乘以测量的葡萄糖输出 使用氚化葡萄糖或（6，6-D2）葡萄糖。 在美联储的数量 使用MRI测量形成的糖原以估计肝脏体积， 13CNMR糖原浓度。 在禁食状态下，MRI和NMR用于 将糖原生成速率的估计值与糖原分解速率相关联。 将在正常受试者、肥胖受试者和 在NIDDM和MODY受试者中。 这些发现应该与肝脏在产生 糖尿病患者的高血糖。 这反过来又影响了 治疗药物和全身给予胰岛素的充足性， 恢复新陈代谢，而不仅仅是血糖浓度，恢复正常。 的 第一次允许安全方便地给予D2O的方法 剂量，以获得足够的葡萄糖标记，用于测量 其形成和转化为糖原的途径。 因为小 剂量的氘水，必须给予和少量的 分析所需的葡萄糖，该方法应该是有用的 儿童以及成人临床研究。