Carbohydrate Metabolic Pathways

碳水化合物代谢途径

• 批准号: 7069057
• 负责人: BERNARD R LANDAU
• 金额: $ 43.54万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069057
• 关键词: carbohydrate metabolism; clinical research; deoxyglucose; enzyme activity; gluconeogenesis; glucose metabolism; glucose transport; glycogenesis; human subject; hyperglycemia; laboratory mouse; laboratory rat; liver metabolism; molecular probes; noninsulin dependent diabetes mellitus; nuclear magnetic resonance spectroscopy; nutrition related tag; pathologic process; patient oriented research; pentose phosphate shunt; positron emission tomography; thiamine; transaldolase /transketolase

DESCRIPTION (provided by applicant): New and improved methods are to be developed and applied for quantitating abnormalities in pathways of carbohydrate metabolism important to understanding the pathophysiology of diabetes and its treatment. There are 5 specific aims. 1) To quantitate transaldolase reaction rates in type 2 diabetes. To their extent gluconeogenesis (GNG) is overestimated by tracer methods. Increased GNG is believed a major contributor to diabetic hyperglycemia. Quantitation is done by tracing the fate of the hydrogens of galactose on their conversion to glucose. 2) To determine the ability of the type 2 diabetic liver to regulate glucose output by changing GNG rates in response to changing glycogenolytic rates. Success reducing output in diabetics by inhibiting GNG and glycogenolysis depends on hepatic regulatory responses. Output is measured using [6,6- 2H2]glucose, GNG using D2O, and increased glycogenolysis simulated by galactose infusion. 3) To quantitate simultaneous hepatic glycogen synthesis and breakdown, i.e. cycling in type 2 diabetes. Cycling can explain in the diabetic decreased hepatic glycogen content and hyperglycemia due to decreased storage of glucose in glycogen. Cycling is equated to the extent glycogen is not formed by the direct and indirect pathways of glycogen formation. 4) To test whether thiamine's prevention of experimental diabetic complications is by shunting glycolytic intermediates from pathways of hyperglycemic damage to the pentose phosphate pathway or generating intermediate(s) of that pathway stimulating utilization of glycolytic intermediates. Therapeutic approaches developed in response to thiamine's actions depend on understanding the mechanism of those actions. Tested by quantitating the pathways in vitro and in vivo in normal and diabetic animals with imidazole acetic acid used to non-invasively sample hepatic ribose formation. 5) To assess possible use of 6-fluoro-6-deoxyglucose (6FDG) as a tracer of glucose transport. Tracers presently used to characterize rates of glucose transport in the diabetic are not specific or difficult to use. Uptake in diabetic animals will be imaged by PET using 6-18FDG and 6FDG's metabolic fate determined using 19F-NMR.

描述（由申请人提供）：将开发和应用新的和改进的方法来定量碳水化合物代谢途径中的异常，这对于理解糖尿病的病理生理学及其治疗很重要。有5个具体目标。 1) 定量 2 型糖尿病的转醛酶反应率。在某种程度上，示踪方法高估了糖异生（GNG）。 GNG 增加被认为是糖尿病高血糖的主要原因。通过追踪半乳糖中的氢转化为葡萄糖的命运来进行定量。 2) 确定 2 型糖尿病肝脏通过改变 GNG 速率以响应糖原分解速率的变化来调节葡萄糖输出的能力。通过抑制 GNG 和糖原分解来成功减少糖尿病患者的输出量取决于肝脏的调节反应。使用[6,6-2H2]葡萄糖测量输出，使用D2O测量GNG，并通过半乳糖输注模拟增加的糖原分解。 3) 定量同时进行的肝糖原合成和分解，即 2 型糖尿病的循环。骑自行车可以解释糖尿病患者肝糖原含量减少以及由于糖原中葡萄糖储存减少而导致的高血糖。循环等同于糖原不通过糖原形成的直接和间接途径形成的程度。 4) 测试硫胺素预防实验性糖尿病并发症的作用是否是通过将糖酵解中间体从高血糖损伤途径中分流到戊糖磷酸途径，或者生成该途径的中间体刺激糖酵解中间体的利用。针对硫胺素作用开发的治疗方法取决于对这些作用机制的理解。通过使用咪唑乙酸对正常和糖尿病动物的体外和体内途径进行定量来进行测试，用于无创地取样肝核糖形成。 5) 评估 6-氟-6-脱氧葡萄糖 (6FDG) 作为葡萄糖转运示踪剂的可能性。目前用于表征糖尿病患者葡萄糖转运速率的示踪剂不具有特异性或难以使用。糖尿病动物的摄取将使用 6-18FDG 通过 PET 成像，并使用 19F-NMR 确定 6FDG 的代谢命运。