Carbohydrate Metabolic Pathways

描述（由申请人提供）：新的和改进的方法将被开发和应用于定量碳水化合物代谢途径的异常，这对了解糖尿病的病理生理及其治疗非常重要。有5个具体目标。1)定量测定2型糖尿病的转醛缩酶反应率。在一定程度上，示踪剂方法高估了糖异生（GNG）。GNG的增加被认为是糖尿病高血糖的主要原因。定量是通过追踪半乳糖中氢转化为葡萄糖的过程来完成的。2)通过改变GNG速率以响应糖原溶解速率的变化来确定2型糖尿病肝脏调节葡萄糖输出的能力。通过抑制GNG和糖原溶解来成功降低糖尿病患者的输出取决于肝脏的调节反应。用[6,6- 2H2]葡萄糖测量输出，用D2O测量GNG，用半乳糖输注模拟糖原溶解增加。3)定量测定2型糖尿病患者肝糖原同时合成和分解，即循环。循环可以解释糖尿病患者肝糖原含量降低和由于糖原中葡萄糖储存减少而引起的高血糖。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)检验硫胺素对实验性糖尿病并发症的预防是通过将糖酵解中间体从高血糖损伤途径分流到戊糖磷酸途径，还是通过产生糖酵解中间体刺激糖酵解中间体的利用。针对硫胺素作用而开发的治疗方法取决于对这些作用机制的理解。用咪唑乙酸对正常动物和糖尿病动物的肝核糖形成过程进行了体外和体内定量检测。5)评估6-氟-6-脱氧葡萄糖（6FDG）作为葡萄糖运输示踪剂的可能性。目前用于表征糖尿病患者葡萄糖转运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通过PET使用6-18FDG成像，并使用19F-NMR确定6FDG的代谢命运。

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.