Carbohydrate Metabolic Pathways

描述（由申请人提供）：将开发和应用新的和改进的方法，用于定量碳水化合物代谢途径中的异常，这对理解糖尿病及其治疗的病理生理学非常重要。有五个具体目标。1)定量2型糖尿病患者的转醛醇酶反应率。在一定程度上，示踪方法高估了自生（GNG）。GNG增加被认为是糖尿病高血糖症的主要原因。通过追踪半乳糖转化为葡萄糖时氢的去向进行定量。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和糖原分解成功降低糖尿病患者的输出取决于肝脏调节反应。使用[6，6 - 2 H2]葡萄糖、使用D2 O的GNG和通过半乳糖输注模拟的增加的糖原分解来测量输出。3)定量同时肝糖原合成和分解，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和高血糖症，这是由于糖原中葡萄糖的储存减少。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)测试硫胺素是否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或产生刺激糖酵解中间体利用的该途径的中间体来预防实验性糖尿病并发症。针对硫胺素的作用而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测试，用于非侵入性地对肝脏核糖形成进行采样。5)评估6-氟-6-脱氧葡萄糖（6-FDG）作为葡萄糖转运示踪剂的可能用途。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。糖尿病动物中的摄取将使用6-18FDG通过PET成像，并且使用19 F-NMR确定6 FDG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.