CARBOHYDRATE AND LIPID METABOLIC PATHWAYS

我们的长期目标是开发和应用新的方法，这将大大提高我们对生理和病理状态下碳水化合物和脂质代谢的理解，特别是糖尿病。这些方法的共同点是用2 H2O安全地富集身体水的2 H。我们计划实现以下七个相互关联的具体目标。1.定量糖原水解、循环和周转作为肝糖原含量的函数。2.为了通过从2 H2O标记来测量从头甘油形成的速率，并定义：（i）肝脏和肾脏在甘油产生、脂肪酸再酯化和脂解定量中的作用。和（ii）脂肪组织使用的甘油-3-P的碳源， 使脂肪酸还原。3.确定2 H20标记葡萄糖C1上H的途径，并确定这种标记如何影响糖原生成和糖原分解的计算。4.建立一种基于体内水2 H富集的糖异生定量方法。5.评价转醛醇酶反应在多大程度上影响糖原合成和糖原分解的定量。将这些技术应用于NIDDM高风险受试者的血管生成测量（i）。(ii)在NIDDM患者中，和（iii）在随后用二甲双胍治疗的NIDDM患者中。7.将这些技术应用于肥胖患者的骨再生测量。受试者将摄入2 H2O（从葡萄糖中的C5/C2 2 H-标记比率测量造血对葡萄糖产生的贡献），并将输注（6，6 - 2 H2）葡萄糖（测量葡萄糖转换）。通过将葡萄糖碳处的2 H富集物掺入六亚甲基四胺中进行测定，将其放大6倍。肝细胞再生的贡献将与通过13 C-NMR光谱测量的肝糖原含量相关。我们的研究将确定代谢的作用（i）在糖尿病高血糖中，（ii）作为NIDDM发病的可能病因因素，（iii）在二甲双胍的作用机制中。它们将有助于确定上半身肥胖受试者对胰岛素抵抗、NIDDM和心血管疾病的倾向是否与增加的胰岛素生成有关。此外，糖原直接转化为葡萄糖可能被证明是糖原含量的重要调节剂。我们的研究将为脂肪组织中的葡萄糖和脂质代谢如何适应禁食提供新的线索。

Our long-term objective is to develop and apply novel methods that will significantly advance our understanding of carbohydrate and lipid metabolism in physiological and pathological states, in particular diabetes. These methods have in common the safe 2H- enrichment of body water with 2H20. We plan to achieve the following seven interrelated specific aims. 1. To quantitate glycogen hydrolysis, cycling, and turnover as a function of liver glycogen content. 2. To measure the rate of de novo glycerol formation via labeling from 2H20, and to define: (i)the role of liver and kidney in glycerol production, fatty acid reesterification, and lipolysis quantitation., and (ii) the source of carbon of glycerol-3-P used by adipose tissue to reesterify fatty acids. 3. To determine the pathway(s) by which 2H20 labels H on C1 of glucose, and to define how this labeling affects calculations of gluconeogenesis and glycogenolysis. 4. To develop a method for quantitating glyconeogenesis, based on 2H-enrichment of body water. 5. To evaluate to what extent the transaldolase reactions affect quantitations of gluconeogenesis and glycogenolysis 6. To apply these techniques to measurements of gluconeogenesis (i) in subjects who are at high risk for NIDDM. (ii) in NIDDM patients, and (iii) in the NIDDM patients then treated with metformin. 7. To apply these techniques to measurements of gluconeogenesis in obese patients. The subjects will ingest 2H2O (to measure the contribution of gluconeogenesis to glucose production from the C5/C2 2H-labeling ratio in glucose), and will be infused with (6,6-2H2) glucose (to measure glucose turnover). The 2H-enrichment at the glucose carbons will be amplified six-fold by incorporating them into hexamethylenetetramine for assay. The contribution of gluconeogenesis will be related to hepatic glycogen content measured by 13C-NMR spectroscopy. Our studies will define the role of gluconeogenesis (i) in diabetic hyperglycemia, (ii) as a possible etiologic factor in the onset of NIDDM, and (iii) in the mechanism of metformin's action. They will help establish whether the propensity of upper body obese subjects to insulin resistance, NlDDM, and cardiovascular disease is related to increased gluconeogenesis. Also, the direct conversion of glycogen to glucose may prove to be an important regulator of glycogen content. Our studies will shed new light on how glucose and lipid metabolism in adipose tissue adapts to fasting.