SUBSTRATE CONTROL OF GLYCOGEN SYNTHESIS IN VIVO

体内糖原合成的底物控制

• 批准号: 3245783
• 负责人: W FREDERICK SCHWENK
• 金额: $ 20.15万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3245783
• 关键词: acetaminophen; carbohydrate metabolism; child (0-11); dietary aminoacid; dietary carbohydrates; dietary proteins; dogs; eating; fasting; fructose; glucose; glycogen storage disease; glycogenesis; human subject; liver metabolism; nutrient bioavailability; nutrition related tag; radiotracer; stable isotope; uridine diphosphate glucose

The importance of understanding the substrate and hormonal control of hepatic carbohydrate storage and mobilization is most apparent in the many disease states where this process goes awry, including diabetes and the hypoglycemia observed in a number of disorders in children. Recent data has made it clear that the process of carbohydrate storage following a meal is more complex than previously thought: during absorption and utilization of a carbohydrate meal, there is continued synthesis of new glucose as well as continued breakdown of hepatic glycogen. However, most of the data that support these new concepts have been determined in in vitro rat studies; in vivo studies in humans addressing the mechanisms of carbohydrate storage have been hard to carry out because of the difficulty of sampling hepatic glycogen. The primary thrust of this research is to extend our understanding of the substrate control of intrahepatic storage of ingested carbohydrate in vivo. Preliminary data support the hypothesis that hepatic glycogen turnover continues both in fasting and during refeeding. Using acetaminophen to "biochemically biopsy" the immediate precursor of intrahepatic glycogen (UDP-glucose) during simultaneous infusion of multiple radioactive and stable isotopically labeled compounds, the hypothesis that glycogen turnover is a continuing process will be tested under a variety of conditions. Rates of hepatic glycogen synthesis will be estimated by measuring intrahepatic UDP-glucose flux. The hypothesis that increased amounts of glucose will increase UDP-glucose flux, as well as the contribution of the direct pathway to glycogen synthesis, will be tested in humans. Additional studies will test the hypotheses that UDP-glucose flux is dependent upon whether glycogen stores are deplete or replete, and on the amount of protein in the previously ingested diet. We will also test the hypotheses that the ingestion of fructose along with glucose will have more than an additive effect on glycogen synthesis, and that amino acids can stimulate glycogen synthesis, as they have been shown to do in vitro. Finally, these techniques will be applied to children with type I glycogen storage disease (GSD) to test the hypothesis that increased glucose administration will decrease rather than increase UDP-glucose flux and provide support for the concept that these patients produce sugar by having an increased rate of glycogen turnover. Completion of these studies will make significant contributions to our understanding of how substrates control glycogen synthesis in normal humans, as well as in children with type I GSD. The technique to be utilized in these studies should be directly applicable to the diabetic state, as well as to other abnormal nutritional states such as infection, cancer cachexia, and surgery in both adults and children. An improved understanding of the alterations in normal physiology should help maximize the nutritional and hormonal therapy in such patients.

了解基质和激素控制的重要性