Role of excess glycogenolysis in fasting hyperglycemia in obesity-associated T2DM

过量糖原分解在肥胖相关 T2DM 空腹高血糖中的作用

• 批准号: 7470349
• 负责人: EUNSOOK JIN
• 金额: $ 8.48万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470349
• 关键词: Accounting; Adenoviruses; Age; Animal Model; Animals; Automobile Driving; Clinical; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Epidemic; Esterified Fatty Acids; Euglycemic Clamping; Fasting; Fatty acid glycerol esters; Future; Gluconeogenesis; Glucose; Glucose Clamp; Glycerol; Glycogen; Glycogenolysis Inhibition; Goals; Hepatic; Homeostasis; Human; Hydrolysis; Hyperglycemia; Image; Impairment; Individual; Insulin Resistance; Label; Learning; Link; Lipolysis; Liver; Liver Failure; Liver Glycogen; Magnetic Resonance; Magnetic Resonance Spectroscopy; Mediating; Metabolic; Metabolic Diseases; Metabolism; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phosphorylation; Physiology; Principal Investigator; Protein Overexpression; Protein phosphatase; Protocols documentation; Regulation; Reporting; Research; Research Project Grants; Rodent Model; Role; Source; Sprague-Dawley Rats; Staging; Study of magnetics; System; Technology; Tracer; Zucker Rats; day; diabetic; glucose production; glycemic control; glycogen metabolism; glycogenolysis; human data; human study; human subject; improved; in vivo; instrument; long chain fatty acid; method development; prevent; programs; research study; skills; stable isotope; training project

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus (T2DM) is getting epidemic threatening millions of people and its increase is tightly related with the rapid increase of obesity throughout the world. Insulin resistance may proceed decades before the onset of diabetes and it is common in obese individuals. My long term goal in research is finding primary cause(s) of insulin resistance and elucidating glucose-fat metabolic interactions in T2DM, which are essential for strategy development to prevent the onset of diabetes and to find a cure or better treatments for the disease. A key clinical observation for the diagnosis of diabetes is fasting hyperglycemia. Hepatic glucose overproduction contributes to fasting hyperglycemia, but controversial data have been reported about the roles of glycogenolysis and gluconeogenesis in T2DM. Recently I found that preserved liver glycogen in fasting resulted in excess glycogenolysis, and subsequently contributed to fasting hyperglycemia in the rodent models of obesity-associated T2DM. This observation could be important in understanding the failure of hepatic glucose auto-regulation in obese T2DM patients because increased hepatic glycogen in fasting was reported in obese humans and T2DM patients. The excess liver glycogen could be critical in fasting hyperglycemia because endogenous glucose production is sensitive to the amount of hepatic glycogen available for hydrolysis. In this proposal, liver metabolic changes in obesity and in obesity-associated T2DM will be evaluated in animal models and in human subjects. Hepatic insulin resistance induced by short high-fat diet and glucose-fat metabolic interaction in obesity-associated T2DM will be evaluated focusing hepatic glycogen. It will be determined if the inhibition of excess glycogenolysis improves fasting hyperglycemia in obesity-associated T2DM. The Advanced Imaging Research Center has pioneered in method development to evaluate comprehensive metabolic fluxes in vivo and to study intermediary metabolism using simultaneous administration of stable isotope tracers. The technologies with high field nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance (MR) spectroscopy will be adapted in performing proposed research projects.

描述（由申请人提供）： 2型糖尿病（T2DM）正在流行，威胁着数百万人，其增长与全球肥胖率的迅速增加密切相关。胰岛素抵抗可能在糖尿病发病前几十年就已经出现，并且在肥胖个体中很常见。我的长期研究目标是找到胰岛素抵抗的主要原因并阐明 T2DM 中葡萄糖-脂肪代谢的相互作用，这对于制定预防糖尿病发作和找到治愈方法或更好的治疗方法至关重要。诊断糖尿病的一个关键临床观察是空腹高血糖。肝葡萄糖过量产生导致空腹高血糖，但关于糖原分解和糖异生在 T2DM 中的作用的数据存在争议。最近我发现，空腹时保留的肝糖原会导致糖原分解过量，从而导致肥胖相关 T2DM 啮齿动物模型中出现空腹高血糖。这一观察结果对于理解肥胖 T2DM 患者肝脏葡萄糖自动调节的失败可能很重要，因为据报道肥胖人和 T2DM 患者空腹时肝糖原增加。过量的肝糖原可能对空腹高血糖至关重要，因为内源性葡萄糖的产生对可用于水解的肝糖原的量敏感。在该提案中，将在动物模型和人类受试者中评估肥胖和肥胖相关 T2DM 中的肝脏代谢变化。肥胖相关 T2DM 中由短期高脂饮食诱导的肝胰岛素抵抗和糖脂代谢相互作用将重点评估肝糖原。将确定抑制过量糖原分解是否可以改善肥胖相关 T2DM 的空腹高血糖。先进成像研究中心在方法开发方面处于领先地位，可评估体内综合代谢通量，并使用同时施用稳定同位素示踪剂来研究中间代谢。高场核磁共振（NMR）波谱和磁共振（MR）波谱技术将用于执行拟议的研究项目。