MECHANISM OF EXCESS GLUCOSE PRODUCTION IN TYPE 2 DIABETES

2 型糖尿病中葡萄糖产生过多的机制

• 批准号: 7956975
• 负责人: EUNSOOK JIN
• 金额: $ 1.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956975
• 关键词: Animals; Clinical; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Epidemic; Fasting; Fatty acid glycerol esters; Funding; Gluconeogenesis; Glucose; Glycogenolysis Inhibition; Goals; Grant; Hepatic; Homeostasis; Human; Hydrolysis; Hyperglycemia; In Vitro; Individual; Institution; Insulin Resistance; Lipids; Liver; Liver Failure; Liver Glycogen; Mentored Research Scientist Development Award; Metabolic; Metabolism; Methodology; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Patients; Physiology; Regulation; Reporting; Research; Research Personnel; Resources; Rodent Model; Role; Source; United States National Institutes of Health; Work; carbohydrate metabolism; feeding; glucose production; glycogen metabolism; glycogenolysis; in vivo; lipid metabolism; prevent; response; stable isotope

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. June-10-2009 This collaboration is described in detail in my response to PAR-05-66, NIDDK Mentored Research Scientist Development Award (K01). The goal of the work is to undertake observational studies using in vitro and in vivo NMR and stable isotope methodologies to assess glycogen metabolism and its regulation in normal physiology and in obesity-associated diabetes in high-fat-fed and fasted conditions. 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 the interactions between glucose and lipid metabolism in T2DM, which are essential for strategy development to prevent the onset of diabetes and to fine a cure or better treatments for the disease. A key clinical observation for diagnosis of diabetes is fasting hyperglycemia. Hepatic glucose overproduction contributes 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 fasting hyperglycemia in rodent models for obesityassociated T2DM. This observation could be important in understanding the failure of hepatic glucose autoregulation in obese T2DM patients because increased fasting hepatic glycogen was reported in obese humans and T2DM patients. Excess liver glycogen in fasting could be critical in fasting hyperglycemia in those individuals 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 the connection with systemic metabolic fluxes of whole animals. A short-term high-fat diet induced hepatic insulin resistance and the interaction between lipid and carbohydrate metabolism in obesity-associated T2DM will be evaluated focusing hepatic glycogen. It will be determined whether inhibition of glycogenolysis alters fasting hyperglycemia in rodent models of obesity-associated T2DM.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 2009年6月10日 NIDDK指导了研究科学家发展奖（K01），在我对PAR-05-66的回应中详细描述了这一合作。这项工作的目的是使用体外和体内NMR和稳定的同位素方法进行观察性研究，以评估糖原代谢及其在正常生理学和肥胖相关糖尿病中的调节。 2型糖尿病（T2DM）正在引起流行病威胁数百万人，其增加与全球肥胖的迅速增加密切相关。胰岛素抵抗可能在糖尿病发作前数十年进行，并且在肥胖个体中很常见。我的研究长期目标是找到胰岛素抵抗的主要原因，并阐明T2DM中葡萄糖与脂质代谢之间的相互作用，这对于防止糖尿病的爆发和治疗或更好地治疗这种疾病至关重要。诊断糖尿病的关键临床观察是禁食性高血糖。肝葡萄糖过量产生有助于禁食性高血糖，但已经报道了有关糖原分解和糖异生在T2DM中的作用的有争议的数据。最近，我发现禁食中保存的肝糖原导致过量的糖原分解，随后在啮齿动物模型中促进了禁食性高血糖，用于肥胖与肥胖症相关的T2DM。该观察结果对于了解肥胖T2DM患者肝葡萄糖自动调节的失败可能很重要，因为肥胖人和T2DM患者的禁食肝糖原增加增加。在禁食中，过量的肝糖原对于那些个体的禁食高血糖至关重要，因为内源性葡萄糖的产生对可用于水解的肝糖原量敏感。在此提案中，将评估肥胖和与肥胖相关的T2DM的肝脏代谢变化，以与全动物的全身代谢通量有关。短期高脂饮食诱导的肝胰岛素抵抗以及肥胖相关T2DM中脂质和碳水化合物代谢之间的相互作用将被评估，以焦点凝聚。 将确定抑制糖原分解是否会改变与肥胖相关T2DM啮齿动物模型中禁食高血糖。