MECHANISM OF EXCESS GLUCOSE PRODUCTION IN TYPE 2 DIABETES

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 2009 年 6 月 10 日 我在 PAR-05-66、NIDDK 指导研究科学家发展奖 (K01) 的回复中详细描述了这种合作。这项工作的目标是利用体外和体内核磁共振和稳定同位素方法进行观察性研究，以评估高脂肪喂养和禁食条件下正常生理和肥胖相关糖尿病中的糖原代谢及其调节。 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 中葡萄糖和脂质代谢之间的相互作用，这对于制定预防糖尿病发作和更好地治愈该疾病的策略至关重要。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，并随后在肥胖相关 T2DM 啮齿动物模型中导致空腹高血糖。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 患者空腹肝糖原增加。空腹时过量的肝糖原可能对这些个体的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，将结合整个动物的全身代谢通量来评估肥胖和肥胖相关 T2DM 中的肝脏代谢变化。将评估短期高脂肪饮食诱导的肝脏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，重点关注肝糖原。 将确定抑制糖原分解是否会改变肥胖相关 T2DM 啮齿动物模型中的空腹高血糖。

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.