MECHANISM OF EXCESS GLUCOSE PRODUCTION IN TYPE 2 DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 2009年6月10日 这种合作在我对NIDDK指导研究科学家发展奖(K01)PAR-05-66的回应中有详细的描述。这项工作的目标是使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，以评估正常生理条件下的糖原代谢及其调节，以及高脂饮食和禁食条件下肥胖相关糖尿病的糖原代谢及其调节。2型糖尿病(T2 DM)正在流行，威胁着数以百万计的人，它的增加与世界范围内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几十年就开始了，这在肥胖者中很常见。我的长期研究目标是找到胰岛素抵抗的主要原因(S)，并阐明T2 DM患者糖和脂代谢之间的相互作用，这对于制定预防糖尿病发病的策略和寻找治疗这种疾病的方法或更好的方法至关重要。诊断糖尿病的关键临床观察是空腹高血糖。肝脏葡萄糖过量生产导致空腹高血糖，但关于糖原分解和糖异生在T2 DM中的作用，有争议的数据报道。最近，我发现禁食保存的肝糖原导致过度的糖原分解，随后导致肥胖相关的T2 DM啮齿动物模型的空腹高血糖。由于肥胖者和T2 DM患者的空腹肝糖原增加，这一观察结果对于理解肥胖T2 DM患者的肝糖自动调节失败具有重要意义。禁食中过量的肝糖原可能是这些个体空腹高血糖的关键，因为内源性葡萄糖的产生对可用于水解的肝糖原的量很敏感。在这项建议中，肥胖和肥胖相关的T2 DM患者的肝脏代谢变化将与整个动物的全身代谢通量相联系进行评估。短期高脂饮食诱导的肝脏胰岛素抵抗以及肥胖相关的T2 DM患者脂肪和碳水化合物代谢之间的相互作用将以肝糖原为重点进行评估。将确定抑制糖原分解是否改变肥胖相关的T2 DM啮齿动物模型的空腹高血糖。

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.