MECHANISM OF EXCESS GLUCOSE PRODUCTION IN TYPE 2 DIABETES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项工作的目标是利用体外和体内NMR和稳定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高脂饮食和禁食条件下肥胖相关糖尿病中的调节。2型糖尿病（Type 2 Diabetes Mellitus，T2 DM）是一种流行性疾病，它的发病与肥胖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发生，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，并阐明T2 DM中葡萄糖和脂质代谢之间的相互作用，这对于预防糖尿病发作和找到治愈或更好治疗该疾病的策略至关重要。诊断糖尿病的关键临床观察是空腹高血糖。肝脏葡萄糖过度生成导致空腹高血糖，但关于糖原分解和糖原异生在T2 DM中的作用，已有争议性数据报道。最近，我发现在肥胖相关的T2 DM啮齿动物模型中，禁食时保存的肝糖原导致过多的肝糖原分解，随后导致空腹高血糖。这一观察结果对于了解肥胖T2 DM患者中的肝葡萄糖自动调节失败可能很重要，因为在肥胖人类和T2 DM患者中报告了空腹肝糖原增加。在这些个体中，空腹时过多的肝糖原可能是空腹高血糖的关键，因为内源性葡萄糖的产生对可用于水解的肝糖原的量敏感。在本提案中，将结合整个动物的全身代谢通量评价肥胖和肥胖相关T2 DM中的肝脏代谢变化。将评价短期高脂饮食诱导的肝脏胰岛素抵抗以及肥胖相关T2 DM中脂质和碳水化合物代谢之间的相互作用，重点是肝糖原。 将确定糖原分解抑制是否改变肥胖相关T2 DM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. 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.