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

描述（由申请人提供）： 2型糖尿病（Type 2 Diabetes Mellitus，T2DM）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T2DM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T2DM中的作用，已有争议性数据报道。最近，我发现在肥胖相关T2DM的啮齿动物模型中，禁食时保留的肝糖原导致过度的糖原分解，随后导致空腹高血糖。这一观察结果对于了解肥胖T2DM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T2DM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T2DM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T2DM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T2DM啮齿动物模型中的空腹高血糖。先进的成像研究中心已率先在方法开发，以评估全面的代谢通量在体内，并研究中间代谢，同时管理的稳定同位素示踪剂。高场核磁共振（NMR）光谱技术将适用于执行拟议的研究项目。

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 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 obesity-associated 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. 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 will be adapted in performing proposed research projects.