DETERMINATION OF METFORMIN AND INSULIN EFFECT ON HEPATIC TRIGLYCERIDE CONTENT

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。肝脏的脂肪渗透可以通过四种不同的机制发生：1)增加进入肝脏的脂肪酸流量；2)增加肝细胞中脂肪酸的合成；3)以极低密度脂蛋白的形式减少肝细胞对脂肪酸的分泌；4)减少肝细胞对脂肪酸的氧化。动物模型表明，在胰岛素抵抗的形成过程中，脂肪酸的从头合成在肝脏脂肪的积累中起着重要作用。重要的是，肝脏中的脂肪酸合成水平是循环胰岛素水平的函数，即使在肝细胞胰岛素抵抗的情况下也是如此。人们预计，随着胰岛素抵抗的恶化和胰岛素水平的上升(要么是由于胰岛细胞产量增加，要么是由于外源性胰岛素的补充)，肝细胞脂肪酸合成的速度也会增加。这可能会增加肝脏的脂肪含量。这项研究的研究人员建议检查目前两种治疗2型糖尿病的标准护理疗法对肝脏脂肪含量的影响：二甲双胍和胰岛素。在治疗前和治疗4个月后，使用质子磁共振波谱对肝脏脂肪含量进行评估。受试者将被随机分配到两种药物中的一种进行研究，并密切监测与其使用相关的任何药物特定毒性。

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. Fatty infiltration of the liver can occur by four distinct mechanisms: 1) increased flux of fatty acids to the liver; 2) increased synthesis of fatty acids in hepatocytes; 3) decreased hepatocyte secretion of fatty acids in the form of very-low-density-lipoprotein and; 4) decreased oxidation of fatty acids by hepatocytes. Animal models suggest that de novo synthesis of fatty acids plays a significant role in the accumulation of liver fat in the setting of insulin resistance. Importantly, the level of fatty acid synthesis in the liver is a function of circulating insulin levels, even in the setting of hepatocyte insulin resistance. One would expect that as insulin resistance worsens and insulin levels rise (either as a result of increased pancreatic islet cell output or supplementation with exogenous insulin), so to would the rate of hepatocyte fatty acid synthesis. This could potentially increase the liver fat content. Investigators in the study propose to examine the effect of two current standard care therapies for type 2 diabetes mellitus on liver fat content: metformin and insulin. Liver fat content will be assessed using proton magnetic resonance spectroscopy before and after 4 months of therapy. Subjects will be randomly assigned to one of the two medication to be studied and closely monitored for any drug-specific toxicities associated with their use.