PROTOCOL V: EFFECT OF CHRONICALLY ELEVATED PLASMA FFA ON HGP AND GLUCONEOGENESIS

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。 目的/背景：2型糖尿病的特征是对肝脏中胰岛素作用的抵抗。 2型糖尿病受试者还具有升高的基础FFA水平/脂质氧化，其不能响应于胰岛素而正常抑制。 以前的研究表明，血浆FFA浓度升高和/或脂质氧化损害胰岛素抑制2型糖尿病患者肝葡萄糖产生的能力。 然而，目前尚不清楚是否升高的血浆FFA水平和/或脂质氧化或这些异常的一些后果，增强血管生成或糖原分解。 目前还不清楚，在两个糖尿病父母的胰岛素抵抗正常葡萄糖耐受后代中，血浆FFA浓度/脂质氧化升高是否会诱导肝胰岛素抵抗。 我们将通过定量胰岛素对长时间输注Intraperoid后肝脏新生和糖原分解的影响来检验这一假设。 方法：10名瘦健康非糖尿病受试者和10名非糖尿病子女的两个糖尿病父母将进行研究。 受试者将接受基线评价，包括口服葡萄糖耐量试验和胰岛素钳夹研究。 然后，受试者将接受胰岛素输注8天，以将血浆FFA浓度增加至2型糖尿病个体中观察到的水平。 在胰岛素输注之前和之后，受试者将在基础状态下和响应生理性高胰岛素血症时接受使用氚化葡萄糖（以测量总肝葡萄糖产生）和氘化水（以测量肝葡萄糖生成）的4小时正葡萄糖钳夹。

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. OBJECTIVE/BACKGROUND: Type 2 diabetes mellitus is characterized by resistance to the action of insulin in liver. Type 2 diabetic subjects also have elevated basal FFA levels/lipid oxidation, which fail to suppress normally in response to insulin. Previous studies have suggested that elevated plasma FFA concentrations and/or lipid oxidation impair insulin's ability to suppress hepatic glucose production in type 2 diabetic subjects. However, it remains unclear whether elevated plasma FFA levels and/or lipid oxidation or some consequence of these abnormalities augments gluconeogenesis or glycogenolysis. It is also unclear whether, in the insulin resistant normal glucose tolerant offspring of two diabetic parents, elevated plasma FFA concentrations/lipid oxidation induce hepatic resistance to insulin. We will test this hypothesis by quantitating the effect of insulin on hepatic gluconeogenesis and glycogenolysis following prolonged Intralipid infusion. METHODS: Ten lean healthy non-diabetic subjects and 10 non-diabetic offspring of two diabetic parents will be studied. Subjects will undergo a baseline evaluation consisting of an oral glucose tolerance test and an insulin clamp study. Subjects will then receive an intralipid infusion for eight days to increase the plasma FFA concentration to levels observed in type 2 diabetic individuals. Before and following Intralipid infusion, subjects will receive a four hour euglycemic clamp with tritiated glucose (to measure total hepatic glucose production) and deuterated water (to measure gluconeogenesis) in the basal state and in response to physiologic hyperinsulinemia.