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。 目的/背景：2型糖尿病以肝脏胰岛素抵抗为特征。2型糖尿病患者的基础FFA水平/脂质氧化水平也升高，对胰岛素的反应无法正常抑制。先前的研究表明，血浆FFA浓度升高和/或脂质氧化损害了2型糖尿病受试者胰岛素抑制肝脏葡萄糖产生的能力。然而，目前尚不清楚血浆FFA水平升高和/或脂质氧化或这些异常的某些后果是否会促进糖异生或糖原分解。同样不清楚的是，在两个糖尿病父母的胰岛素抵抗的正常糖耐量的后代中，血浆FFA浓度升高/脂质氧化是否导致肝脏对胰岛素的抵抗。我们将通过量化胰岛素在长时间注射Intralipid后对肝脏糖异生和糖原分解的影响来验证这一假设。 方法：对10例瘦身健康的非糖尿病受试者和10例糖尿病双亲的非糖尿病子女进行研究。受试者将接受由口服葡萄糖耐量试验和胰岛素钳试验组成的基线评估。然后受试者将接受为期8天的脂肪输注，以将血浆FFA浓度提高到在2型糖尿病患者中观察到的水平。在注射Intralipid之前和之后，受试者将在基础状态和生理性高胰岛素血症中接受四小时的正常血糖钳夹，其中含有氚葡萄糖(用于测量肝脏总葡萄糖产量)和氚水(用于测量糖异生)。

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.