ROLE OF NUTRIENTS IN AGE-RELATED INSULIN RESISTANCE

营养过剩和肥胖在胰岛素抵抗综合征的发病机制中起着核心作用，具有重要的年龄相关后遗症，包括加速动脉粥样硬化和2型糖尿病（T2DM），并且是本计划项目的主题。这项计划将研究衰老、肥胖和己糖胺生物合成途径（HBP）在诱导人类营养诱导的胰岛素抵抗中的相互关系。HBP提供细胞“饱腹感”信号，增加循环水平的营养物如葡萄糖和游离脂肪酸，并增加重要细胞内因子（包括转录因子）的糖基化，最终影响许多基因的表达。动物模型中HBP流量增加诱导胰岛素抵抗，并增加脂肪细胞基因表达和许多细胞因子的循环水平 和急性期反应物。这些蛋白质的血浆水平与人类的胰岛素抵抗密切相关，可能导致许多与年龄相关的疾病的病理生理学。重要的是，衰老本身与细胞内蛋白质糖基化的增加有关，这表明HBP的上调，因此增加了对效应的易感性。 营养物质。然而，尚未在人类中建立HBP、营养物质可利用性和衰老诱导的胰岛素抵抗之间的因果关系。我们将在4组受试者中比较增加营养供应对全身胰岛素作用、HBP产物积累和脂肪细胞基因表达的影响：年轻瘦、年轻肥胖、老年瘦 和肥胖的老年人。因此，实验设计将与项目2在随意进食和热量限制的老龄啮齿动物中的实验设计平行。因此，我们将确定是否增加流入HBP介导营养诱导的代谢变化在人类中，以及是否上调HBP与衰老可能加剧营养过剩的代谢影响。此外，我们将检查皮下和内脏脂肪组织，以确定衰老和营养对特定脂肪细胞基因表达的影响。与项目2一起，该项目旨在确定内脏脂肪库的生物学特征，这些特征构成衰老代谢综合征的重要风险因素。

Nutrient excess and obesity play a central role in the pathogenesis of the insulin resistance syndrome, with important age-related sequelae including accelerated atherosclerosis and type 2 diabetes mellitus (T2DM), and is the subject of this Program Project. This proposal will study the interrelationships of aging, obesity and the hexosamine biosynthetic pathway (HBP) in the induction of nutrient-induced insulin resistance in humans. The HBP provides cellular "satiety" signals with increased circulating levels of such nutrients as glucose and free fatty acids, and increases glycosylation of important intracellular factors including transcription factors, ultimately affecting the expression of many genes. Increased HBP flux in animal models induces insulin resistance, and increases adipocyte gene expression and circulating levels of many cytokines and acute phase reactants. These proteins, whose plasma levels are strongly correlated with insulin resistance in humans, likely contribute to the pathophysiology of many age-related diseases. Importantly, aging itself is associated with increased glycosylation of intracellular proteins, suggesting upregulation of the HBP and therefore increased susceptibility to the effects of nutrients. However, a causal link between the HBP, nutrient availability and aging-induced insulin resistance has not yet been established in humans. We will compare the effects of increased nutrient availability on whole-body insulin action, accumulation of HBP products, and adipocyte gene expression in 4 groups of subjects: young lean, young obese, lean elderly and obese elderly. The experimental design will therefore parallel that of Project 2 in aging ad libitum fed and caloric restricted rodents. We will thereby determine whether increased flux into the HBP mediates nutrient-induced metabolic changes in humans, and whether upregulation of the HBP with aging might exacerbate the metabolic impact of nutrient excess. Furthermore, we will examine subcutaneous and visceral adipose tissue to determine effects of aging and nutrients on depot-specific adipocyte gene expression. Together with Project 2, this project aims to define the biological characteristics ot the visceral fat depot that pose significant risk factors for the metabolic syndrome of aging.