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，并有重要的年龄相关后遗症，包括动脉粥样硬化加速和2型糖尿病(T2 DM)，也是本计划项目的主题。这项建议将研究衰老、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通过增加循环中葡萄糖和游离脂肪酸等营养物质的水平，为细胞提供“饱腹感”信号，并增加包括转录因子在内的重要细胞内因子的糖基化，最终影响许多基因的表达。动物模型中HBP流量增加导致胰岛素抵抗，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，可能与许多与年龄相关的疾病的病理生理有关。重要的是，衰老本身与细胞内蛋白质的糖基化增加有关，这意味着HBP的上调，因此增加了对这种影响的易感性。 营养物质。然而，在人类中，HBP、营养可获得性和衰老诱导的胰岛素抵抗之间的因果关系尚未确定。我们将在4组受试者中比较营养供应增加对全身胰岛素作用、HBP产物的积累和脂肪细胞基因表达的影响：年轻瘦肉者、年轻肥胖者、瘦削老年人。 和肥胖的老年人。因此，实验设计将与项目2类似，用于随意喂养和限制卡路里的老化啮齿动物。因此，我们将确定进入HBP的流量增加是否介导了营养诱导的人类代谢变化，以及随着年龄的增长HBP的上调是否会加剧营养过剩的代谢影响。此外，我们将研究皮下和内脏脂肪组织，以确定衰老和营养物质对库特异性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性，这些特性对衰老的代谢综合征构成重要的风险因素。

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.