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，包括动脉粥样硬化加速和2型糖尿病（T2DM），是本项目的主题。本课题将研究衰老、肥胖和己糖胺生物合成途径（HBP）在诱导营养性胰岛素抵抗中的相互关系。HBP通过增加葡萄糖和游离脂肪酸等营养物质的循环水平提供细胞“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通量增加可诱导胰岛素抵抗，并增加脂肪细胞基因表达和许多细胞因子的循环水平

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.