Anthocyanins, Macronutrient Utilization and Insulin Sens

胰岛素抵抗是代谢综合征的一个重要病理生理特征，与心血管危险因素并存和动脉粥样硬化加速密切相关。通过药物手段改善胰岛素抵抗的策略代表了临床医学的传统方法。然而，由于普通公众广泛使用膳食补充剂，营养补充剂与使用植物药物的营养补充 增加胰岛素敏感性是一种有吸引力的干预代谢综合征发展的新方法。我们在小鼠身上进行的假说生成研究的结果表明，补充花青素可能会增加胰岛素敏感性，减少异位脂肪。参与碳水化合物和脂肪酸代谢的基因在肝脏中发生了变化，这与胰岛素敏感性的增加是一致的。在心脏中，参与脂肪酸摄取和氧化的基因增加，这与外周脂肪酸利用增加是一致的。此外，在我们的初步研究中观察到的基因表达模式表明，特定的转录因子参与其中，包括但不限于固醇调节元件结合蛋白-1c、PPAR-γ共激活-1α和-1β。最后，组织培养研究(3T3-L1)表明，花青素逆转了脂肪酸介导的抑制胰岛素信号、糖原积累和脂联素分泌的作用。我们推测，花青素通过调节特定转录因子如肝脏x受体、过氧化物酶体增殖物激活受体(PPARpha、PPARDelta、PPARGamma)、固醇调节元件结合蛋白(SREBP)-1c、PPARGamma辅活化子-1α和-1β的活性，增加脂肪酸的外周氧化，从而减少异位脂肪在肌肉和肝脏中的堆积，影响胰岛素信号转导，并改善整体胰岛素敏感性。我们建议进行一系列动物和细胞培养研究，旨在批判性地评估这一总体假设及其推论。我们的具体目标如下：1)检测半纯化葡萄花青素制剂对胰岛素抵抗小鼠的胰岛素敏感性、能量消耗、脂肪酸和碳水化合物的氧化和处置以及组织脂质积累的影响；2)在相关细胞培养模型中，评价半纯化葡萄花青素制剂对转录因子、基因表达水平、蛋白质丰度、胰岛素受体信号转导途径和底物代谢的影响。3)鉴定花色苷制剂中与观察到的基因表达和底物代谢变化有关的活性成分(S)。因此，我们的研究计划旨在全面评估花色苷在导致胰岛素抵抗和代谢综合征发展的致病机制中的作用，并评估其作用的细胞机制。

Insulin resistance is a key pathophysiologic feature of the "metabolic syndrome" and is strongly associated with co-existing cardiovascular risk factors and accelerated atherosclerosis. Strategies to improve insulin resistance by pharmacological means have represented the traditional approach for clinical medicine. However, because of the widespread use of dietary supplements by the general public, nutritional supplementation with the use of botanicals that increase insulin sensitivity represent an attractive and novel approach for intervention of the development of metabolic syndrome. Results of our hypothesis generating studies in mice suggest that anthocyanin supplementation may increase insulin sensitivity and decrease ectopic fat. Genes involved in carbohydrate and fatty acid metabolism were altered in the liver, consistent with increased insulin sensitivity. In the heart, genes involved in fatty acid uptake and oxidation were increased, consistent with increased peripheral fatty acid utilization. Furthermore, the pattern of gene expression observed in our preliminary studies suggests involvement of specific transcription factors including, but not limited to sterol regulatory element binding protein-1c, PPAR-gamma coactivatory-1alpha and -1beta. Finally, tissue culture studies (3T3-L1) demonstrated that anthocyanins reverse the fatty acid mediated suppression of insulin signaling, glycogen accumulation and adiponectin secretion. We hypothesize that anthocyanins, through modulation of the activities of specific transcription factors such as liver x-receptor, peroxisome proliferators activated receptors (PPARalpha, PPARdelta, PPARgamma), sterol regulatory element binding protein (SREBP)-1c, PPARgamma coactivator-1alpha and -1beta, increase the peripheral oxidation of fatty acids and thereby decrease ectopic fat accumulation in muscle and liver, affect insulin signaling, and improve overall insulin sensitivity. We propose to conduct a series of animal and cell culture studies designed to critically evaluate this overall hypothesis and its corollaries. Our specific aims are as follows: 1) To examine the in vivo effects of a semipurified grape anthocyanin preparation on insulin sensitivity, energy expenditure, fatty acid and carbohydrate oxidation and disposal, and tissue lipid accumulation in a mouse model of insulin resistance; 2) To evaluate the effects of a semipurified grape anthocyanin preparation on transcription factors, gene expression levels, protein abundance, intracellular pathways of insulin receptor signaling, and substrate metabolism in relevant cell culture models. 3) To identify the active component(s) within the anthocyanin preparation responsible for the observed changes in gene expression and substrate metabolism. Thus, our research plan is designed to comprehensively evaluate the effect of anthocyanins on pathogenic mechanisms leading to the development of insulin resistance and metabolic syndrome, and evaluates the cellular mechanisms of action for their effects.