Effekte von flavonoiden/Polyphenolen auf Transporter und Enzyme der Glucose / Glycogen Homöostase in verschiedenen Zelltypen und im Menschen

计划研究的目的是提高对黄酮类化合物/多酚对转化和非转化细胞系统中葡萄糖和糖原稳态影响的认识。据报道，某些多酚类/类黄酮具有降糖/胰岛素样作用，提示它们可能具有抗糖尿病作用。另一方面，诱导低血糖，特别是在大量摄入此类类黄酮的情况下，可能代表一种健康风险，也值得深入研究。关于多酚对糖原磷酸化酶（GP）、糖原合成酶（GS）和糖原合成酶激酶（GSK3）等调节糖原稳态的关键酶的影响的研究很少。GSK3是糖原合成的重要调节因子。然而，GSK3也参与调控胚胎发生、细胞增殖和凋亡，例如在Wnt信号通路的背景下。在作为Wnt下游效应物的大肠腺瘤性息肉病（APC）复合体中，GSK3是一个重要成分。因此，这些食源性化合物对gsk3活性的调节可能导致一系列下游后果，这取决于细胞/组织环境。由于活性gsk -3 β有助于正常APC复合物功能，确定β -连环蛋白的周转，其抑制可能导致有害影响，例如在结肠细胞中。因此，我们计划研究黄酮类化合物对糖原稳态关键酶（包括gsk -3 β）和细胞葡萄糖转运蛋白的影响，比较不同来源细胞（血液、结肠和肝脏）的反应。比较处理和未处理细胞中糖原稳态的关键酶和调节因子的基因表达谱将有助于识别相关的新生物标志物。此外，细胞下游对转录活性的影响，特别是通过监测β -连环蛋白水平和β -连环蛋白依赖的转录，将被检查。

The aim of the planned study is to enhance knowledge on the effects of flavonoids/polyphenols on glucose and glycogen homeostasis in transformed and non-transformed cell systems. Hypoglycemic/insulin-like effects reported for certain polyphenols/flavonoids are suggestive for their potential usefulness as antidiabetics. On the other hand, induction of hypoglycemia, especially at high intake of such flavonoids might represent a health risk that also deserves thorough investigation. Information on effects of polyphenols on key enzymes regulating glycogen homeostasis, including glycogen phosphorylase (GP), glycogen synthase (GS) and glycogen synthase kinase (GSK3) are scarce. GSK3 is an important regulator of glycogen synthesis. However, GSK3 is also involved in regulating embryogenesis, cell proliferation and apoptosis e.g. within the context of the Wnt signaling pathway. In the adenomatous polyposis coli (APC) complex as a downstream effector of Wnt, GSK3 is an important constituent.Modulation of GSK3-activity by such food borne compounds may therefore lead to a spectrum of downstream consequences, depending on the cellular/tissue context. Because active GSK-3beta is instrumental for normal APC complex function, ascertaining beta-catenin turnover, its inhibition could lead to detrimental effects e.g. in colon cells. We therefore plan to study effects of flavonoids on key enzymes of glycogen homeostasis (including GSK-3beta) and on cellular glucose transporters, comparing responses in cells of different origin (blood, colon and liver). Comparison of gene expression profiles of key enzymes and regulators of glycogen homeostasis from treated and non-treated cells will help to identify relevant novel biomarkers. Moreover, cellular downstream effects on transcriptional activity, especially by monitoring beta-catenin levels and beta-catenin dependent transcription, will be examined.