Investigating metabolic responses to high sugar diets and the onset of diabetic phenotypes

项目摘要 2型糖尿病（T2 D）是一种进行性代谢疾病，其特征在于从糖尿病患者的肾脏分泌的胰岛素不足。 胰腺B细胞，外周组织中胰岛素敏感性降低（即，胰岛素抵抗），以及禁食 和餐后高血糖。尽管T2 D的表型和负面结果已经被 广泛研究，生活方式，营养和遗传风险因素相互作用触发的机制， T2 D发病和早期进展仍然知之甚少。例如，尽管GWAS研究 确定了数百个可能在T2 D中发挥作用的基因座，假定的遗传风险因素之间的相互作用， 并且内分泌信号、代谢流和营养加工难以在体内研究。而且由于 T2 D涉及多个器官系统的代谢功能障碍，包括胰腺、肌肉、肝脏、心脏， 肠、白色脂肪组织、肾脏和大脑，遗传研究必须考虑细胞和组织， 特殊基因功能考虑到目前世界人口的10%以上患有某种形式的 糖尿病，其中大多数人被认为患有T2 D，全球迫切需要有效地 快速确定遗传风险因素、基因与饮食的相互作用以及组织特异性基因的破坏 功能诱导T2 D的发作和进展。我们正在通过使用多组学来满足这一需求， 对果蝇（Drosophila melanogaster）的代谢基因进行全基因组研究，目标是 确定代谢酶和小分子转运蛋白，有助于发病和进展， 2型糖尿病我们会采用三管齐下的方法进行这些研究。首先，我们将使用一种新型的高通量 代谢组学方法与果蝇TRiP RNAi收集相结合，以确定个体 代谢酶和转运蛋白保护动物细胞免受过量糖的消耗。我们 代谢组学方法将与snRNAseq互补，促进组织和细胞的发现， 个别酶/转运蛋白防止HSD有害作用的特定机制。 最后，我们将在官方的FlyBase中策划一套标准的果蝇代谢途径图。 果蝇知识库，它将告知本提案中的实验数据， 为更广泛的研究社区提供了宝贵的生物信息学资源。一旦完成，我们的研究将 已经产生了有史以来在动物中进行的最全面的体内代谢研究之一， 大大推进了我们对过量糖消费如何重新连接中介的理解， 个别细胞类型的代谢，并确定了新的代谢机制，过量的糖 糖尿病和其他代谢性疾病。

Project Summary Type 2 diabetes (T2D) is a progressive metabolic disease characterized by deficient insulin secretion from the pancreatic b-cells, decreased insulin sensitivity in peripheral tissues (i.e., insulin resistance), and both fasting and postprandial hyperglycemia. Although the phenotypes and negative outcomes surrounding T2D have been extensively studied, the mechanisms by which lifestyle, nutrition, and genetic risk factors interact to trigger the onset and early progression of T2D remain poorly understood. For example, although GWAS studies have identified hundreds of loci that potentially play a role in T2D, interactions between putative genetic risk factors and endocrine signaling, metabolic flux, and nutrient processing are difficult to study in vivo. Moreover, since T2D involves metabolic dysfunction in multiple organ systems, including the pancreas, muscle, liver, heart, intestine, white adipose tissue, kidneys, and brain, genetic studies must account for the cell- and tissue- specific gene functions. Considering that >10% of the world population currently suffers from some form of diabetes, with most of these individuals assumed to have T2D, there is a pressing global need to efficiently and rapidly determine how genetic risk factors, gene-by-diet interactions, and disruptions of tissue-specific gene function induce the onset and progression of T2D. We are addressing this need by using multi-omics to conduct a genome-wide study of metabolic genes in the fruit fly Drosophila melanogaster, with the goal of identifying metabolic enzymes and small molecule transporters that contribute to onset and progression of T2D. We will use a three-prong approach to spearhead these studies. First, we will use a novel high-throughput metabolomics method combined with the Drosophila TRiP RNAi collection to determine how individual metabolic enzymes and transporters protect animal cells against excess sugar consumption. Our metabolomics approach will be complemented with snRNAseq, facilitating the discovery of tissue- and cell- specific mechanisms by which individual enzymes/transporters guard against the detrimental effects of a HSD. Finally, we will curate a canonical set of Drosophila metabolic pathway diagrams within FlyBase, the official Drosophila knowledgebase, which will inform and be informed by the experimental data in this proposal, and provide an invaluable bioinformatic resource for broader research community. Once completed, our studies will have generated one of the most comprehensive in vivo metabolic studies ever conducted in animals, significantly advanced our understanding of how excess sugar consumption rewires the intermediary metabolism of individual cell types, and identified novel metabolic mechanism by which excess sugar consumption contributes to T2D and other metabolic diseases.