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

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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.