Interactions between Sugar-Sweetened Beverage Consumption and ChREBP in the Development of Insulin Resistance

There is current debate over whether excessive intake of added sugars is linked to metabolic syndrome and type 2 diabetes mellitus. The link between these negative health outcomes and sugar-sweetened beverage (SSB) intake has been of particular interest, as SSB are significant contributors to added sugar intake in the United States. Sucrose and high fructose corn syrup (HFCS), the two major sugars in the diet, are disaccharide sugars composed of the monosaccharide sugars glucose and fructose. It has been already established that these monosaccharides increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). Previous work has shown that ChREBP regulates the expression of glycolytic and lipogenic gene programs in an insulin-independent manner. However, the role of genes in maintaining a balance between sugar utilization and sugar-induced metabolic disturbances in the context of high sugar intake is not well established. We hypothesize that the effect of ChREBP on glucose homeostasis and insulin sensitivity is dependent on consumption of sugar intake. In addition, we hypothesize that polymorphisms associated with increased ChREBP activity will reduce glycemia and insulin levels when dietary sugar intake is low. In contrast, activating polymorphisms in ChREBP will increase glycemia and insulin resistance when sugar availability is high. We will use data generated from The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium to examine our hypotheses. Our specific aims are to conduct a meta analysis determining whether polymorphisms in 15 single nucleotide polymorphisms (SNPs) including (1) ChREBP, (2) genes thought to regulate ChREBP activity, or (3) polymorphisms identified as determinants of hypertriglyceridemia interact with SSB to promote insulin resistance. The results of this meta-analysis may serve as preliminary data linking gene-diet interactions to glucose/insulin metabolism and, thus, may lead to specific interventions based on reducing dietary sugar intake in genetically predisposed individuals.