Metabolic Pathways in Carbohydrate Digestion-Related Amylase Variation and Type 2 Diabetes

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PROJECT SUMMARY Type 2 diabetes (T2D) is a global health issue causing a variety of life-threatening complications. Carbohydrates are the primary energy source and have substantial effects on blood glucose and insulin secretion. There is widespread consensus that the quantity and quality of carbohydrates play a pivotal role in controlling glucose metabolism and determining risks of T2D and impaired glucose metabolism. However, complex associations of carbohydrates with glucose metabolism may exist, partly attributable to genetic adaptation to starch (carbohydrate)-rich diets. Salivary and pancreatic amylases (encoded by amylase genes AMY1 and AMY2) are responsible for carbohydrate/starch digestion. The AMY genes exhibit copy number variations (CNVs), leading to individual differences in the amount and activity of amylase enzymes. The overarching goal of this project is to prospectively investigate interrelations between the carbohydrate-digestion determining AMY CNVs, dietary intakes of carbohydrates and starch (both quantity and quality), and longitudinal changes in glucose metabolism and risks of incident hyperglycemia and T2D. The Bogalusa Heart Study is an ongoing epidemiological study among a biracial sample (35% Black and 65% White) of men and women in Bogalusa, Louisiana, a state with the highest burden of obesity and T2D in the United States. The AMY1-AMY2 CNVs will be measured by a novel droplet digital PCR approach in 1250 participants of the Bogalusa Heart Study. This project examines associations of AMY1-AMY2 CNVs with subsequent changes in markers of glucose metabolism (fasting glucose, hemoglobin A1c, fasting insulin, and insulin resistance) and the risks of incident hyperglycemia and T2D over 7- 9 years. This project investigates whether the AMY CNVs influence the outcomes through mediating effects on plasma enzymatic levels of AMY1 and AMY2. Also, prospective gene-diet interactions analyses will be performed to test whether dietary intakes of carbohydrate and starch (both quantity and quality) significantly modify the relations between the AMY CNVs and the outcomes. This project also utilizes circulating metabolomic signatures covering a broad range of carbohydrate/glucose metabolism pathways and a carbohydrate-intake-related hormone, fibroblast growth factor 21, as mediators to test whether these biomarkers mediate the relations between the AMY CNVs and the outcomes. The findings of this project would lead to the identification of new risk factors for impaired glucose metabolism and T2D and advance the development of novel preventive and therapeutic strategies. The COBRE support will help the Research Project Leader acquire experience leading a multidisciplinary research project, publishing high-quality research papers, and obtaining pilot data for applying for R01 funding and transitioning into a competitive independent investigator.