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

项目总结 2型糖尿病(T2D)是一个全球性的健康问题，会导致各种危及生命的并发症。碳水化合物 是主要的能量来源，对血糖和胰岛素分泌有很大影响。的确有 人们普遍认为碳水化合物的数量和质量在控制血糖方面起着关键作用 代谢和确定T2D和糖代谢受损的风险。然而，复杂的关联 具有葡萄糖代谢的碳水化合物可能存在，部分归因于对淀粉的遗传适应 (碳水化合物)-丰富的饮食。唾液和胰腺淀粉酶(由淀粉酶基因AMY1和AMY2编码)是 负责碳水化合物/淀粉的消化。AMY基因表现出拷贝数变异(CNV)，主要 淀粉酶的数量和活性的个体差异。这个项目的首要目标是 前瞻性研究碳水化合物消化测定AMY CNV与膳食的相关性 碳水化合物和淀粉的摄入量(数量和质量)和葡萄糖代谢的纵向变化 以及发生高血糖和T2D的风险。博加卢萨心脏研究是一项正在进行的流行病学研究 在路易斯安那州博加卢萨州的一个混血样本中(35%是黑人，65%是白人)，男性和女性 肥胖和T2D的负担在美国是最高的。AMY1-AMY2 CNV将由一种新的 博加卢萨心脏研究中1250名参与者的Droplet数字聚合酶链式反应方法。这个项目考察了 AMY1-AMY2 CNV与糖代谢标志物(空腹血糖、 血红蛋白A1c、空腹胰岛素和胰岛素抵抗)和发生高血糖和T2D超过7- 9年了。本研究旨在探讨艾米CNV是否通过中介效应影响实验结果。 血浆AMY1和AMY2的酶水平。此外，还将进行前瞻性的基因-饮食相互作用分析。 为了测试饮食中碳水化合物和淀粉的摄入量(数量和质量)是否显著改变了 艾米CNV与结果之间的关系。该项目还利用了循环新陈代谢特征 涵盖了广泛的碳水化合物/葡萄糖代谢途径和与碳水化合物摄入相关的 激素，成纤维细胞生长因子21，作为中介，以测试这些生物标志物是否中介关系 艾米·CNV和结果之间的关系。该项目的发现将导致确定新的 糖代谢受损的危险因素和T2D，推进新型预防和治疗的发展 治疗策略。Cobre的支持将帮助研究项目负责人获得领导 多学科研究项目，发表高质量的研究论文，获得应用的试点数据 为R01提供资金，并转型为一家有竞争力的独立调查员。

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.