Impact of the gut microbiome and diet on change in insulin homeostasis and cardiometabolic risk

项目摘要 不能增加胰岛素分泌和降低胰岛素清除率以克服组织胰岛素抵抗导致 2型糖尿病（T2 D）的发展。胰岛素轴的组成部分（胰岛素敏感性，胰岛素分泌， 胰岛素清除率）对T2 D的发生至关重要，但导致其功能障碍及其 与其他因素的相互作用尚不清楚。饮食中的营养成分通过 肠道屏障与肠道微生物群（微生物组）复杂相互作用，影响葡萄糖 体内平衡我们的假设是，三个胰岛素轴性状的变化与肠道微生物 组成和功能，并且这种关联通过膳食组分（例如，全谷物，红肉） 包括由肠道微生物群产生的系统性短链脂肪酸。这项研究将评估胰岛素 轴，肠道微生物群和饮食在一个队列的500名非糖尿病成年人（一半非洲裔美国人，一半非 西班牙裔白色）超过2.5年（在三个时间点采样）。具体目标1将在每个诊所实施 访视，75 g口服葡萄糖激发，0、30、60、120 min测量（胰岛素、葡萄糖和C肽） 确定胰岛素敏感性、分泌和清除;将使用经验证的 食物频率问卷。具体目标2将通过以下方式表征每位参与者的肠道微生物组： 对收集的粪便样品进行16 S rDNA测序和低通宏基因组测序， 三次访问。总之，这些数据将检验增加胰岛素抵抗，受损胰岛素 随着时间的推移，胰岛素分泌和胰岛素清除率降低（所有致糖尿病变化）与 随着减少的（在基线）或下降的（随着时间的推移）丰度的短链脂肪酸生产细菌， 肠道，部分原因是不健康的饮食模式。具体目标3将利用在 三个时间点，通过进行深层宏基因组研究来探测肠道微生物组的功能谱 对180名患有以下疾病的人的循环短链脂肪酸水平进行测序和评估 极端变化（增加和减少）与胰岛素轴性状无变化的人相比，从而确定 微生物功能的变化与胰岛素轴性状的稳定性。这项研究影响很大， 产生可以导致新的基于微生物组的诊断、预防和/或治疗的知识 措施（例如，特定饮食;抗生素或益生菌治疗），以减少T2 D的公共卫生负担。

PROJECT SUMMARY Failure to increase insulin secretion and reduce insulin clearance to overcome tissue insulin resistance leads to the development of type 2 diabetes (T2D). Components of the insulin axis (insulin sensitivity, insulin secretion, insulin clearance) are critical to the genesis of T2D, yet the factors that account for their dysfunction and their interactions with other factors are not understood. The nutritional components of diet pass through the intestinal barrier in a complex interaction with the gut microbiota (the microbiome) to impact glucose homeostasis. Our hypothesis is that change in three insulin axis traits is associated with gut microbial composition and function, and this association is modified by dietary components (e.g., whole grains, red meat) including systemic short chain fatty acids produced by the gut microbiota. This study will assess the insulin axis, the gut microbiota and diet in a cohort of 500 non-diabetic adults (half African American, half non- Hispanic White) over 2.5 years (sampled at three time points). Specific Aim 1 will administer, at each clinic visit, a 75-g oral glucose challenge with 0, 30, 60, 120 min measurements (of insulin, glucose, and C-peptide) to determine insulin sensitivity, secretion, and clearance; habitual diet will be determined by use of a validated Food Frequency Questionnaire. Specific Aim 2 will characterize the gut microbiome for each participant by performing 16S rDNA sequencing and low-pass metagenomic sequencing on stool samples collected at all three visits. Together, these data will test the hypothesis that increased insulin resistance, impaired insulin secretion, and decreased insulin clearance (all diabetogenic changes) developing over time are associated with a reduced (at baseline) or declining (over time) abundance of short chain fatty acid-producing bacteria in the gut, in part attributable to unhealthy dietary patterns. Specific Aim 3 will utilize samples collected at the three time points to probe the functional profile of the gut microbiome by conducting deep metagenomic sequencing and assessment of circulating short chain fatty acid levels in a subset of 180 individuals with extreme changes (increase and decrease) versus those with no change in insulin axis traits, thereby identifying microbial functions that underlie change versus stability in insulin axis traits. This study has high impact, yielding knowledge that can lead to novel microbiome-based diagnostics, prevention, and/or treatment measures (e.g., specific diets; antibiotic or probiotic treatment) to reduce the public health burden of T2D.