The Gut Microbiome in Lean and Obese Youth with Type 1 Diabetes and Novel Mechanism of Action of Metformin

项目摘要 有证据表明，1型糖尿病（T1D）的风险和进展与肠道细菌失衡有关。 肠道微生物组的差异也与肥胖有关，并被认为是导致肥胖的原因。肥胖症越来越多 在T1D儿童中普遍存在。值得注意的是，肥胖儿童在胰岛素减少的情况下更快地进展到T1D 敏感性相比，他们瘦同行。这是有问题的，因为胰岛素敏感性降低 与更高的外源性胰岛素需求、慢性炎症以及更高的低血糖风险相关， 血脂异常和长期糖尿病并发症。目前尚不清楚肠道微生物组在多大程度上发挥作用 T1D青少年的肥胖及其更糟糕的结果。因此，分析和比较T1D中的肠道微生物组 与瘦的同龄人相比，肥胖的年轻人很重要，因为微生物组可能 可修改.在T1D青少年中，除胰岛素治疗外，二甲双胍的使用已被证明可降低 每日胰岛素总剂量以及改善全身和外周胰岛素敏感性， 超重和肥胖最近，在患有2型糖尿病的成年人中，它已被证明部分发挥其作用， 通过诱导肠道微生物组的变化以及短链脂肪酸（SCFA）和胆汁的继发性变化， 酸（BA）水平。这些变化最终影响胰岛素的分泌和敏感性。但不清楚 是否在患有肥胖症的T1D青年中观察到类似的效果。我们假设，患有T1D的儿童和 肥胖者与瘦的肥胖者相比，其肠道微生物组特征存在差异， 二甲双胍辅助治疗6个月将改变肠道微生物组特征、SCFA产生和 肥胖T1D青年中BA池的组成。我们的初步数据支持差异的存在 在这两组的微生物组中。拟议研究的具体目标是确定 T1D青少年中瘦型与肥胖型肠道微生物组的差异，以及这些差异是否 可修改.因此，我们的目的是确定：i）在不同的肠道微生物组，SCFA和BA谱的差异， 瘦型与肥胖型T1D青年，以及ii）二甲双胍治疗对肠道微生物组SCFA的影响 T1D肥胖青年的BA和BA特征。我的长期目标是找到新的治疗方法来改善疾病 管理对于目标1，我们将招募84名患有T1D的青少年，其中42名肥胖，42名消瘦。他们将根据年龄匹配， 性别和种族对于目标2，我们将在临床试验中前瞻性招募目标1中招募的肥胖T1D青少年 使用二甲双胍。我们将使用最先进的微生物组分析标志物分析粪便和血清样本， 宏基因组学和代谢组学。我们已经制定并确定了明确的计划和预算， 登记和分析在资助期间收集的样本。因此，这项研究将使我能够进一步 发展我在T1D和肠道微生物组领域的研究技能，临床试验开发和 实施和发展与宏基因组测序和生物信息学分析相关的新技能。

PROJECT ABSTRACT Evidence suggests that type 1 diabetes (T1D) risk and progression are associated with gut bacterial imbalance. Gut microbiome differences are also associated with and thought to contribute to obesity. Obesity is increasingly prevalent among children with T1D. Notably, obese children progress faster to T1D with reduced insulin sensitivity compared to their lean counterparts. This is problematic because reduced insulin sensitivity is associated with higher exogenous insulin needs, chronic inflammation as well as higher risk for hypoglycemia, dyslipidemia and long-term diabetes complications. It is unknown to what extent the gut microbiome plays a role in obesity in T1D youth and their worse outcomes. Therefore, profiling and comparing the gut microbiome in T1D youth who are obese compared to their lean counterparts is important since the microbiome is potentially modifiable. In adolescents with T1D, metformin use, in addition to insulin therapy, has been shown to reduce total daily insulin doses as well as improve whole-body and peripheral insulin sensitivity in those who were overweight and obese. More recently, in adults with type 2 diabetes, it has been shown to exert its effect in part, by inducing changes in the gut microbiome with secondary changes in short chain fatty acid (SCFA) and bile acid (BA) levels. These changes ultimately affect insulin secretion and sensitivity. However, it is unknown whether similar effects are seen in T1D youth with obesity. We hypothesize, that children with T1D and obesity, as compared to their lean counterparts, exhibit differences in their gut microbiome profile and that metformin adjuvant therapy for 6 months will alter the gut microbiome profile, SCFA production and composition of the BA pool in obese T1D youth. Our preliminary data supports the presence of differences in the microbiome in these two groups. The specific objective of the proposed research is to determine differences in the gut microbiome in T1D youth who are lean versus obese and whether these differences are modifiable. We, therefore, aim to determine: i) the differences in the gut microbiome, SCFA and BA profile in T1D youth who are lean versus obese, and ii) the effects of metformin treatment on the gut microbiome, SCFA and BA profile in T1D youth with obesity. My long-term goal is to identify novel treatments to improve disease management. For aim 1, we will enroll 84 youth with T1D, 42 obese and 42 lean. They will be matched by age, sex and race. For aim 2, we will prospectively enroll T1D youth enrolled in aim 1 who are obese in a clinical trial using metformin. We will analyze stool and serum samples using state-of-the-art markers of microbiome profiling, metagenomics, and metabolomics. We have developed and identified a clear plan and budget to adequately enroll and analyze samples collected during the funding period. Therefore, this study will allow me to further develop my research skills in the area of T1D and the gut microbiome, clinical trial development and implementation and develop new skills related to metagenomic sequencing and bioinformatic analysis.