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。 肠道微生物群的差异也与肥胖有关，并被认为是肥胖的原因。肥胖症日益严重 在患有T1D的儿童中流行。值得注意的是，肥胖儿童进展到T1D的速度更快，胰岛素减少 与苗条的同龄人相比，他们更敏感。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有关， 血脂异常和糖尿病的长期并发症。目前还不清楚肠道微生物群在多大程度上起到了作用 T1D青少年的肥胖及其更糟糕的结局。因此，对T1D的肠道微生物群进行了分析和比较 与苗条的年轻人相比，肥胖的年轻人很重要，因为微生物群有可能 可修改的。在患有T1D的青少年中，除了胰岛素治疗外，二甲双胍的使用已被证明可以减少 每日总胰岛素剂量以及改善全身和外周胰岛素敏感性的那些 超重和肥胖。最近，在患有2型糖尿病的成年人中，它被证明在一定程度上发挥了作用， 通过引起肠道微生物群的变化，继而引起短链脂肪酸(SCFA)和胆汁的变化 酸(BA)水平。这些变化最终会影响胰岛素的分泌和敏感性。然而，它是未知的 肥胖的T1D青少年是否也有类似的影响。我们假设，患有T1D和 与苗条的同龄人相比，肥胖者的肠道微生物群组和 二甲双胍辅助治疗6个月将改变肠道微生物组分布，SCFA产生和 肥胖T1D青年的BA池组成。我们的初步数据支持存在差异 在这两组的微生物群中。拟议研究的具体目标是确定 T1D瘦与肥胖青年肠道微生物群的差异以及这些差异是否 可修改的。因此，我们的目标是确定：i)肠道微生物组、SCFA和BA图谱的差异 T1D的年轻人是瘦的还是肥胖的，以及II)二甲双胍治疗对肠道微生物群的影响 肥胖青年T1D组的BA谱。我的长期目标是找到新的治疗方法来改善疾病 管理层。对于目标1，我们将招募84名患有T1D的年轻人，42名肥胖者和42名瘦子。他们将在年龄上相匹配， 性和种族。对于AIM 2，我们将前瞻性地招募在AIM 1中登记的肥胖T1D青少年参加临床试验 使用二甲双胍。我们将使用最先进的微生物组图谱标记来分析粪便和血清样本， 元基因组学和代谢组学。我们已经制定并确定了一个明确的计划和预算，以充分 登记和分析在资助期内收集的样本。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 实施和发展与元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.