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) 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之一。肥胖现象日益严重 多见于 1 型糖尿病 (T1D) 儿童。值得注意的是，随着胰岛素减少，肥胖儿童进展为 T1D 的速度更快 与精益同行相比的敏感性。这是有问题的，因为胰岛素敏感性降低 与较高的外源性胰岛素需求、慢性炎症以及较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群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，对 T1D 肠道微生物组进行分析和比较 与瘦人相比，肥胖的年轻人很重要，因为微生物组可能会影响健康。 可修改的。在患有 T1D 的青少年中，除了胰岛素治疗外，使用二甲双胍已被证明可以减少 每日总胰岛素剂量以及改善全身和外周胰岛素敏感性 超重和肥胖。最近，它已被证明在患有 2 型糖尿病的成人中发挥了部分作用， 通过诱导肠道微生物组的变化以及短链脂肪酸 (SCFA) 和胆汁的二次变化 酸（BA）水平。这些变化最终影响胰岛素的分泌和敏感性。然而，尚不清楚 是否在患有肥胖症的 T1D 青少年中也观察到类似的影响。我们假设患有 T1D 的儿童和 与瘦人相比，肥胖者的肠道微生物组特征表现出差异，并且 6 个月的二甲双胍辅助治疗将改变肠道微生物组特征、SCFA 产生和 肥胖 T1D 青少年 BA 库的组成。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 瘦与肥胖 T1D 青少年肠道微生物组的差异，以及这些差异是否与 可修改的。因此，我们的目标是确定：i) 肠道菌群、SCFA 和 BA 谱的差异 瘦与肥胖的 T1D 青少年，以及 ii) 二甲双胍治疗对肠道微生物组 SCFA 的影响 肥胖 T1D 青少年的 BA 概况。我的长期目标是找到改善疾病的新疗法 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 名瘦。他们将按年龄匹配， 性别和种族。对于目标 2，我们将前瞻性地招募目标 1 中肥胖的 T1D 青少年进行临床试验 使用二甲双胍。我们将使用最先进的微生物组分析标记物来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，以充分 登记并分析资助期间收集的样本。因此，这项研究将使我进一步 培养我在 T1D 和肠道微生物组、临床试验开发和 实施并开发与宏基因组测序和生物信息分析相关的新技能。

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.