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

患有 1 型糖尿病的瘦和肥胖青年的肠道微生物组和二甲双胍的新作用机制

• 批准号: 10525313
• 负责人: Hebatullah Ismail
• 金额: $ 18.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525313
• 关键词: Adjuvant Therapy; Adolescent; Adult; Affect; Age; Area; Bacteria; Beta Cell; Bile Acids; Bioinformatics; Budgets; C-Peptide; Child; Chronic; Clinical Trials; Complications of Diabetes Mellitus; Data; Development; Diagnosis; Diagnostic; Disease; Disease Management; Dose; Dyslipidemias; Enrollment; Exhibits; Feces; Functional disorder; Funding; Gluconeogenesis; Goals; Health; Hormone secretion; Hypoglycemia; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Link; Measures; Metabolic; Metagenomics; Metformin; Modality; Modification; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Pathway interactions; Peripheral; Persons; Play; Prevalence; Probiotics; Production; Proinsulin; Public Health; Race; Research; Risk; Role; Sampling; Serum; Taxonomy; Therapeutic; Thinness; Volatile Fatty Acids; Work; Youth; base; cohort; diabetes risk; dysbiosis; fecal microbiome; feeding; genome sequencing; gut bacteria; gut microbiome; high risk; improved; incretin hormone; insulin secretion; insulin sensitivity; metabolomics; metagenomic sequencing; microbiome; microbiome analysis; microbiome composition; novel; obesity in children; prospective; recruit; sex; skills; stool sample; whole genome

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.

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有助于肥胖。肥胖越来越多 T1D儿童中普遍存在。值得注意的是，肥胖儿童以减少胰岛素的速度更快地发展到T1D 与他们的精益相比，灵敏度。这是有问题的，因为降低的胰岛素敏感性是 与较高的外源胰岛素需求，慢性炎症以及低血糖症的风险相关， 血脂血症和长期糖尿病并发症。肠道微生物组在多大程度上发挥作用是未知的 在T1D青年中的肥胖症及其更糟的结果。因此，分析和比较T1D中的肠道微生物组 肥胖的年轻人与瘦弱的年轻人很重要，因为微生物组可能是 可修改。在具有T1D的青少年中，除胰岛素治疗外，二甲双胍的使用已被证明可减少 每日胰岛素总剂量以及改善那些人的全身和周围胰岛素敏感性 超重和肥胖。最近，在患有2型糖尿病的成年人中，它已显示出其作用部分，部分作用 通过诱导肠道微生物组的变化，短链脂肪酸（SCFA）和胆汁的次要变化 酸（BA）水平。这些变化最终会影响胰岛素的分泌和敏感性。但是，这是未知的 在肥胖症的T1D青年中是否看到类似的影响。我们假设有T1D和 与瘦肉相比，肥胖症在其肠道微生物组概况和 二甲双胍佐剂治疗6个月将改变肠道微生物组的概况，SCFA产生和 肥胖T1D青年中BA池的组成。我们的初步数据支持存在差异 在这两组中的微生物组中。拟议研究的具体目标是确定 T1D年轻人与肥胖的T1D青年的肠道微生物组的差异以及这些差异是否为 可修改。因此，我们的目的是确定：i）肠道微生物组，SCFA和BA轮廓的差异 瘦肉与肥胖的T1D青年，以及ii）二甲双胍治疗对肠道微生物组的影响 T1D青年肥胖症的BA概况。我的长期目标是确定新的治疗方法以改善疾病 管理。对于AIM 1，我们将注册84名T1D，42肥胖和42个精益的青年。它们将按年龄匹配， 性与种族。对于AIM 2，我们将前瞻性地注册T1D青年参加AIM 1，他们肥胖参加了临床试验 使用二甲双胍。我们将使用微生物组分析的最新标记来分析粪便和血清样品， 宏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 在资金期间注册和分析采集的样品。因此，这项研究将使我进一步 在T1D和肠道微生物组，临床试验开发以及 实施和发展与宏基因组测序和生物信息学分析有关的新技能。