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: 10674064
• 负责人: Hebatullah Ismail
• 金额: $ 18.22万
• 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/10674064
• 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; Fatty Acids; Feces; Functional disorder; Funding; Gluconeogenesis Inhibition; 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; Prevalence; Probiotics; Production; Proinsulin; Public Health; Race; Research; Risk; Role; Sampling; Serum; Taxonomy; Therapeutic; Thinness; Volatile Fatty Acids; Work; Youth; beta diversity; 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

项目成果

Gut microbial changes associated with obesity in youth with type 1 diabetes.

• DOI: 10.1101/2023.12.01.23299251
• 发表时间: 2023-12
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Heba M Ismail;Dimuthu Perera;Rabindra K. Mandal;Linda A. DiMeglio;C. Evans-Molina;Tamara Hannon