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Understanding and Targeting the Pathophysiology of Youth-onset Type 2 Diabetes-Texas Children's Center.

了解并针对青年发病 2 型糖尿病的病理生理学 - 德克萨斯儿童中心。

基本信息

批准号：
10583407
负责人：
FIDA BACHA
金额：
$ 5.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-05 至 2029-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583407
关键词：
19 year old Adult Age Algorithms Behavioral Beta Cell Biochemical Black race Body Composition Body fat Catecholamines Cell physiology Child Childhood Clinical Collaborations Collection Communities Complex Conceptions County DNA Methylation Deposition Deterioration Development Diagnosis Disease Disease Outcome Dual-Energy X-Ray Absorptiometry Early identification Enrollment Ensure Environmental Risk Factor Epigenetic Process Equilibrium Evolution Failure Family Fatty acid glycerol esters Functional disorder Genetic Gestational Diabetes Goals Gonadal Steroid Hormones Growth Factor Growth and Development function Health Insurance Health Surveys Hepatic Hispanic Hormonal Hormones Hydrocortisone Individual Inflammation Insulin Resistance Intervention Investigation Knowledge Latino Longitudinal Surveys Magnetic Resonance Imaging Measurement Measures Mediating Metabolic Methodology Methylation Mission Modeling Non-Insulin-Dependent Diabetes Mellitus Not Hispanic or Latino OGTT Obesity Onset of illness Organ Pathogenesis Pathway interactions Pediatric Hospitals Phenotype Physiological Population Prediabetes syndrome Predisposing Factor Predisposition Prevalence Prevention Process Puberty Research Design Research Infrastructure Research Personnel Resources Risk Risk Factors Standardization Stress Surveys Texas United States National Institutes of Health Variant Visceral fat Youth abdominal fat adverse childhood events clinical center clinical phenotype cohort comorbidity design diabetes pathogenesis disease phenotype disorder risk epigenetic marker epigenetic regulation ethnic diversity ethnic minority falls federal poverty level glucose tolerance glycemic control health determinants high risk hypothalamic-pituitary-adrenal axis improved indexing innovation insight insulin secretion insulin sensitivity inter-individual variation maternal obesity member multidisciplinary novel patient population peripheral blood personalized intervention predicting response prediction algorithm predictive modeling prevent progression risk puberty transition racial minority recruit risk prediction risk stratification social social factors social health determinants stem success treatment strategy urinary

项目摘要

Project Summary Youth-onset type 2 diabetes (T2D) is a heterogeneous disease, more rapidly progressive than adult-onset disease, and is associated with increased comorbidities. Yet, it is not clear which high-risk youth will eventually progress to T2D. T2D pathogenesis is related to complex hormonal mechanisms that result in β-cell dysfunction, influenced by genetic, epigenetic, social and environmental factors. The overarching goal of this proposal is to prevent youth-onset T2D. Our aims are to identify the risk factors and pathophysiologic changes that lead to the development of youth-onset T2D. We will collaborate as a member of a consortium of clinical centers to achieve these aims. We will leverage our community and stakeholders’ engagement, our robust research infrastructure and the diverse high-risk patient population at our Center, to recruit a high-risk diverse cohort of children from early through mid-puberty (age range 8 to 14 years, Tanner stage II-IV at enrollment), with normal glucose tolerance and with prediabetes. We will screen 300 children aiming to retain 200 children longitudinally, perform in-depth assessments and survey them for the progression to T2D. We will investigate complementary pathways which, by disrupting the delicate balance between insulin sensitivity and secretion, are most likely to modulate the risk of progression to T2D in youth. To that end, we will 1) characterize the evolution of β-cell dysfunction in relation to changes in adiposity, sex steroids and growth factors during the pubertal transition. We will combine clinical phenotypes with physiologic measures of glucose tolerance, β-cell function and insulin sensitivity (derived from serial oral glucose tolerance tests), circulating metabolites, body composition and abdominal fat changes (dual-energy X-ray absorptiometry and magnetic resonance imaging); 2) employ novel epigenetic markers of DNA methylation at correlated regions of systemic interindividual variation (CoRSIVs) to evaluate epigenetic changes that may predispose to β-cell dysfunction; and 3) evaluate social and behavioral determinants of health that could lead to long-term disease phenotype through promotion of adiposity and activation of the hypothalamic-pituitary-adrenal axis (as measured by urinary catecholamines and cortisol), and inflammation pathways. Our innovative study design will allow us to determine the evolution of the risk factors for youth-onset T2D during the pubertal transition, the underlying metabolic changes, and the modifying social and environmental effects, in the context of genetic/epigenetic susceptibility. The findings from this study are highly significant to improve the identification of high-risk children vulnerable to progression to T2D, and characterize the pathophysiology of the disease during a critical window of childhood growth and development. The knowledge gained will allow the consortium to develop risk stratification algorithms and design personalized precision interventions, to prevent youth-onset T2D.

项目总结