Understanding and Targeting the Pathophysiology of Youth-onset Type2 Diabetes

了解并针对青年发病 2 型糖尿病的病理生理学

• 批准号: 10583413
• 负责人: Michael Isaac Goran
• 金额: $ 6.53万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-21 至 2029-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583413
• 关键词: Abdomen; Adipose tissue; Adolescent; Adult; Air Pollutants; Air Pollution; Beta Cell; Biochemical Markers; Bioinformatics; Biological; Biopsy; Body fat; California; Cell physiology; Child; Childhood; Childhood diabetes; Clinical; Collaborations; Collection; Communities; Continuous Glucose Monitor; DNA; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet; Dietary Sugars; Dual-Energy X-Ray Absorptiometry; Endocrine Disruptors; Environmental Exposure; Environmental Risk Factor; Enzymes; Ethnic Origin; Ethnic Population; Etiology; Exposure to; Family; Family dynamics; Family history of; Fasting; Fatty acid glycerol esters; Feces; Functional disorder; Funding; Future; Gender; Glucose; Glycosylated hemoglobin A; Goals; Gonadal Steroid Hormones; Health; Health Food; Image; Individual; Inflammatory; Insulin Resistance; Intervention; Investigation; Knowledge; Latino; Latino Population; Life Style; Lipids; Liver; Longitudinal Studies; Los Angeles; Magnetic Resonance Imaging; Measurement; Measures; Medical Care Costs; Metabolic; Metabolic Marker; Methods; Minority Groups; Modeling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; OGTT; Obesity; Obesity Epidemic; Outcome Measure; Pancreas; Participant; Physical activity; Plasma; Poly-fluoroalkyl substances; Population; Population Heterogeneity; Populations at Risk; Predictive Factor; Predisposition; Prevention; Prevention strategy; Protocols documentation; Puberty; Publications; Race; Resources; Risk; Risk Factors; Saliva; Sampling; Site; Sleep; Structure; Subgroup; Time; Underserved Population; Urine; Visceral; Work; Youth; biobank; biomarker discovery; biomarker identification; clinical center; cohort; critical developmental period; design; diabetes risk; diagnostic criteria; experience; food environment; glycemic control; high risk; improved; insulin secretion; metabolic phenotype; multidisciplinary; obesity risk; predictive marker; recruit; risk prediction; screening; sex; social determinants; social factors; social health determinants; specific biomarkers; subcutaneous; tool

Type 2 diabetes (T2D) in childhood has an aggressive etiology, with substantial short- and long-term health complications and medical costs. There is an urgent need to: 1) identify children and adolescents at highest risk; 2) identify modifiable contributing factors; 3) understand the underlying pathophysiology; and, 4) determine how these factors vary across sex and race/ethnicity. A comprehensive and holistic understanding of these issues is required to develop models that can identify individual factors and susceptible time windows for T2D conversion and requires a nationwide effort and multidisciplinary consortium. We propose to serve as 1 of the 15 Clinical Centers operating within the proposed NIDDK consortium that will recruit and track a national cohort of children (estimate = 3,750) representing the diversity of the pediatric population at risk for T2D. Our multidisciplinary team has extensive expertise in longitudinal studies of obesity and diabetes in children, including an NIDDK-funded 15-year longitudinal study (R01 DK 59211; PI: Goran) that followed a cohort of 300 Latino children at risk for T2D, resulting in almost 100 publications. From this and other prior studies, we have identified the need for a larger and more diverse cohort, incorporation of environmental exposures, and inclusion of comprehensive nutritional, metabolic, and social determinants. At our site, we will recruit 250 participants with obesity and family history of T2D with bi-annual assessments. We will work with stakeholders and other consortium sites to optimize recruitment and retention. We propose three complementary approaches to assess the metabolic basis of T2D: insulin secretion, clearance, and β-cell function from an oral glucose tolerance test with frequent sampling; hemoglobin A1c, and percent time in range from continuous glucose monitoring. We will monitor metabolic and environmental factors by measuring: 1) total body fat, visceral and subcutaneous abdominal adipose tissue, and liver and pancreatic fat by DEXA and MRI; 2) biochemical markers (free fatty acids, sex steroids, lipids, inflammatory profiles, incretins, and liver enzymes); 3) lifestyle (diet, sleep, and physical activity); 4) exposure to endocrine-disrupting chemicals and air pollution; 5) social determinants of health. In addition, we propose collection of biological samples (eg DNA, stool, saliva) to create a biobank for future investigation. We will work with the consortium to develop a unified protocol and harmonized outcome measures. We hypothesize: 1) Children who develop T2D will have a greater pubertal decline in β-cell function, and decreased glucose time-in-range, which will be associated with greater increase in overall adiposity and liver fat, compared to children who do not develop T2D, and that these relationships will differ across sex and ethnicity; and, 2) High dietary sugar, limited access to healthy foods, and higher exposure to perfluoroalkyl substances and/or air pollutants will also be associated with risk of T2D. Through harnessing the power of this consortium, we also propose development of a structured risk score analysis to characterize different endotypes, exposures and risk factors that predict progression to T2D during pubertal development.

儿童期 2 型糖尿病 (T2D) 具有侵袭性病因，具有显着的短期和长期影响 迫切需要： 1) 确定儿童和青少年的健康状况。 最高风险；2) 确定可改变的影响因素；3) 了解潜在的病理生理学；4) 确定这些因素在性别和种族/民族之间的差异。对这些因素有全面而全面的了解。 这些问题需要开发模型来识别个体因素和易受影响的时间窗口 T2D 转换需要全国范围内的努力和多学科联盟，我们建议作为其中之一。 拟议的 NIDDK 联盟内运营的 15 个临床中心将招募和跟踪全国 儿童队列（估计 = 3,750）代表了有 T2D 风险的儿科人群的多样性。 多学科团队在儿童肥胖和糖尿病的纵向研究方面拥有广泛的专业知识，包括 NIDDK 资助的一项为期 15 年的纵向研究（R01 DK 59211；PI：Goran）跟踪了 300 名拉丁裔人群 儿童有患 T2D 的风险，我们从这项研究和之前的其他研究中发现了近 100 篇出版物。 需要更大、更多样化的群体、纳入环境暴露以及纳入 全面的营养、代谢和社会决定因素 在我们的网站，我们将招募 250 名参与者。 我们将与利益相关者和其他方面合作，对肥胖和 T2D 家族史进行每两年一次的评估。 我们提出了三种互补的评估方法。 T2D 的代谢基础：口服葡萄糖耐量试验的胰岛素分泌、清除和 β 细胞功能 频繁采样；血红蛋白 A1c，以及连续血糖监测范围内的时间百分比。 通过以下测量来监测代谢和环境因素：1) 全身脂肪、内脏脂肪和皮下脂肪 通过 DEXA 和 MRI 检测腹部脂肪组织、肝脏和胰腺脂肪；2) 生化标记物（游离脂肪） 酸、性类固醇、脂质、炎症特征、肠促胰岛素和肝酶）；3）生活方式（饮食、睡眠和 4) 接触内分泌干扰化学品和空气污染； 5) 社会决定因素 此外，我们建议收集生物样本（例如DNA、粪便、唾液）来创建生物库。 我们将与该联盟合作制定统一的协议和统一的结果。 我们采取了以下措施：1) 患有 T2D 的儿童青春期 β 细胞功能会出现更大程度的下降， 以及葡萄糖时间范围内的减少，这将与整体肥胖和肥胖的更大增加有关 与未患 T2D 的儿童相比，肝脏脂肪含量不同，并且这些关系因性别和性别而异 种族；以及，2) 高膳食糖分，获得健康食品的机会有限，以及接触更多的全氟烷基 通过利用这种力量，物质和/或空气污染物也将与 T2D 风险相关。 联盟，我们还建议开发结构化风险评分分析来表征不同的内型， 预测青春期发育期间进展为 T2D 的暴露和危险因素。