Puberty, diabetes, and the kidneys, when eustress becomes distress

当良性压力变成痛苦时，青春期、糖尿病和肾脏

基本信息

批准号：
10654000
负责人：
Petter M Bjornstad
金额：
$ 52.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-27 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654000
关键词：
Acceleration Address Adolescent Adult Biological Markers Carrier Proteins Cessation of life Charge Complex Complication Conceptions Continuous Glucose Monitor Data Development Dextrans Diabetes Mellitus Diabetic Nephropathy Diagnosis Dialysis procedure Distress Energy Metabolism Enrollment Evaluation Exhibits Experimental Designs Frequencies Functional Magnetic Resonance Imaging Glomerular Filtration Rate Glucose tolerance test Glycosylated hemoglobin A Gonadal Steroid Hormones Growth Growth Factor Health Heart Height Hyperglycemia IgG4 Immunoglobulin G Impairment Injury to Kidney Insulin Resistance Insulin-Dependent Diabetes Mellitus Iohexol Kidney Kidney Diseases Knowledge Link Longitudinal Studies Machine Learning Magnetic Resonance Imaging Measurement Metabolic Metabolism Methods Mitochondria Modeling Non-Insulin-Dependent Diabetes Mellitus Obesity Oxygen Oxygen Consumption Pathogenesis Phenotype Physiological Physiological Processes Physiology Prediabetes syndrome Predisposition Puberty Renal Plasma Flow Renal function Research Design Risk Risk Factors Severities Somatotropin Structure Tissues Weight maintenance regimen Youth design epidemiologic data experience follow-up girls hemodynamics high risk high risk population imaging modality insulin sensitivity intravenous glucose tolerance test kidney dysfunction lifetime risk metabolomics modifiable risk multidimensional data novel novel therapeutics obesity development organ growth organ injury premature preservation renal hypoxia reproductive therapeutic target type I and type II diabetes

项目摘要

PROJECT SUMMARY / ABSTRACT: Diabetic kidney disease (DKD) is a common and serious complication in youth with 2 diabetes (T2D). Epidemiological data implicate puberty as a major accelerator of kidney injury in youth with obesity and diabetes, yet the mechanisms by which reproductive maturation results in kidney disease remain unknown. A better understanding of the pubertal mechanisms contributing to kidney disease is needed to promote preservation of native kidney function, especially in high-risk youth with obesity and/or T2D. We hypothesize that youth with obesity and/or T2D experience relative kidney hypoxia during puberty due to a metabolic mismatch between increased renal energy expenditure and impaired substrate metabolism. In turn, the kidney hypoxia results in loss of glomerular charge and size selectivity with increased transglomerular transport of protein, and kidney dysfunction. To address these hypotheses, we propose to design an accelerated longitudinal study in which we will enroll adolescents (8-14 years, 50% girls) with obesity and elevated hemoglobin A1c (HbA1c ≥6%) [n=60], and healthy normal weight controls [n=40] at Tanner (pubertal) stages 1-4 and examine them at baseline, 1 and 2-year follow-up. We will combine state-of- the-art magnetic resonance imaging (MRI) methods for quantifying kidney growth, oxygen availability and hemodynamic function with gold-standard measurements of glomerular filtration rate (iohexol clearance), renal plasma flow (p-aminohippurate clearance), glomerular size and charge selectivity (dextran and IgG/IgG4 clearance) and assessments of insulin sensitivity and mitochondrial function (intravenous glucose tolerance test and metabolomics). These experiments are designed to define the mechanisms contributing to kidney injury during puberty and identify novel risk factors and therapeutic targets to mitigate the development of obesity and diabetes-related nephropathy.

项目摘要/摘要：糖尿病肾病 (DKD) 是青年 2 型糖尿病 (T2D) 患者常见且严重的并发症。流行病学数据表明，青春期是肥胖和青少年肾损伤的主要加速因素。糖尿病，但生殖成熟导致肾脏疾病的机制仍不清楚。需要更好地了解导致肾脏疾病的青春期机制，以促进保护天然肾功能，尤其是患有肥胖和/或 T2D 的高危青少年。我们研究发现，患有肥胖症和/或 T2D 的青少年在青春期会因以下原因而经历相对的肾脏缺氧：肾能量消耗增加和底物代谢受损之间的代谢不匹配。反过来，肾脏缺氧会导致肾小球电荷和尺寸选择性的丧失，并增加为了解决这些假设，我们建议：设计一项加速纵向研究，我们将招募青少年（8-14 岁，50% 女孩）肥胖和血红蛋白 A1c 升高 (HbA1c ≥6%) [n=60]，以及健康正常体重对照 [n=40] Tanner（青春期）第 1-4 阶段并在基线、1 年和 2 年随访时对其进行检查，我们将结合状态。最先进的磁共振成像 (MRI) 方法，用于量化肾脏生长、氧气利用率和血流动力学功能与肾小球滤过率（碘海醇清除率）的金标准测量，肾血浆流量（p-氨基马尿酸清除率）、肾小球大小和电荷选择性（右旋糖酐和 IgG/IgG4 清除率）以及胰岛素敏感性和线粒体功能评估（静脉注射葡萄糖耐受性测试和代谢组学）这些实验旨在确定有助于的机制。青春期肾损伤，并确定新的危险因素和治疗目标以减轻肥胖和糖尿病相关肾病的发展。