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

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

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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：糖尿病肾脏疾病（DKD）是2种糖尿病（T2D）青年的常见和严重并发症。流行病学数据暗示青春期是肥胖症青年肾损伤的主要加速器糖尿病，但是复制成熟导致肾脏疾病的机制仍然未知。需要更好地了解导致肾脏疾病的青春期机制以促进保存本地肾脏功能，尤其是在肥胖和/或T2D的高风险青年中。我们假设患有肥胖和/或T2D的青年在青春期期间相对肾脏缺氧肾脏能量消耗增加与底物代谢受损之间的代谢不匹配。转弯，肾脏缺氧导致肾小球电荷的丧失和尺寸选择性随着增加而增加蛋白质和肾功能障碍的跨斜体转运。为了解决这些假设，我们建议设计一项加速的纵向研究，我们将在其中注册青少年（8-14岁，50％的女孩）肥胖和血红蛋白A1c升高（HBA1C≥6％）[n = 60]，健康的正常体重对照[n = 40] Tanner（青春期）第1-4阶段，并在基线，1和2年的随访中对其进行检查。我们将结合最新 ART磁共振成像（MRI）方法，用于量化肾脏生长，氧气可用性和血液动力学功能，具有肾小球滤过率的金标准测量（iohexol清除率），肾脏血浆流（p-氨基酸盐清除率），肾小球尺寸和电荷选择性（葡聚糖和 IgG/IgG4清除率）和胰岛素敏感性和线粒体功能的评估（静脉葡萄糖耐受性测试和代谢组学）。这些实验旨在定义有助于青春期期间的肾脏损伤，并确定新颖的危险因素和治疗靶点以减轻肥胖和与糖尿病有关的肾病的发育。