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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：
10272687
负责人：
Petter M Bjornstad
金额：
$ 52.71万
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/10272687
关键词：
Address Adolescent Adult Biological Markers Carrier Proteins Cessation of life Charge Complex Complication Conceptions Data Development Dextrans Diabetes Mellitus Diabetic Nephropathy Diagnosis Dialysis procedure Distress Energy Metabolism Enrollment Evaluation Exhibits Frequencies Functional Magnetic Resonance Imaging Glomerular Filtration Rate Glucose tolerance test Glycosylated hemoglobin A Gold 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 Puberty Renal Plasma Flow Renal function Research Design Risk Risk Factors Severities Somatotropin Structure Tissues Weight maintenance regimen Youth design epidemiologic data experience experimental study follow-up girls glucose monitor 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：