Renal HEIR Study: Renal Hemodynamics, Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes Study

肾脏 HEIR 研究：青年发病 2 型糖尿病研究中的肾脏血流动力学、能量学和胰岛素抵抗

基本信息

批准号：
10397016
负责人：
Petter M Bjornstad
金额：
$ 19.22万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397016
关键词：
Address Adipose tissue Adolescent Adult Albuminuria Automobile Driving Beta Cell Blood Plasma Volume Cardiology Chicago Childhood Clinical Investigator Clinical Trials Closure by clamp Colorado Complex Consumption Data Data Analyses Data Collection Development Diabetic Nephropathy Disease Endocrinology Equation Experimental Models Functional disorder Glomerular Filtration Rate Glucose Glucose Clamp Goals Gold Health High Prevalence Hyperglycemia Hypergravity Hypertension Insulin Resistance Intervention Intervention Studies Iohexol Kidney Kidney Diseases Kidney Failure Learning Magnetic Resonance Imaging Measures Mentored Patient-Oriented Research Career Development Award Mentors Metabolic Methodology Methods Nephrology Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Obesity Epidemic Oxygen Pathology Pathway interactions Patients Performance Perfusion Peripheral Persons Phenotype Prevalence Radiology Specialty Renal Plasma Flow Research Research Design Research Methodology Research Personnel Resistance Risk Techniques Testing Thinness Time Tissues Training Translational Research United States Universities Youth animal data arterial spin labeling blood oxygen level dependent career experience fatty acid oxidation hemodynamics improved insulin sensitivity lifetime risk mid-career faculty mortality multidisciplinary new therapeutic target non-diabetic novel therapeutic intervention novel therapeutics oxidation patient oriented research pre-clinical pressure public health priorities renal damage renal hypoxia standard measure stem therapeutically effective translational study

项目摘要

Project Summary Diabetic kidney disease (DKD) is the leading cause of renal failure in the United States. Current treatments, such as control of hyperglycemia and hypertension, are beneficial, but only partially protective in patients with type 2 diabetes (T2D). Clinical trials in DKD have yielded disappointing results, partly due to limited understanding of what initiates DKD, a potentially misguided focus on albuminuria, and lack of intervention at an early stage of disease when benefit is most likely. Therefore, identifying new therapeutic targets to impede progression of DKD remains a public health priority. Early DKD, including hyperfiltration, is common in youth with T2D. Renal hypoxia, stemming from a mismatch between renal oxygen utilization and consumption, is increasingly proposed to be a unifying pathway in the development of DKD. The kidneys have a high-energy requirement to sustain normal hemodynamic function. However, in T2D, there are emerging animal data that the kidneys are not able to sufficiently compensate for hyperfiltration and the effects of insulin resistance (IR) on fuel utilization. The pathophysiology underlying the relationship between IR and early DKD in youth-onset T2D is unclear, and it remains unproven whether the relationship is attributed to changes in intrarenal hemodynamic function and/or renal hypoxia. Dedicated translational studies are needed to unravel the complex metabolic pathophysiology behind the development of DKD in T2D. Dr. Bjornstad is establishing himself as a young investigator who is committed to patient-oriented research focused on early DKD. This K23 award would provide Dr. Bjornstad with the support necessary to accomplish the following goals: 1) to define intrarenal hemodynamic function (by iohexol and para-aminohippurate clearance); 2) renal oxygenation and perfusion (by MRI) in T2D youth vs. obese and lean controls, and between T2D youth with and without hyperfiltration; 3) to test the associations between insulin sensitivity (by hyperinsulinemic-euglycemic clamp) with intrarenal hemodynamic function and renal oxygenation. This proposal will provide dedicated time for Dr. Bjornstad to 1) perform translational research in a multi- disciplinary setting that integrates expertise from the fields of endocrinology, nephrology, cardiology and radiology; 2) gain hands-on experience in patient-oriented research, including primary data collection and analysis, study design, and execution; 3) acquire expertise in advanced and unique translational research methods; 4) set the platform for a career as an independent clinical investigator focused on interventional studies that will test novel therapies to impede the development of early DKD. To achieve these goals, Dr. Bjornstad has assembled a nationally-recognized mentoring team led by his primary mentors, Dr. Nadeau, Associate Professor of Pediatric Endocrinology and Dr. Johnson, Chief of Division of Nephrology at University of Colorado, Denver (UCD), in addition a broader mentor team composed of Drs. Truong (Cardiology/Radiology, UCD), Prasad (Radiology, U. of Chicago) and Cherney (Nephrology, U. of Toronto).

项目摘要糖尿病肾脏疾病（DKD）是美国肾衰竭的主要原因。当前治疗，例如控制高血糖和高血压，是有益的，但仅在患有 2型糖尿病（T2D）。 DKD中的临床试验产生了令人失望的结果，部分原因是了解启动DKD的原因，潜在地误导了对蛋白尿的关注，以及缺乏干预措施疾病的早期阶段很可能是有益的。因此，确定新的治疗靶标的 DKD的进展仍然是公共卫生的重点。早期DKD，包括过滤在内，在青年中很常见与T2D。肾脏缺氧是由于肾脏氧利用和消费之间的不匹配而引起的，越来越多地认为是DKD发展的统一途径。肾脏具有高能维持正常血液动力学功能的要求。但是，在T2D中，有一些新兴的动物数据肾脏无法充分补偿过滤和胰岛素抵抗的影响（IR）在燃料利用率上。 IR与青年发病的IR与早期DKD之间关系的病理生理学 T2D尚不清楚，并且该关系是否归因于肾脏的变化仍然未证实血液动力学功能和/或肾脏缺氧。需要专门的翻译研究来揭示 DKD在T2D中的发展背后的复杂代谢病理生理学。 Bjornstad博士正在建立自己是一名年轻的调查员，他致力于以患者为导向的研究专注于早期DKD。该K23奖将为Bjornstad博士提供完成所需的支持以下目标：1）定义肾内血液动力学功能（由Iohexol和Para-Aminohippurate作者清除）; 2）T2D青年与肥胖控制和益年控制中的肾脏氧合和灌注（由MRI）以及在T2D青年之间有和没有过度滤清的青年； 3）测试胰岛素敏感性之间的关联（通过具有肾内血液动力学功能和肾脏氧合的高胰岛素血糖夹）。该提案将为Bjornstad博士提供专门的时间，1）纪律环境，集成了内分泌，肾脏学，心脏病学领域的专业知识放射学； 2）在以患者为导向的研究中获得动手实践经验，包括主要数据收集和分析，研究设计和执行； 3）获得高级和独特的转化研究专业知识方法; 4）为专注于介入的独立临床调查员设定了职业平台将测试新疗法以阻止早期DKD发展的研究。为了实现这些目标，博士 Bjornstad召集了由他的主要导师Nadeau博士领导的全国认可的指导团队小儿内分泌学副教授和大学肾脏科主任约翰逊博士丹佛（UCD）的科罗拉多州，还有一个由DRS组成的更广泛的导师团队。 Truong （心脏病学/放射学，UCD），Prasad（芝加哥美国放射学）和Cherney（多伦多大学肾脏科）。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of Glomerular Permselectivity in Type 2 Diabetes Associates With Progression to Kidney Failure.

2 型糖尿病肾小球通透性丧失与肾衰竭进展相关。

DOI：
10.2337/db23-0310
发表时间：
2023
期刊：
Diabetes
影响因子：
7.7
作者：
Saulnier,PierreJ;Looker,HelenC;Layton,Anita;Lemley,KevinV;Nelson,RobertG;Bjornstad,Petter
通讯作者：
Bjornstad,Petter

Youth versus adult-onset type 2 diabetic kidney disease: Insights into currently known structural differences and the potential underlying mechanisms.

DOI：
10.1042/cs20210627
发表时间：
2022-11-11
期刊：
Clinical science (London, England : 1979)
影响因子：
0
作者：
通讯作者：

Importance of standardizing renal outcomes in clinical trials: illustration by recent sodium glucose cotransporter 2 inhibitor studies.

DOI：
10.1016/j.kint.2020.12.006
发表时间：
2021-03
期刊：
Kidney international
影响因子：
19.6
作者：
van Raalte DH;Bjornstad P;Heerspink HJL;Persson F;Cherney DZI
通讯作者：
Cherney DZI

Tubular Secretion Markers, Glomerular Filtration Rate, Effective Renal Plasma Flow, and Filtration Fraction in Healthy Adolescents.

DOI：
10.1016/j.xkme.2020.05.013
发表时间：
2020-09
期刊：
Kidney medicine
影响因子：
3.9
作者：
Seegmiller JC;Wolfe BJ;Albtoush N;Melena I;Gross SP;Vinovskis C;Ix JH;Bjornstad P
通讯作者：
Bjornstad P

Dapagliflozin in young people with type 2 diabetes.