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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).

项目摘要糖尿病肾病（DKD）是美国肾衰竭的主要原因。目前的治疗方法，例如控制高血糖症和高血压，是有益，但在患有 2型糖尿病（T2 D）。DKD的临床试验取得了令人失望的结果，部分原因是有限的了解什么引发DKD，对蛋白尿的潜在误导性关注，以及缺乏干预，最有可能获益的疾病早期阶段。因此，确定新的治疗靶点， DKD的进展仍然是公共卫生的优先事项。早期DKD，包括超滤，在青年中很常见关于T2 D肾缺氧，源于肾氧利用和消耗之间的不匹配，越来越多地被认为是DKD发展的统一途径。肾脏具有高能量维持正常血流动力学功能的要求。然而，在T2 D中，有新兴的动物数据，肾脏不能充分补偿超滤和胰岛素抵抗（IR）的影响燃料利用率。青年型糖尿病肾病早期与胰岛素抵抗关系的病理生理学研究 T2 D尚不清楚，其关系是否归因于肾内血液动力学功能和/或肾缺氧。需要专门的翻译研究来解开 T2 D中DKD发展背后的复杂代谢病理生理学。博士比约恩斯塔德是建立自己作为一个年轻的调查谁是致力于以病人为导向的研究专注于早期DKD。这项K23奖将为Bjornstad博士提供必要的支持，目的：1）测定肾内血流动力学功能（碘海醇和对氨基马尿酸 2）T2 D青年与肥胖和瘦对照组的肾氧合和灌注（通过MRI），以及有和没有超滤的T2 D青年之间的关系; 3）测试胰岛素敏感性（通过高胰岛素-正葡萄糖钳夹）与肾内血流动力学功能和肾氧合。该提案将为Bjornstad博士提供专门的时间，以1）在多学科领域进行转化研究，学科设置，整合了内分泌学，肾脏病学，心脏病学和放射学; 2）在以患者为导向的研究中获得实践经验，包括原始数据收集，分析，研究设计和执行; 3）获得先进和独特的转化研究的专业知识方法; 4）作为一名独立的临床研究者，专注于介入治疗，这些研究将测试阻止早期DKD发展的新疗法。为了实现这些目标，博士。比约恩斯塔德组建了一个由他的主要导师纳多博士领导的全国公认的指导团队，儿科内分泌学副教授和大学肾脏科主任约翰逊博士科罗拉多，丹佛（UCD），此外，更广泛的导师团队组成的博士。（心脏病学/放射学，UCD），普拉萨德（放射学，U。of芝加哥）和Cherney（Nephrology，U.（来自多伦多）。

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）

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

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：

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

Dapagliflozin in young people with type 2 diabetes.