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

• 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
• 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

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).

项目概要 糖尿病肾病（DKD）是美国肾衰竭的主要原因。目前的治疗方法， 例如控制高血糖和高血压，是有益的，但对患有糖尿病的患者仅具有部分保护作用。 2 型糖尿病 (T2D)。 DKD 的临床试验取得了令人失望的结果，部分原因是有限的 对引发 DKD 的原因的理解、对蛋白尿的潜在误导性关注以及缺乏干预 最有可能受益的疾病早期阶段。因此，确定新的治疗靶点以阻止 DKD 的进展仍然是公共卫生优先事项。早期 DKD，包括超滤，在青少年中很常见 与 T2D。肾缺氧是由于肾氧利用和消耗之间的不匹配而引起的 越来越多的人认为这是 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需要。然而，在 T2D 中，新出现的动物数据表明 肾脏无法充分补偿超滤和胰岛素抵抗 (IR) 的影响 关于燃料利用。 IR 与青年发病的早期 DKD 之间关系的病理生理学 T2D 尚不清楚，并且尚未证实这种关系是否归因于肾内变化 血流动力学功能和/或肾缺氧。需要专门的转化研究来阐明 T2D 中 DKD 发展背后的复杂代谢病理生理学。 Bjornstad 博士正在将自己打造成一名致力于以患者为中心的研究的年轻研究者 专注于早期DKD。该 K23 奖项将为 Bjornstad 博士提供实现这一目标所需的支持 目标如下： 1) 定义肾内血流动力学功能（通过碘海醇和对氨基马尿酸 清除）; 2) T2D 青少年与肥胖和瘦对照者的肾脏氧合和灌注（通过 MRI），以及 有和没有超滤的 T2D 青少年之间； 3）测试胰岛素敏感性之间的关联（通过 高胰岛素-正常血糖钳夹）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来 1）在多个领域进行转化研究 学科设置整合了内分泌学、肾脏病学、心脏病学和 放射学； 2）获得以患者为导向的研究的实践经验，包括原始数据收集和 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) 为专注于介入治疗的独立临床研究者的职业生涯奠定平台 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。 Bjornstad 组建了一支全国认可的导师团队，由他的主要导师 Nadeau 博士领导， 大学儿科内分泌学副教授和肾内科主任 Johnson 博士 科罗拉多州丹佛市 (UCD)，此外还有一个由 Drs 组成的更广泛的导师团队。长 （心脏病学/放射学，都柏林大学）、Prasad（芝加哥大学放射学）和 Cherney（多伦多大学肾脏病学）。

项目成果

Elevated plasma cyclic guanosine monophosphate may explain greater efferent arteriolar tone in adults with longstanding type 1 diabetes: A brief report.

血浆环磷酸鸟苷升高可能可以解释患有长期 1 型糖尿病的成人传出小动脉张力增大：一份简短报告。

• 发表时间: 2019
• 影响因子: 3
• 作者: Bjornstad, Petter;Lovshin, Julie A;Lytvyn, Yuliya;Lovblom, Leif E;Scarr, Daniel;Boulet, Geneviève;Farooqi, Mohammed A;Orszag, Andrej;Bai, Johnny;Weisman, Alanna;Keenan, Hillary A;Brent, Michael H;Paul, Narinder;Bril, Vera;Perkins, Bruce
• 通讯作者: Perkins, Bruce

Serum uromodulin is associated with urinary albumin excretion in adolescents with type 1 diabetes.

血清尿调节素与 1 型糖尿病青少年的尿白蛋白排泄有关。

• 发表时间: 2019
• 影响因子: 3
• 作者: Wiromrat, Pattara;Bjornstad, Petter;Roncal, Carlos;Pyle, Laura;Johnson, Richard J;Cherney, David Z;Lipina, Tyler;Bishop, Franziska;Maahs, David M;Wadwa, R Paul
• 通讯作者: Wadwa, R Paul

Fructose tolerance test in obese people with and without type 2 diabetes.

患有和不患有 2 型糖尿病的肥胖人群的果糖耐受性测试。

• 发表时间: 2020-03
• 作者: Al;Rivard, Christopher J;Sanchez Lozada, Laura Gabriela;Lanaspa, Miguel A;Bjornstad, Petter;Al Salem, Danah;Alhubail, Asma;Megahed, Amira;Kuwabara, Masanari;Johnson, Richard J;Asad, Reem A
• 通讯作者: Asad, Reem A

Tubular injury in diabetic ketoacidosis: Results from the diabetic kidney alarm study.

糖尿病酮症酸中毒中的肾小管损伤：糖尿病肾脏警报研究的结果。

• 发表时间: 2021
• 影响因子: 3.4
• 作者: Piani, Federica;Melena, Isabella;Severn, Cameron;Chung, Linh T;Vinovskis, Carissa;Cherney, David;Pyle, Laura;Roncal;Lanaspa, Miguel A;Rewers, Arleta;van Raalte, Daniël H;Obeid, Wassim;Parikh, Chirag;Nelson, Robert G;Pavkov
• 通讯作者: Pavkov

Atherosclerosis and Microvascular Complications: Results From the Canadian Study of Longevity in Type 1 Diabetes.

动脉粥样硬化和微血管并发症：加拿大 1 型糖尿病长寿研究的结果。

• 发表时间: 2018
• 影响因子: 16.2
• 作者: Lovshin, Julie A;Bjornstad, Petter;Lovblom, Leif E;Bai, Johnny;Lytvyn, Yuliya;Boulet, Geneviève;Farooqi, Mohammed A;Santiago, Sam;Orszag, Andrej;Scarr, Daniel;Weisman, Alanna;Keenan, Hillary A;Brent, Michael H;Paul, Narinder;Bril, Vera
• 通讯作者: Bril, Vera