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

项目摘要 糖尿病肾病(DKD)是美国肾功能衰竭的主要原因。目前的治疗方法， 如控制高血糖和高血压，是有益的，但对患有糖尿病的患者只有部分保护作用 2型糖尿病(T2D)。DKD的临床试验结果令人失望，部分原因是有限 对引发DKD的原因的了解，对蛋白尿的潜在误导关注，以及缺乏干预 疾病的早期阶段，最有可能受益。因此，寻找新的治疗靶点来阻碍 DKD的进展仍然是公共卫生的优先事项。包括高滤过在内的早期DKD在年轻人中很常见。 使用T2D。肾脏缺氧，源于肾脏氧利用和消耗之间的不匹配， 越来越多地提出成为DKD发展的统一途径。肾有高能 需要维持正常的血流动力学功能。然而，在T2D中，有新兴的动物数据 肾脏不能充分补偿高滤过和胰岛素抵抗(IR)的影响 关于燃料利用率。青年患者胰岛素抵抗与早期DKD关系的病理生理学基础 T2D尚不清楚，这种关系是否归因于肾内的变化仍未得到证实 血流动力学功能和/或肾脏缺氧。需要专门的翻译研究来解开 T2D中DKD发生的复杂代谢病理生理机制。 比约恩斯塔德博士将自己确立为一名致力于以患者为导向的研究的年轻研究员 重点关注早期DKD。这项K23奖项将为比约恩斯塔德博士提供必要的支持，以实现 以下目标：1)确定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青年与肥胖和瘦对照组的肾脏氧合和血流灌注(通过MRI)，以及 有和没有高滤过的T2D青年之间的关系；3)测试胰岛素敏感性之间的关系(通过 高胰岛素-正常血糖钳夹)，具有肾内血流动力学功能和肾脏氧合功能。 这项建议将为比约恩斯塔德博士提供专门的时间来1)在多个 学科设置整合了内分泌学、肾脏病学、心脏病学和 放射学；2)在以患者为中心的研究方面获得实践经验，包括初级数据收集和 分析、研究设计和实施；3)获得先进和独特的翻译研究专业知识 方法；4)为职业生涯奠定平台，成为专注于介入治疗的独立临床研究员 将测试阻碍早期DKD发展的新疗法的研究。为了实现这些目标，Dr。 比约恩斯塔德组建了一个全国认可的指导团队，由他的主要导师纳多博士领导。 儿科内分泌学副教授和大学肾脏病学部主任约翰逊医生 科罗拉多州丹佛市(UCD)，此外还有一个由Truong博士组成的更广泛的导师团队 (心脏病/放射学，UCD)，Prasad(芝加哥大学放射学)和Cherney(多伦多大学肾脏病)。

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).