Puberty, diabetes, and the kidneys, when eustress becomes distress

项目摘要/摘要： 糖尿病肾病(DKD)是青年2型糖尿病(T2D)患者常见而严重的并发症。 流行病学数据表明，青春期是肥胖和青春期青少年肾脏损伤的主要加速因素 糖尿病，但生殖成熟导致肾脏疾病的机制仍不清楚。 需要更好地了解青春期导致肾脏疾病的机制，以促进 保护天然肾功能，特别是在肥胖和/或T2D的高危青年中。 我们假设肥胖和/或T2D的青少年在青春期经历了相对的肾脏缺氧，这是由于 肾脏能量消耗增加和底物代谢受损之间的代谢不匹配。在……里面 反过来，肾脏缺氧导致肾小球电荷丢失和大小选择性增加 蛋白跨肾小球转运与肾功能障碍。为了解决这些假设，我们建议 设计一项加速的纵向研究，我们将招募青少年(8-14岁，50%为女孩) 肥胖和糖化血红蛋白升高(HbA1c≥6%)[n=60]，健康正常体重对照组[n=40] Tanner(青春期)1-4期，并在基线、1年和2年随访时进行检查。我们将结合国家- 最先进的磁共振成像(MRI)方法，以量化肾脏生长，氧气利用率和 血流动力学功能-肾小球滤过率(碘海醇清除率)的金标准测量， 肾血浆流量(对氨基马尿酸清除量)、肾小球大小和电荷选择性(右旋糖苷和 Ig G/Ig G4清除)以及胰岛素敏感性和线粒体功能的评估(静脉葡萄糖 耐受性试验和代谢组学)。这些实验的目的是为了确定有助于 青春期肾脏损伤，找出新的危险因素和治疗目标，以减轻 肥胖和糖尿病相关肾病的发展。

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.