Quantitative characterization of the liver-pancreas axis in diabetes via multiparametric magnetic resonance elastography

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）与许多代谢途径的损伤密切相关， 包括肝脏胰岛素敏感性和分泌降低，胰高血糖素增加，以及发生2型糖尿病的风险 糖尿病（T2 DM）。相反，糖尿病患者的脂肪性肝炎患病率更高， 肝病分期作为在临床环境中容易检测到的高血糖症的中间状态，前驱糖尿病是 T2 DM之前的疾病，但进展是可变的，可能会随着时间的推移而增加， 危险因素到目前为止，糖尿病前期进展的机制仍然不清楚。我们认为 腹部器官异常沿着肝胰轴的同步成像和胰岛素测量 作用，分泌和肝脏提取可以提供对T2 DM发展的见解，更好地了解T2 DM的作用， NAFLD和糖尿病之间的关系，以及干预糖尿病前期进展的机会。 这项工作的总体目标是开发一种先进的多参数腹部MRE方法， 表征NAFLD中肝-胰轴的病理生理状态和糖尿病前期进展。 ·在目标1中，一种多频率、自导航和混合径向-笛卡尔3D矢量磁共振， 弹性成像（MRE）技术将在肝脏、胰腺和脂肪数据采集方面得到发展和扩展 和图像重建。在MRE驱动程序、成像序列和 重建发展和优化。技术成功的基准将通过重新测试进行评估 重复性和测量一致性研究10例诊断为NAFLD的患者。 ·在目标2中，我们将在一项横断面研究中对肝脏-胰腺轴进行定量成像评估， 150例诊断为NAFLD的患者，具有不同的糖尿病风险或进展（即，50名无糖尿病患者， 50例前驱糖尿病患者，50例糖尿病患者）。实验室和临床数据，以及胰岛素分泌 将在MRI/MRE的30天内收集活动测量值。前驱组织异常和 将训练和评价综合代谢-机械模型，以评估发生T2 DM的风险。 ·在目标3中，假设退出率为20%，我们计划对120名患者进行为期一年的随访检查， 目标2中有基线检查的人。在目标2中训练的模型将进一步调整纵向 MRI/MRE变化，用于评估对组织组成、结构和代谢的双向治疗效应 特征，将细胞、腺体、酶和激素连接到肝-胰轴，从而预测 NAFLD中糖尿病发展的进展或消退方向。 我们预计，该计划将提供多参数MRI/MRE的初步验证和衍生的 替代评估NAFLD中糖尿病进展的肝-胰腺轴。该项目的成功将 还为新兴的治疗干预提供了有价值的非侵入性评估工具。

PROJECT SUMMARY / ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is closely associated with the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and secretion, increased glucagon, and the risk of developing type 2 diabetes mellitus (T2DM). Conversely, patients with diabetes have a higher prevalence of steatohepatitis and end- stage liver disease. As an intermediate state of hyperglycemia easily detectable in clinical settings, prediabetes is the condition that precedes T2DM but the progression is variable, which could increase over time with associated risk factors. To date, the mechanisms underlying prediabetic progression are still not understood. We think simultaneous imaging of the abdominal organs’ abnormalities along the liver-pancreas axis and measures of insulin action, secretion, and hepatic extraction can provide insights into T2DM development, a better understanding of the relationship between NAFLD and diabetes, and an opportunity to intervene in prediabetic progression. The overall goal of this work is to develop an advanced multiparametric abdominal MRE method for characterizing pathophysiologic state of the liver-pancreas axis and prediabetic progression in NAFLD. • In Aim 1, A multifrequency, self-navigating, and hybrid radial-Cartesian 3D vector magnetic resonance elastography (MRE) technology will be developed and expanded on the liver, pancreas and fat data acquisition and image reconstruction. Ten healthy volunteers will be recruited during MRE driver, imaging sequence and reconstruction development and optimization. Benchmark for technical success will be evaluated with a test-retest repeatability and measurement agreement study on ten patients with diagnosed NAFLD. • In Aim 2, We will perform quantitative imaging assessments of the liver-pancreas axis in a cross-sectional study in 150 patients with diagnosed NAFLD with varying risk or progression to diabetes (i.e., 50 patients without diabetes, 50 patients with prediabetes, 50 patients with diabetes). Laboratory and clinical data, as well as insulin secretion and action measurements, will be collected within 30 days of MRI/MRE. Precursory tissue abnormalities and integrative metabolic-mechanical models will be trained and evaluated to assess the risk of developing T2DM. • In Aim 3, assuming 20% withdrawal rate, we plan to have one-year follow-up examinations in 120 patients out of those who have baseline examinations in Aim 2. The models trained in Aim 2 will be further tuned with longitudinal MRI/MRE changes for assessing bi-directional treatment effects on tissue composition, structural and metabolic features, bridging the cellular, gland, enzymes, and hormones to the liver-pancreas axis, thereby predicting progression or regression direction of diabetes development in NAFLD. We anticipate that this program will provide initial validation of multiparametric MRI/MRE and the derived surrogate to assess the liver-pancreas axis of diabetes progression in NAFLD. This project’s success will also provide a valuable noninvasive assessment tool for emerging therapeutic interventions.