Adipose tissue metabolic changes in chronic kidney disease and its contribution to adiponectin resistance and post-transplant diabetes mellitus

项目摘要： 移植后糖尿病（PTDM）是肾移植后的常见诊断， 其病理生理机制尚不清楚。脂肪组织产生多个 参与炎症和葡萄糖代谢的细胞因子或脂肪因子。慢性肾脏 在慢性肾脏病（CKD）中，脂肪组织细胞因子的产生改变。我们已经证明，随着肾功能的丧失 脂肪组织中炎性细胞因子和脂联素的产生增加， 外周肌肉组织脂联素抵抗。我们额外的初步数据表明：1）TNFα水平 与PTDM相关，2）发生PTDM的患者TNFα mRNA表达增加， 与未发生PTDM的人相比，内脏脂肪中的脂联素表达，3）在成肌细胞培养物中， TNFα减弱脂联素衍生的葡萄糖转运。我们的理论是脂联素抵抗在 葡萄糖摄取受损和胰岛素抵抗。此外，在肾移植后，尽管 在肾功能改善的情况下，脂联素抵抗和脂联素 发生PTDM的患者中的产量。我们对这项研究的总体假设是， 介导的脂肪组织炎症和ROS通过促进PTDM的发生而促进PTDM的发生。 肌肉和脂肪组织脂联素抵抗。我们的研究将调查炎症的作用， ROS对脂联素抵抗以及脂肪和肌肉组织代谢表型的影响， 发展PTDM有2个目的：1）确定尿毒症、炎症和/或ROS 我们将促进肌肉和脂肪细胞中的脂联素抗性; i）将肌细胞和脂肪细胞暴露于 尿毒症，炎性细胞因子和ROS与和不与脂联素，ii）研究脂联素下游 细胞因子/尿毒症暴露后的效应物和功能（葡萄糖转运和β-氧化），和iii） 确定抗氧化剂/抗炎治疗是否减轻肌肉/脂肪中的脂联素抵抗 细胞因子/尿毒症。我们还将进行基因调节实验， 蛋白质从炎症途径和抗氧化调节剂，以确定我们是否可以扭转 细胞因子/尿毒症暴露诱导的代谢表型; 2）确定脂肪和 在发生PTDM的患者的肌肉组织中，我们将i）研究巨噬细胞浸润、ROS和ER应激， ii）研究PTDM患者的代谢特征， 研究PTDM患者的肌肉线粒体功能和脂联素途径， 与未患PTDM的患者相比。该项目将开发数据，以填补 了解CKD中影响血糖调节和调节异常的组织代谢变化 导致PTDM的机制。从这项研究中获得的见解将有助于随后的研究， 改善肾移植后代谢并发症的新治疗策略。

Project Summary: Post-transplant diabetes (PTDM), a common diagnosis following kidney transplantation, is strongly associated with adverse outcomes and its pathophysiology is poorly understood. Adipose tissue produces multiple cytokines or adipokines involved in inflammation and glucose metabolism. In patients with chronic kidney disease (CKD), adipose tissue cytokine production is altered. We have shown that with loss of kidney function there is increased production of both inflammatory cytokines and adiponectin in adipose tissue with concurrent adiponectin resistance in peripheral muscle tissue. Our additional preliminary data indicate 1) TNFα levels are associated with PTDM, 2) patients who develop PTDM have increased mRNA expression of TNFα and lower adiponectin expression in visceral fat compared to those who do not develop PTDM, 3) in myoblast culture, TNFα blunts adiponectin derived glucose transport. Our theory is that adiponectin resistance plays a key role in impaired glucose uptake and insulin resistance in CKD. Moreover following kidney transplantation despite improvement in kidney function, there will be a residual imbalance in adiponectin resistance and adiponectin production among patients who develop PTDM. Our overall hypothesis for this study is that CKD mediated adipose tissue inflammation and ROS contribute to development of PTDM by promoting muscle and adipose tissue adiponectin resistance. Our study will investigate the role of inflammation and ROS on adiponectin resistance and also the adipose and muscle tissue metabolic phenotype of patients that develop PTDM in 2 aims: 1) To define mechanistic pathways by which uremia, inflammation and/or ROS promote adiponectin resistance in muscle and adipose cells we will; i) expose myocytes and adipocytes to uremia, inflammatory cytokines and ROS with and without adiponectin, ii) study adiponectin downstream effectors and function (glucose transport and β-oxidation) following cytokine/uremia exposure, and iii) determine if an antioxidant/anti-inflammatory treatment mitigates adiponectin resistance in muscle/adipose cells exposed to cytokines/uremia. We will also conduct genetic modulation experiments by altering key proteins from the inflammatory pathway and antioxidant regulators in order to determine if we can reverse the metabolic phenotype induced by cytokine/uremia exposure; 2) To determine the phenotype of adipose and muscle tissue in patients that develop PTDM, we will i) study macrophage infiltration, ROS, and ER stress in adipose tissue of patients that develop PTDM compared to patients that do not, ii) study the metabolic profile of adipose tissue from PTDM patients, and iii)study muscle mitochondrial function and adiponectin pathway in patients that develop PTDM compared to patients that do not . This project will develop data to fill gaps in knowledge on tissue metabolic changes in CKD that influence glucose regulation and on dysregulatory mechanisms that contribute to PTDM. Insights gained from this study will facilitate subsequent research on novel therapeutic strategies to ameliorate metabolic complications post-kidney transplant.