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

项目总结： 移植后糖尿病(PTDM)是肾移植后的一种常见诊断，与 其不良后果及其病理生理学还知之甚少。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。在慢性肾脏病患者中 疾病(CKD)，脂肪组织细胞因子的产生发生改变。我们已经证明，随着肾功能的丧失， 同时，脂肪组织中炎性细胞因子和脂联素的产生增加。 周围肌肉组织中的脂联素抵抗。我们的其他初步数据表明：1)肿瘤坏死因子α水平为 与PTDM相关的2)PTDM患者肿瘤坏死因子α的表达增加或降低 脂联素在内脏脂肪中的表达与未发生PTDM的人相比，3)在成肌细胞培养中， 肿瘤坏死因子α钝化脂联素衍生的葡萄糖转运。我们的理论是脂联素抵抗起着关键作用 CKD患者葡萄糖摄取受损和胰岛素抵抗。此外，肾移植后，尽管 肾功能改善，脂联素抵抗与脂联素残留失衡 发展为PTDM的患者的生产。我们对这项研究的总体假设是CKD 介导的脂肪组织炎症和ROS通过促进PTDM的发生发展 肌肉和脂肪组织脂联素抵抗。我们的研究将调查炎症和 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的目标有2个：1)明确尿毒症、炎症和/或ROS的机制 我们将在肌肉和脂肪细胞中促进脂联素抵抗；i)将肌肉细胞和脂肪细胞暴露于 伴有和不伴有脂联素的尿毒症、炎性细胞因子和ROS，II)研究脂联素下游 细胞因子/尿毒症暴露后的效应器和功能(葡萄糖转运和β氧化) 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 暴露于细胞因子/尿毒症的细胞。我们还将通过改变密钥进行遗传调制实验 从炎症途径和抗氧化调节剂中提取蛋白质，以确定我们是否可以逆转 细胞因子/尿毒症暴露诱导的代谢表型；2)测定脂肪和 发生PTDM患者的肌肉组织，我们将I)研究巨噬细胞浸润、ROS和内质网应激在 发生PTDM的患者与未发生PTDM的患者的脂肪组织比较，II)研究 和III)研究PTDM患者肌肉线粒体功能和脂联素途径 患有PTDM的患者与没有PTDM的患者相比。该项目将开发数据以填补空白 慢性肾脏病组织代谢改变影响血糖调节和调节失调的认识 导致PTDM的机制。从这项研究中获得的见解将有助于后续的研究 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.