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

项目总结:

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.