Despite recent advances in diabetes therapy, diabetes in the majority of patients is poorly controlled. This failure to achieve optimum glycemic control partly results from the limitations in our understanding of diabetes pathophysiology and gaps in understanding molecular mechanisms of action of conventional treatments. The overall objective (immediate career goal) of this K01 application is to identify the implication of dipeptidyl peptidase 4 (DPP4) non-catalytic activity in type 2 diabetes Mellitus (T2DM) and test its potential to be a novel therapeutic target which could limit metabolic inflammation in T2DM. In this application, we posit a key role for DPP4 in the pathogenesis of T2DM. Our overarching hypothesis is driven by three key sets of preliminary data: a) DPP4 on immune cells was up-regulated in both circulation and visceral adipose tissue of diabetic humans, correlating strongly with markers of insulin resistance, b) Activation of Toll-like receptor/MyD88 pathway increased DPP4 expression and deficiency of MyD88 improved incretin-mediated blood glucose lowering effect through down-regulation of DPP4. c) DPP4 exacerbated adipose inflammation and insulin resistance through catalytic independent interaction with adenosine deaminase (ADA). We propose to test the significance of T cell-expressing DPP4 as part of an ongoing inter-disciplinary investigation that will significantly enhance my training and propel my career towards ultimate goal (to be an independent scientist working in translational diabetes research involving multiple disciplines):
In Aim 1, we will explore the mechanisms by which DPP4 is up-regulated in T2DM and test the contribution of T cell derived DPP4 to pathogenesis of T2DM. Our hypothesis is that postprandial remnant lipoprotein in T2DM increases DPP4 expression via TLR/MyD88 pathway.
In Aim 2, we hypothesize that T cell DPP4 promotes inflammation & insulin resistance through its non-catalytic function, forming a feed-forward loop to exacerbate T2DM. DPP4 non-catalytic function enhances T cell inflammation by interacting with ADA. By using DPP4-/- mice and DPP4mut mice with point mutation in DPP4 catalytic site, we will dissociate DPP4 catalytic and non-catalytic function and dissect the contribution of DPP4 non-catalytic function to diabetes. Involving mechanisms will be examined by detection of DPP4/ADA interaction. Collectively, the experimental findings from this application should help drive new understanding of pathophysiology of T2DM. Successful execution of this application may lead to a new therapeutic strategy for T2DM. It's well-known that inhibition of DPP4 catalytic function modulates postprandial hyperglycemia symptoms. In this application, we will test the hypothesis that DPP4 non-catalytic function promotes inflammation, an important cause of diabetes. Targeting DPP4 may improve both hyperglycemia and inflammation in T2DM.
Gliptins, a novel class of anti-diabetic drugs that modulate postprandial hyperglycemia through inhibiting DPP4 catalytic activity, are increasingly used in clinical for the treatment of type 2 diabetes. Our recent findings suggested non-catalytic function but not catalytic function of DPP4 is involved in the development of fat inflammation and insulin resistance. In this application, we will investigate the regulation of DPP4 and implication of DPP4 non-catalytic function in the process of type 2 diabetes.
| Rao, Xiaoquan; Zhong, Jixin; Brook, Robert D et al. (2018) Effect of Particulate Matter Air Pollution on Cardiovascular Oxidative Stress Pathways. Antioxid Redox Signal 28:797-818 |
| Duan, Lihua; Rao, Xiaoquan; Braunstein, Zachary et al. (2017) Role of Incretin Axis in Inflammatory Bowel Disease. Front Immunol 8:1734 |
| Xia, Chang; Braunstein, Zachary; Toomey, Amelia C et al. (2017) S100 Proteins As an Important Regulator of Macrophage Inflammation. Front Immunol 8:1908 |
| Duan, Lihua; Rao, Xiaoquan; Xia, Chang et al. (2017) The regulatory role of DPP4 in atherosclerotic disease. Cardiovasc Diabetol 16:76 |
| Xia, Chang; Goud, Aditya; D'Souza, Jason et al. (2017) DPP4 inhibitors and cardiovascular outcomes: safety on heart failure. Heart Fail Rev 22:299-304 |
| Xia, Chang; Rao, Xiaoquan; Zhong, Jixin (2017) Role of T Lymphocytes in Type 2 Diabetes and Diabetes-Associated Inflammation. J Diabetes Res 2017:6494795 |
| Waldrop, Greer; Zhong, Jixin; Peters, Matthew et al. (2016) Incretin-Based Therapy for Diabetes: What a Cardiologist Needs to Know. J Am Coll Cardiol 67:1488-1496 |
| Rajagopalan, Sanjay; Waldrop, Greer; Zhong, Jixin (2016) Reply: Trading Lower HbA1c for Increased Adverse Events: A Zero Sum Game? J Am Coll Cardiol 68:1373-4 |
| Wang, Yanan; Zhong, Jixin; Zhang, Xiangzhi et al. (2016) The Role of HMGB1 in the Pathogenesis of Type 2 Diabetes. J Diabetes Res 2016:2543268 |
| Zhong, Jixin; Allen, Katryn; Rao, Xiaoquan et al. (2016) Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice. Inhal Toxicol 28:383-92 |
Showing the most recent 10 out of 14 publications
