Type 1 diabetes is an autoimmune disease characterized by inflammation in and around pancreatic islets followed by the selective destruction of ?-cells. Loss of insulin producing ?-cells leads to a lifelong dependency on exogenous insulin as well as numerous secondary complications. Cytokines produced by the infiltrating inflammatory cells have been implicated in the destruction of ?-cells by mechanisms that included ?-cell production of nitric oxide. While nitric oxide is responsible for ?-cell death, it also activates a program that promotes functional recovery of ?-cells if the insult is removed. Based on our preliminary data showing that the AMP-activated protein kinase (AMPK) is activated by cytokines and nitric oxide, this application will test the hypothesis that AMPK is a primary regulator of a protective program that facilitates functional recovery of ?-cells from cytokine and nitric oxide-mediated damage. There are two specific aims. 1. Elucidate the mechanism by which cytokines activate AMPK in ?-cells. Proposed studies will evaluate the role of nitric oxide in cytokine-induced activation of AMPK;and the role of kinases upstream of AMPK such as LKB1 and CamKKp. 2. To test the hypothesis that AMPK is required for functional recovery of insulin secretory function and oxidative metabolism in cytokine treated ?-cells. Proposed studies will examine the mechanisms through which AMPK and potential down stream targets FoxOI and PGC-1 D regulate the transcriptional program that ultimately influences ?-cell recovery from cytokine and nitric oxide-induced damage. The proposed studies will be performed using insulinoma cell lines and islets isolated from rodents and, when available, islets isolated from human cadaver donors. Numerous cellular, molecular, pharmacological and biochemical techniques will be used to evaluate the role of AMPK in the functional recovery of p-cells from cytokine and nitric oxide-induced damage. These studies are relevant to public health as insights into mechanisms by which ?-cells protect themselves from cytokine and oxidative damage could be translated to the protection of ?-cells in the transplantation setting. This includes protection of islets from damage during isolation, during engraphment and rejection following transplantation. Relevance to public health and NIDDK mission: The proposed studies will test the role of the AMP-activated protein kinase (AMPK) in ?-cell survival following cytokine-induced damage. If AMPK controls a survival pathway this would potentially be a new target for therapeutic intervention to attenuate ?-cell loss in prediabetic persons and in islet transplantation.
| Meares, Gordon P; Fontanilla, Dominique; Broniowska, Katarzyna A et al. (2013) Differential responses of pancreatic ?-cells to ROS and RNS. Am J Physiol Endocrinol Metab 304:E614-22 |
| Meares, Gordon P; Ma, Xiangyu; Qin, Hongwei et al. (2012) Regulation of CCL20 expression in astrocytes by IL-6 and IL-17. Glia 60:771-81 |
| Meares, Gordon P; Hughes, Katherine J; Naatz, Aaron et al. (2011) IRE1-dependent activation of AMPK in response to nitric oxide. Mol Cell Biol 31:4286-97 |
