Endoplasmic Reticulum Is at the Crossroads of Autophagy, Inflammation, and Apoptosis Signaling Pathways and Participates in the Pathogenesis of Diabetes Mellitus
Diabetes mellitus (DM) is a chronic metabolic disease, and its incidence is growing worldwide. The endoplasmic reticulum (ER) is a central component of cellular functions and is involved in protein folding and trafficking, lipid synthesis, and maintenance of calcium homeostasis. The ER is also a sensor of both intra- and extracellular stress and thus participates in monitoring and maintaining cellular homeostasis. Therefore, the ER is one site of interaction between environmental signals and a cell’s biological function. The ER is tightly linked to autophagy, inflammation, and apoptosis, and recent evidence suggests that these processes are related to the pathogenesis of DM and its complications. Thus, the ER has been considered an intersection integrating multiple stress responses and playing an important role in metabolism-related diseases including DM. Here, we review the relationship between the ER and autophagy, inflammation, and apoptosis in DM to better understand the molecular mechanisms of this disease. 1. Introduction Diabetes mellitus (DM) is a chronic metabolic disease, and its incidence is growing worldwide. Long-term hyperglycemia is the fundamental factor that promotes vascular lesions and dysfunction, leading to a variety of complications of DM [1]. Diabetic complications, such as neuropathy vasculopathy, are the main cause of death or disablement in DM patients [2]. The main purpose of clinical treatments for DM is to control blood glucose and consequently inhibit or alleviate the initiation and progression of complications. However, the control of blood glucose is not easy to achieve [3]. Therefore, a better understanding of the pathogenesis of DM is very important for the development of new treatment strategies. The endoplasmic reticulum (ER) is an important membranous organelle; its functions include folding and trafficking of protein, lipid synthesis, maintaining calcium homeostasis, and participating in a number of crucial cellular functions [4]. The ER can monitor and maintain cellular homeostasis by acting as a sensor of various changes (stresses) in the intra- and extracellular environment [5]. The ER may therefore provide a platform for interactions between environmental signals and basic cellular biological functions and act as an intersection to integrate multiple stress responses. The interruption of cellular homeostasis can lead to a gradual reduction of organ function, and in turn decreased ability to respond to physiological stress. Recently, a growing body of research has suggested that the ER is involved in the
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