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In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver. Insulin signaling induces the translocation of glucose transporter GLUT4 to cell membrane of muscle cells and adipocytes, leading to the uptake of glucose into cells as an energy source. Circulating insulin then acts on cells in a variety of tissues including liver, muscle, and fat through interacting with insulin receptor on the cell membrane. The resulting increase of intracellular calcium concentration promotes the secretion of insulin into circulation of blood. The metabolism of glucose in β cells leads to the increase of ATP/ADP ratio, which causes the closing of ATP-sensitive potassium channels and further leads to the open of calcium channels on membrane. Pancreatic β cells sense increased blood glucose level by taking up glucose through GLUT2, a glucose transporter. The glucose is then absorbed across the intestinal wall and travel to the circulating bloodstream. After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose. They keep blood glucose level in a normal range by coordinating with each other ( Figure 1). Insulin and glucagon have opposite functions on glucose regulation. Pancreatic γ cells secrete pancreatic polypeptide that is responsible for reducing appetite. Pancreatic δ cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production. Pancreatic β cells and α cells make up about 70% and 17% of islet cells respectively, and both of them are responsible for the blood glucose regulation by producing insulin (β cells) and glucagon (α cells) (6). They contain the following 4 types of cells, in order of abundance: β cells, α cells, δ cells, and γ cells. Islets of Langerhans are clusters of pancreatic cells that execute the endocrine function of pancreas. Blood glucose is monitored by the cells in the islets of Langerhans (6). According to the American Diabetes Association, a normal fasting blood glucose level is between 70 to 100 mg/dL, and the recommended fasting level is to aim for 70 to 130 mg/dL and less than 180 mg/dL after meals (5). Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs. For a better understanding of the pathogenesis of type 1 diabetes, the regulatory mechanisms of blood glucose by pancreaswill briefly introduced. The major cause of type 1 diabetes is loss of insulin-secreting pancreatic β cell and insulin inadequacy (3 4).
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Here I will summarize the functional involvement of ER stress in the pathogenesis of type 1 diabetes and the potential underlying mechanisms.Ģ.1. Furthermore, β cell loss caused by autoimmune attack results in an increased ER burden on the rest pancreatic β cells and induces unfolded protein response (UPR) and ER stress, which further exacerbates β cell death. There is also evidence supporting that ER stress regulates the immune cell functionality and cytokine production that is relevant to autoimmune processes in type 1 diabetes. Pancreatic β cells exhibit exquisite sensitivity to ER stress due to their high development in order to secrete large amounts of insulin. Accumulating evidence suggests an involvement of endoplasmic reticulum (ER) stress in multiple biological processes during the development of type 1 diabetes. However, the underlying mechanisms are not fully understood. Autoimmune-mediated β cell death has been considered as the major cause of β-cell loss in type 1 diabetes. Unlike type 2 diabetes, which is caused by the loss of insulin sensitivity, type 1 diabetes is caused by insulin deficiency following destruction of insulin-producing pancreatic β cells. Recent epidemiologic studies revealed that the incidence for type 1 diabetes in most regions of the world has increased by 2-5% (2). Although most commonly presented in childhood, type 1 diabetes also accounts for 5-10% cases of adult diabetes (1). Despite the increasing rate of Type 2 diabetes in the United States, type 1 diabetes accounts for over 2/3 of new adolescent diabetes diagnoses. Type 1 diabetes mellitus, used to known as juvenile diabetes, is typically developed in children and juveniles. Diabetes can be categorized into two main types: type 1 and type 2. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. In United States alone, according to the statistical fact sheet released 2011 by American Diabetes Association, 25.8 million children and adults accounting for 8.3% of the population are affected by diabetes. As one of the major health problems in the world, diabetes affects over 346 million people worldwide.