Science, Technology and Medicine open access publisher.Publish, read and share novel research. Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 DiabetesJixin Zhong1, 2[1] Department of Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, China[2] Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio, USA1. Espino-Paisan L, Urcelay E, Concha EGdl, Santiago JL: Early and Late Onset Type 1 Diabetes: One and the Same or Two Distinct Genetic Entities? Zhong J, Xu J, Yang P, Liang Y, Wang C-Y: Innate immunity in the recognition of beta-cell antigens in type 1 diabetes. Schroder,M, Friedl,P: Overexpression of recombinant human antithrombin III in Chinese hamster ovary cells results in malformation and decreased secretion of recombinant protein. Martinez,IM, Chrispeels,MJ: Genomic analysis of the unfolded protein response in Arabidopsis shows its connection to important cellular processes. How Blood Sugar Levels WorkYour blood sugar levels can rise and fall in accordance with the sugar content in the food you eat.
Share This Story on Facebook BackNext Guava Leaves Can 100% Stop Your Hair Loss and Make it Grow Like Crazy! GET FREEUPDATESEnter your email below and click "Get Free Updates!" Email GET FREE UPDATES! This Stomach Vacuum Exercise Is The Easiest Way To Get a Thinner Waist And Flat Abs NASA-Recommended: 18 Plants To Effectively Purify The Air In Your House! I’m sure you know of someone, maybe even yourself, that believes they can’t cut out the sugar from their diet.
The concept of “food addiction” materialized in the diet industry on the basis of subjective reports, clinical accounts and case studies described in self-help books. Do you crave, lose control, and eat more than you plan?  You just may be addicted to sugar.  Now that you know the problem, you can make a decision, take action, and live in the solution. Be careful of BBQ sauces, ketchup, salad dressings, baked beans and processed foods!  They are usually loaded with sugar. The glycemic index (GI) is a ranking of carbohydrates on a scale from 0 to 100 according to the extent to which they raise blood sugar levels after eating. Lettuce contain a low content of fat and sugar, and has some insulin activator which can help produce the insulin from the body.
The sugar content in crisp cucumbers is 1.6% and they can provide diabetes patients with vitamin c, beta carotene, fiber and minerals. White fungus is rich in dietary fibre and Tremella polysaccharide which is helpful to slow down the process of blood sugar rises. Onions contain a high level of prostaglandins and sulfur amino acids in blood vessels which can lower the blood pressure and reduce blood lipids. This entry was posted by admin on September 28, 2013 at 6:26 am, and is filed under Diabetes. Sleep is essential for a variety of reasons, but to put it simple, our bodies start the recovering process when we sleep.
Nonetheless, sleep is also directly linked to weight loss and numerous studies had been conducted in order to point out the exact connection between these two aspects. It is essential to keep the cortisol levels as low as possible and one of the fastest, safest and easiest ways to do so is by sleeping enough. The average adult should get between six and eight hours of uninterrupted sleep per night, in order to notice visible weight loss.
Like the name suggests, the growth hormone is a naturally occurring substance that is produced by the pituitary gland and deals with growth.
Sleep stimulates the production of growth hormone, which in turn stimulates the metabolism and turns your body into a real fat burning furnace.
Nonetheless, it must be mentioned that this works the other way round as well: sleep does support weight loss, while weight loss improves sleep at the same time by reducing sleep apnea and habitual snoring, as well as by improving the overall quality of the sleep. Because fast food and junk food don’t contain adequate amounts of protein and good carbohydrates, your blood sugar levels will drop suddenly after eating, leaving you feeling grumpy, fatigued and craving sugar.
Junk food contains large amounts of fat, and as fat accumulates in your body, you’ll gain weight and could become obese.
The high levels of fat and sodium in junk food can cause high blood pressure or hypertension. The high levels of fat and sodium in junk food and fast food can contribute to heart disease by raising blood cholesterol levels and contributing to arterial plaque build up.
Over time, the high levels of sugar and simple carbohydrates in junk food can lead to type 2 diabetes.
Because junk food doesn’t contain the protein or complex carbohydrates that your body needs to maintain consistent blood sugar levels, your blood sugar levels will drop suddenly soon after eating. Over time, this stress damages your body’s ability to use the insulin secreted by your pancrease. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide. This 2-Ingredient Pineapple Dole Whip Recipe Is To Die For What Happens When You Drink Apple Cider Vinegar And Honey In The Morning This 2-Minute Detox Drink Helps You Burn Fat And Fight Diabetes This Is A Must Read Before Ever Using Turmeric Again This Drink Destroys Your Bones And Harms Every Organ On Its Way Out 2-Ingredient Recipe to Detox Organs and Fight Inflammation FAST Eat 3 Dates Daily And These 6 Things Will Happen To Your Body!
The Best Exercises Foar Getting Rid of That Unwanted Double Chin & Neck Fat Cut a Few Lemons and Place Them On The Bedside In Your Bedroom – Here’s Why!
The rise in obesity, coupled with the emergence of scientific findings of parallels between drugs of abuse and palatable foods has given credibility to this idea. Foods with a high GI are those which are rapidly digested and absorbed and result in marked fluctuations in blood sugar levels. The University Of Chicago Medical Center has recently conducted a study which revealed that getting 8 hours of sleep per night can help your body burn up to two times more fat, as opposed to getting only 5 or 6 hours of sleep. Firstly, it interferes with the production of cortisol – cortisol is an essential hormone that is responsible for regulating the appetite.
High levels of cortisol are linked to slow metabolism, not to mention that this will also interfere with your body’s natural ability to build muscle. Ghrelin and leptin are two important hormones that, just like cortisol, are directly linked to the appetite: while leptin is designed to control hunger, ghrelin has exactly the opposite effect and it stimulates the appetite, thus making you eat more. Basically, this hormone is responsible for building muscle mass and with boosting the metabolism. It is important to understand that the amount of sleep you get per night is not as important as the quality. Moreover, low-quality sleep is also linked to reduced levels of growth hormone, which plays a pivotal role when it comes to regulating the body’s fat and muscle proportions. If you are not sure if the supplement is right for your physical condition you must always consult with your physician or medical authority before ordering.
Fast foods and junk foods are high in fat, sodium and sugar, which can lead to obesity and a range of attendant health problems, including diabetes, heart disease and arthritis.
As a result, you may feel chronically fatigued and lack the energy you need to complete daily tasks. The more weight you gain, the more you’ll be at risk for serious chronic illnesses such as diabetes, heart disease and arthritis.
Excessive dietary sodium can also have a negative effect on renal function, even leading to kidney disease. You’ll feel tired and have trouble concentrating because your body might not be getting enough oxygen. The high levels of trans fatty acids found in many junk foods and fast foods can lead to fatty liver deposits, which, over time, can cause liver dysfunction and disease.
This occurs because eating too much sugar puts your metabolism under stress; when you eat a lot of refined white sugar and simple carbohydrates, your body has to pump up insulin production to prevent a dangerous spike in blood sugar levels. It can lead to mood swings and constipation, and lower your energy levels so that you lack interest in the exercise you need to burn off those extra calories. There are several signs that can indicate that your blood sugar levels are out of balance.
What Happens When You Wash Your Face With Baking Soda And Coconut Oil Honey Wraps Gently Cures Cough And Removes Mucus In Just One Night! The reviewed evidence supports the theory that, in some circumstances, intermittent access to sugar can lead to behavior and neurochemical changes that resemble the effects of a substance of abuse. Low-GI foods, by virtue of their slow digestion and absorption, produce gradual rises in blood sugar and insulin levels, and have proven benefits for health. The nutrition experts work out a summary regarding some common kinds of vegetables which can help reduce the blood sugar to a great extent and this list will be much helpful for diabetes patients. Cucumbers are ideal vegetables for the obese diabetes patients or patients with a high level of blood fat. If you do not sleep enough, the body will not produce as much leptin as it is supposed to, therefore you will feel hungry. Your metabolism plays a pivotal role when it comes to weight loss – the faster the metabolism, the more fat you will burn. Moreover, if you are a professional athlete or bodybuilder, then getting enough sleep will undoubtedly benefit you on more than just one level, as it is a known fact that the small injuries inflicted by exercise get healed when you sleep. This site can not be understood as a medical authority and it has no intentions of treating or advising people.
The high levels of sugar in junk food puts your metabolism under stress; when you eat refined sugar, your pancreas secretes high amounts of insulin to prevent a dangerous spike in blood sugar levels. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. According to the evidence in rats, intermittent access to sugar and chow is capable of producing a “dependency”. Low GI diets have been shown to improve both glucose and lipid levels in people with diabetes (type 1 and type 2). Secondly, the lack of sleep affects your body’s ability to process carbohydrates and to regulate the blood sugar level, thus resulting in high blood sugar.
At the same time, the levels of ghrelin (a substance that is secreted in the digestive tract) are dramatically increased.
This was operationally defined by tests for binging, withdrawal, craving and cross-sensitization to amphetamine and alcohol. In turn, this will stimulate the production of insulin, and insulin is known to boost the production of fat. Nobody monitors the authenticity of the photos sent by our customers so we can not guarantee that they are real. Type 1 diabetes mellitus, used to known as juvenile diabetes, is typically developed in children and juveniles. Although most commonly presented in childhood, type 1 diabetes also accounts for 5-10% cases of adult diabetes (1). Recent epidemiologic studies revealed that the incidence for type 1 diabetes in most regions of the world has increased by 2-5% (2). 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 ? cells. Autoimmune-mediated ? cell death has been considered as the major cause of ?-cell loss in type 1 diabetes. Accumulating evidence suggests an involvement of endoplasmic reticulum (ER) stress in multiple biological processes during the development of type 1 diabetes. Pancreatic ? cells exhibit exquisite sensitivity to ER stress due to their high development in order to secrete large amounts of insulin.
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.
Furthermore, ? cell loss caused by autoimmune attack results in an increased ER burden on the rest pancreatic ? cells and induces unfolded protein response (UPR) and ER stress, which further exacerbates ? cell death. Here I will summarize the functional involvement of ER stress in the pathogenesis of type 1 diabetes and the potential underlying mechanisms.2.
Blood glucose regulation by pancreasThe major cause of type 1 diabetes is loss of insulin-secreting pancreatic ? cell and insulin inadequacy (3;4). For a better understanding of the pathogenesis of type 1 diabetes, the regulatory mechanisms of blood glucose by pancreaswill briefly introduced.
Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs. Islets of Langerhans are clusters of pancreatic cells that execute the endocrine function of pancreas.
They contain the following 4 types of cells, in order of abundance: ? cells, ? cells, ? cells, and ? cells.
Pancreatic ? cells and ? 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 (? cells) and glucagon (? cells) (6). Pancreatic ? cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production. Pancreatic ? cells secrete pancreatic polypeptide that is responsible for reducing appetite. They keep blood glucose level in a normal range by coordinating with each other (Figure 1). After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose.
The glucose is then absorbed across the intestinal wall and travel to the circulating bloodstream. Pancreatic ? cells sense increased blood glucose level by taking up glucose through GLUT2, a glucose transporter.
The resulting increase of intracellular calcium concentration promotes the secretion of insulin into circulation of blood. 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. 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. In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver.

Therefore, insulin lowers blood glucose level by promoting glycogenesis and glucose uptake by peripheral tissues (7). In contrast, a drop in blood glucose caused by starving or other situations like extreme exercise suppresses the secretion of insulin by ? cells and stimulates ? cells of pancreas to release glucagon.
The metabolism of glucose in ? cells promotes the secretion of insulin into circulation of blood. Circulating insulin then increases the glucose uptake by a variety of tissues including liver, muscle, and fat. In liver, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis. Both glycogenesis and glucose uptake by peripheral tissues can lead to a decrease of glucose level in blood stream.
In contrast, a drop of blood glucose level suppresses the secretion of insulin by ? cells and stimulates ? cells to release glucagon.
Pancreatic ? cells and insulin biosynthesisEither insulin deficiency or insulin inefficiency can cause diabetes.
As the only cell type producing insulin, ? cell plays a critical role in the development of diabetes.
In type 1 diabetes, autoimmune-mediated destruction of ? cell leads to insufficient insulin production and inability of cells to take up glucose.
In response to insulin resistance, the body secretes more insulin to overcome the impaired insulin action. However, pancreatic ? cells fail to secrete sufficient insulin to overcome insulin resistance in some individuals, resulting in type 2 diabetes (8;9). Therefore, dysfunction of ? cell exists in both types of diabetes.Pancreatic ? cell is specialized for production of insulin to control blood glucose level. In response to hyperglycemia, insulin is secreted from a readily available pool in ? cells. Insulin is first synthesized as preproinsulin with a signal peptide in the ribosomes of the rough endoplasmic reticulum. Preproinsulin is translocated into ER lumen by interaction of signal peptide with signal recognition particle on the ER membrane. Preproinsulin is converted to proinsulin by removing the signal peptide forming three disulfide bonds in the ER. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules that are close to the cell membrane. In the secretory granules, proinsulin is cleaved into equal amounts of insulin and C-peptide (Figure 2).
When the ? cell is appropriately stimulated, insulin is secreted from the cell by exocytosis (11). As the major site for protein synthesis, ER plays an important role in insulin biosynthesis. To fulfill the requirement for secreting large amount of insulin, the pancreatic ? cells are equipped with highly developed ER, leading to the vulnerability of ? cell to ER stress (12). In type 1 diabetes, the loss of ? cell increases the burden of insulin secretion on the residual ? cells. On the other hand, it also increases the ER burden of residual ? cells, which further exacerbates ? cell death. In the ribosomes of rough endoplasmic reticulum, insulin is first synthesized as a precursor, preproinsulin. Preproinsulin has a signal peptide that directs it to translocate into ER lumen by interacting with signal recognition particle on the ER membrane.
In ER lumen, preproinsulin is converted to proinsulin by removing the signal peptide and forming three disulfide bonds. Proinsulin is then translocated into Golgi apparatus and packaged into secretory granules where it is cleaved into equal amounts of insulin and C-peptide. After synthesis, insulin is stored in the secretory granules and secreted from the cell until the ? cell is appropriately stimulated.3. As featured by its name, RER looks bumpy and rough under a microscope due to the ribosomes on the outer surfaces of the cisternae. The newly synthesized proteins are folded into 3-dimensional structure in RER and sent to Golgi complex or membrane via small vesicles.
In contrast, SER appears to have a smooth surface under the microscope as it does not have ribosomes on its cisternae. SER is responsible for the synthesis of lipids and steroids, regulation of calcium concentration, attachment of receptors on cell membrane proteins, and detoxification of drugs.
It is found in smooth and striated muscle, and is important for the regulation of calcium levels. Unfolded protein response and ER stressER stress is defined as the cellular responses to the disturbances of normal function of ER. ER is the place where newly produced proteins fold into 3-dimensional conformation which is essential for their biological function. The sensitive folding environment could be disturbed by a variety of pathological insults like environmental toxins, viral infection, and inflammation.
In addition to pathological insults, it can also be induce by many physiological processes such as overloaded protein biosynthesis on ER, For example, in case of type 1 diabetes, increased insulin synthesis in residual ? cell exceeds the folding capacity of ER, resulting in the accumulation of unfolded insulin.
The accumulation of unfolded or mis-folded proteins in the ER leads a protective pathway to restore ER function, termed as unfolded protein response (UPR). A special type of proteins called chaperones is used as a quality control mechanism in the ER. The unfolded proteins usually have a higher number of hydrophobic surface patches than that of proteins with native conformation (17). Thus, unfolded proteins are prone to aggregate with each other in a crowed environment and directed to degradative pathway (18). Molecular chaperones in the ER preferentially interact with hydrophobic surface patches on unfolded proteins and create a private folding environment by preventing unfolded proteins from interaction and aggregation with other unfolded proteins.
In addition, the concentration of Ca2+ in ER also impairs protein folding by inhibiting the activity of ER-resident chaperones and foldases (19-22). Exhaustion of the protein folding machineries or insufficient energy supply increases the accumulation of unfolded or mis-folded proteins in ER, which is responsible for the activation of UPR. Some physiological processes such as the differentiation of B lymphocytes into plasma cells along with the development of highly specialized secretory capacity can also cause unfolded protein accumulation and activate UPR (29-31). In response to those physiological and pathological insults, cells initiate UPR process to get rid of the unfolded or mis-folded proteins. For instance, UPR can increase the folding capacity by up-regulating ER chaperones and foldases, as well as attenuate the biosynthetic burden through down-regulating the expression of secreted proteins (32-34).
In addition, UPR also eliminates unfolded or mis-folded proteins by activating ER associated degradation process (35-37). However, once the stress is beyond the compensatory capacity of UPR, the cells would undergo apoptosis.
Disruption of those post-translational modifications can also result in the accumulation of incorrectly folded proteins and thereby induce UPR or ER stress.
ER stress pathwaysAs a protective mechanism during ER stress, UPR initiates a variety of process to ensure the homeostasis of ER. UPR can be mediated by three major pathways, which are initiated by the three transmembrane signaling proteins located on the ER membrane. Those transmembrane proteins function as a bridge linking cytosol and ER with their C-terminal in the cytosol and N-terminal in the ER lumen. The N-terminal is usually engaged by an ER resident chaperone BiP (Grp78) to avoid aggregation.
When unfolded proteins accumulate in ER, chaperons are occupied by unfolded proteins and release those transmembrane signaling proteins. There are three axes of signals that are initiated by the pancreatic endoplasmic reticulum kinase (PERK), the inositol-requiring enzyme 1 (IRE1), and the activating transcription factor 6 (ATF6) respectively. Under normal condition, PERK, IRE1, and ATF6 binding to the ER chaperone BiP to remain inactive state. Upon the accumulation of unfolded proteins, BiP preferentially binds to the unfolded proteins, leading to the release of PERK, IRE1, and ATF6. PERK becomes oligomerized and activated once released from BiP, and subsequently phosphorylates eIF2?.
The detachment of ATF6 from BiP results in the translocation of ATF6 to the Golgi apparatus and cleavage of ATF6. In response to ER stress, the binding of unfolded proteins to BiP leads to the release of PERK from BiP. As a result, PERK inactivates eukaryotic initiation factor 2? (eIF2?) by the phosphorylation of Ser51 to inhibit mRNA translation and protein load on ER (34;40). Deficiency of PERK results in an abnormally elevated protein synthesis in response to the accumulation of unfolded proteins in ER.
IRE1? is expressed in most cells and tissues, while IRE1? is restricted in intestinal epithelial cells (42;43). Activated IRE1 possesses endoribonuclease activity and cleaves 26 nucleotides from the mRNA encoding X-box binding protein-1 (XBP-1), resulting in the increased production of XBP-1 (44).
XBP-1 is a transcriptional factor belonging to basic leucine zipper transcription factorfamily.
It heterodimerizes with NF-Y and enhances gene transcription by binding to the ER stress enhancer and unfolded protein response element in the promoters of targeted genes involved in ER expansion, protein maturation, folding and export from the ER, and degradation of mis-folded proteins (44-49). In addition, IRE1? also mediates the degradation of ER-targeted mRNAs, thus decreasing the ER burden (50).
Unlike PERK and IRE1 which oligomerize upon UPR, ATF6 translocates into the Golgi apparatus after released from BiP. The 50-kDa cleaved ATF6 is relocated into the nucleus where it binds to the ER stress response element CCAAT(N)9CCACG to regulate the expression of targeted genes. For example, once released from the ER membrane, ATF6 enhances the transcription of XBP-1 mRNA which is further regulated by IRE1 (44). ER stress and innate immune responseThe importance of innate immunity was highlighted in the pathophysiology of type 1 diabetes (54-57).
Type 1 diabetes was initially considered a T-cell-mediated autoimmune disease (58), in which T-cell was believed as the major immune cell causing ? cell destruction while the involvement of innate immune response has been ignored for a long time. However, recent studies suggest a critical role of innate immune responses in the development of type 1 diabetes (54;55). As the first line of defense mechanism, innate immunity is implicated in the initiation as well as the progression of autoimmune responses against pancreatic ? cell. For example, Cyclic-AMP-responsive-element-binding protein H(CREBH), an ER stress-associated transcription factor, regulates the expression of serum amyloid P-component and C-reactive protein, the two critical factors implicated in innate immune responses. In response to ER stress, CREBH release an N-terminal fragment and transit to nucleus to regulate the expression of target genes. Innate immune response, in turn, regulates the expression of CREBH through inflammatory cytokines such as IL-1? and IL-6 (60). The development of dendritic cells, the major innate immune cells, is also regulated by ER stress response (61). High levels of mRNA splicing for XBP-1 are found in dendritic cell, and mice deficient in XBP-1 show defective differentiation of dendritic cell.
Both conventional (CD11b+ CD11c+) and plasmacytoid dendritic cells (B220+ CD11c+) are decreased by >50%.
Moreover, the secretion of inflammatory cytokine IL-23 by dendritic cell also involves ER stress response.
ER stress combined with Toll-like receptor (TLR) agonists was found to markedly increase the mRNA of IL-23 p19 subunit and the secretion of IL-23, while knockdown of CHOP suppressed the induction of IL-23 by ER stress and TLR signaling (62).
The association of ER stress with innate immune response is confirmed in many disease models.
In consistent with that, polymorphisms of XBP-1 gene were found to be associated with Crohn’s disease and ulcerative colitis in humans (64), the two autoimmune diseases share similar properties with type 1 diabetes. Lack of XBP-1 in intestinal epithelial cells may induce Paneth cell dysfunction which further results in impaired mucosal defense to Listeria monocytogenes and increased sensitivity to colitis (64). ER stress and adaptive immune responseThe presence of ? cell specific autoantibodies is a marker for autoimmune diabetes (66). IRE1 is necessary for the Ig gene rearrangement, production of B cell receptors, and lymphopoiesis.
The expression multiple UPR components including BiP, GRP94, and XBP-1 is up-regulated during the differentiation of B cells (67). Mice with a deficiency of IRE1 in hematopoietic cells have a defective differentiation of pro-B cells towards pre-B cells (68). XBP-1, an IRE1 downstream molecule, is also involved in the differentiation of B cell and antibody production by mature B cells. It was found that the engagement of B-cell receptor induces ubiquitin-mediated degradation of BCL-6, a repressor for B-lymphocyte-induced maturation protein 1 (69), while B-lymphocyte-induced maturation protein 1 negatively regulates the expression of B-cell-lineage-specific activator protein (70), a repressor for XBP-1 (71). In line with these results, B lymphocytes deficient in B-lymphocyte-induced maturation protein 1 failed to express XBP-1 in response to LPS stimulation (72). The expression of XBP-1 is rapidly up-regulated when B cells differentiate into plasma cells.
Furthermore, XBP-1is able to initiate plasma cell differentiation when introduced into B-lineage cells.
XBP-1-deficient lymphoid chimeras have a defective B-cell-dependent immune response due to the absence of immunoglobulin and plasma cells (30). TCR engagement, the first T cell activation signal, induces the expression of ER chaperons including BiP and GRP94. IL-2 promotes XBP-1 mRNA transcription, while TCR ligation induces the splicing of XBP-1 mRNA. A recent report suggests GTPase of the immunity-associated protein 5 (Gimap5) mutation in BioBreeding diabetes-prone rat, a model for type 1 diabetes, leads to ER stress and thus induces spontaneous apoptosis of T cells.

ER stress regulates cytokine productionCytokine production is an important inflammatory process in response to insults of pathogens, mutated self-antigens or tissue damage. ER stress is interconnected with the induction of inflammatory cytokines through multiple mechanisms including reactive oxygen species (ROS), NF?B and JNK (Figure 4). They are important mediators of inflammatory response., Oxidative stress, caused by the accumulation of ROS, was confirmed to be associated with ER stress (77). For example, the disulphide bond formation during the process of protein folding requires oxidizing condition (78). The PERK axis of UPR is able to activate antioxidant pathway by promoting ATF4 and nuclear factor-erythroid-derived 2-related factor 2 (NRF2) (79;80). Therefore, deficiency of PERK markedly increases ROS accumulation in response to toxic chemicals (79;81). The IRE1 axis of UPR can activate NF?B, a key regulator in inflammation, by recruiting I?B kinase (82). As a result, loss of IRE1 reduces the activation of NF?B activation and production of TNF-? (82). In addition, the IRE1 axis can also activate JNK, and subsequently induce the expression of inflammatory genes by activating activator protein 1 (AP1) (83). ATF6, the third axis of UPR signaling, can also activate NF?B pathway and induce inflammatory response. PERK promotes ATF4 and NRF2, which then suppress ROS production by activating antioxidant pathway.
XBP-1 induced by IRE1 can also induce the expression of various genes implicated inflammation.
Furthermore, cleaved ATF6 can promote inflammation via activating NF?B.ER stress regulates the expression of cytokines, while cytokines in turn may also induce ER stress via pathways including inducible nitric oxide synthase (iNOS) and JNK. Suppression of JNK by its inhibitor SP600125 can protect? cells from IL-1?-induced apoptosis (85).
Inflammatory cytokines induce iNOS expression in ? cells and produce copious amount of nitric oxygen (86).Nitric oxygen is an important mediator of ?-cell death in type 1 diabetes. Excessive nitric oxygencan induce DNA damage, which leads to ? cell apoptosis through p53 pathway or necrosis through poly (ADP-ribose) polymerase pathway (87).
In addition, nitric oxygencan also deplete ER Ca2+ stores by activating Ca2+ channels or inhibiting Ca2+ pumps (88-90). ER stress in the autoimmune process of type 1 diabetesGiven the involvement of ER stress in both innate and adaptive immune systems, pathways of ER stress play a role in the autoimmune process of type 1 diabetes.
For example, mice deficient in PERK, a molecule responsible for regulating UPR, are extremely susceptible to diabetes. Although the exocrine and endocrine pancreas developed normally, the null mice display a progressive loss of ? mass and insulin insufficiency postnatally (93) (93). A severe defect of ? cell proliferation and differentiation was also found in PERK null mice, resulting in low pancreatic ? mass and proinsulin trafficking defects (94).
Consistent with those observations in mice, some infant-onset diabetic cases in humans are confirmed to be associated with the mutations in PERK.
Similarly, disruption of UPR by mutating eIF2?, the downstream molecule of PERK signaling, enhances the sensitivity to ER stress-induced apoptosis and results in defective gluconeogenesis.
Mice carrying a homozygous Ser51Ala mutation for eIF2? show multiple defects in pancreatic ? cells including the smaller core of insulin-secreting ? cells and attenuated insulin secretion (41). The activation of IRE1 signaling is involved in the insulin biosynthesis induced by hyperglycemia. Transient exposure to high glucose enhances IRE1? phosphorylation without activation of XBP-1 and BiP dissociation. IRE1? activation induced by transient exposure to high glucose induces insulin biosynthesis by up-regulating WFS1, a component involved in UPR and maintaining ER homeostasis (10;97). However, chronic exposure of ? cells to high glucose may cause activation of IRE1 but with a different downstream signaling, leading to the suppression of insulin biosynthesis (10).
The activation of ATF6 induced by ER stress also suppressed the expression of insulin by up-regulating orphan nuclear receptor small heterodimer partner (98).5. The involvement of ER stress in ? cell destructionIncreasing evidence suggests an important role of ER stress in autoimmune-mediated ? cell destruction (99;100).
It was noted that ? cell loss is the direct causing factor for insufficient insulin secretion in type 1 diabetes patients. Pancreatic ? cells have a very well-developed ER to fulfill their biological function for secreting insulin and other glycoproteins, causing the high sensitivity of ? cells to ER stress and the subsequent UPR.
As described earlier, all the three pathways of ER stress are important in the execution of ? cell function and involved in the autoimmune responses during the process of type 1 diabetes. Pro-inflammatory cytokines are believed as the major mediators contributing to ER stress in ? cell mediated by autoimmune response.
Autoreactive immune cells infiltrated in pancreas produce pro-inflammatory cytokines, the primary causing factor for ? cell death in type 1 diabetes(101). Autoreactive macrophages and T-lymphocytes present in the pancreatic islets in the early stage of type 1 diabetes and secrete massive pro-inflammatory cytokines including IL-1?, IFN-? and TNF-?.
Pro-inflammatory cytokines have been confirmed as strong inducers of ER stress in pancreatic ? cells. Insult of ? cells with IL-1? and IFN-? was reported to induce the expression of death protein 5, a protein involved in the cytokine-induced ER stress and ? cell death (102).
Suppression of death protein 5 by siRNA provides protection for ? cells against pro-inflammatory cytokine-induced ER stress (102). In addition, stimulation of ? cells with IL-1? and IFN-? can decrease the expression of sarcoendoplasmic reticulum pump Ca2+ ATPase 2b, leading to subsequent depletion of Ca2+ in the ER (103). It has been well demonstrated that altered ER Ca2+ concentration induces the accumulation of unfolded proteins in ER associated with the induction of UPR and ER stress in ? cells (104). Reactive oxygen species such as nitric oxygen produced during inflammation are believed to play a critical role in ER stress-induced ? cell death. Excessive nitric oxygen production during insulitis induces ? cell apoptosis in a CHOP-dependent manner (91).
In addition to cytokine-induced ER stress, defective protein processing and trafficking are also a direct cause of ER stress in ? cell. For instance, mis-folding of insulin in ? cells directly induces chronic ER stress as evidenced by the observations in Akita mice. The mutation of Ins2 gene in Akita mouse disrupts a disulfide bond between? and ? chain of proinsulin, leading to the mis-folding of the mutated insulin. This mutation therefore induces chronic ER stress in ? cells and finally causes diabetes in Akita mouse (105). The inefficiency of protein trafficking from ER to Golgi apparatus also causes ER stress in ? cells (106).Hyperglycemia occurs only when ? cells fail to compensate the increased demand for insulin. The increased insulin demandrequires the remaining functional ? cellsto increase insulin synthesis to compensate the decrease of ? mass.
The altered insulin synthesis causes ER stress in the ? cells of patients with type 1 diabetes. In later case, this compensation is beneficial for control of blood glucose homeostasisin a short term.However, the long term alterations of insulin synthesis in the ? cells also induce ER stress which in turn exacerbates ? cell dysfunction and promotes disease progression.
Collectively, there is convincing evidence that ER stress plays an essential role in ? cell destruction during the course of type 1 diabetes. Mechanisms underlying ER stress-induced ? cell deathThe primary purpose of ER stress response is to compensate the damage caused by the disturbances of normal ER function.
The mechanisms underlying ER stress induced cell death are not fully elucidated, due to the fact that multiple potential participants involved but little clarity on the dominant death effectors in a particular cellular context.
Generally, the process of cell death by ER stress can be illustrated in three phases: adaptation, alarm, and apoptosis (39). The adaptation response phase is to protect cells from damage induced by the disturbances of ER function and restore the homeostasis of ER.
As described earlier, UPR signaling involves three axes of responses: IRE1, PERK, and ATF6. These axes interact between each other and form a feedback regulatory mechanism to control the activity of UPR.
The accumulation of unfolded proteins in ER results in the engagement of ER resident chaperon BiP, and as a consequence, IRE1, PERK, and ATF6 are released from BiP. Therefore, over-expression of BiP can prevent cell death induced by oxidative stress, Ca2+ disturbances, and hypoxia (107). Upon ER stress, the transcription of BiP is enhanced by ATF6p50, the cleaved form of ATF6 (108). Therefore, PERK deficiency results in an abnormally elevated protein synthesis in response to ER stress, and renders cells highly sensitive to ER stress-induced apoptosis (109). Consistently, as a downstream molecule of PERK, eIF2? is required for cell survival upon the insult of ER stress. A mutation at the phosphorylation site of eIF2? (Ser51Ala) abolishes the translational suppression in response to ER stress (41). The transmembrane domain of ATF6 is cleaved in the Golgi apparatus and is then relocated into the nucleus, by which it regulates gene expression (51).During the alarm phase, many signal pathways are activated to alert the system. For instance, the cytoplasmic part of IRE1 can bind to TNF receptor-associated factor 2 (TRAF2), a key adaptor mediating TNF-induced innate immune response. TRAF2 then activates NF?B pathway via activating IKK and activates the signaling for c-Jun N-terminal kinases (JNK) by apoptosis signal-regulating kinase 1 (Ask1).
It is reported that dominant negative TRAF2 suppresses the activation of JNK in response to ER stress (110).
In addition, TRAF2 is also a critical component for E3 ubiquitin-protein ligase complex (111). E3 ubiquitin-protein ligase complex binds to Ubc13 and mediates the noncanonical ubiquitination of substrates, which is suggested to be required for the activation of JNK (112). Furthermore, IRE1 can also activate JNK signaling by interacting with c-Jun N-terminal inhibitory kinase (JIK) (113).Although the purpose of UPR is to maintain the homeostasis of ER, apoptosis could occur when the insult of ER stress exceeds the cellular regulatory capacity. Apoptosis is initiated by the activation of several proteases including caspase-12, caspase-4, caspase-2, and caspase-9. Studies in rodents suggest that caspase-12 is activated by IRE1 and is involved in ER stress-induced apoptosis. Mice deficient for caspase-12 are resistant to ER stress-induced apoptosis, but remain susceptible to apoptosis induced by other stimuli (114). In response to ER stress, caspase-7 is translocated from the cytosol to the ER surface, and then activates procaspase-12 (115). Human caspase-4, the closest paralog of rodent caspase-12, can only be activated by ER stress-inducing reagents not by the other apoptotic reagents. Knockdown of caspase-4 by siRNA reduces ER stress-induced apoptosis in neuroblastoma cells, suggesting the involvement of human caspase-4 in ER stress-induced cell death (116). Inhibition of their activation either by inhibitors or siRNA reduces ER stress-induced apoptosis (117).
Other than caspase proteins, Ask1 kinase and CHOP are also critical mediators for ER stress-induced cell death. The activation of JNK then induces apoptosis by inhibiting anti-apoptotic protein BCL-2 (118) and inducing pro-apoptotic protein Bim (119;120). Deficiency of Ask1 suppresses ER stress-induced JNK activation and protects cells against ER stress-induced apoptosis (121). CHOP, a transcription factor belonging to basic leucine zipper transcription factor family, can be activated by many inducers of UPR including ATF4, ATF6, and XBP-1. Upon activation, CHOP induces cells undergoing apoptosis through suppressing anti-apoptotic protein BCL-2 (122-124).6.
Conclusions and future directionsAlthough exogenous insulin therapy partly compensates the function of ? cells, it cannot regulate blood glucose as accurately as the action of endogenous insulin. As a result, long-term improperly control of blood glucose homeostasis predisposes patients with type 1 diabetes to the development of diverse complications such as diabetic retinopathy (125-127), nephropathy (128;129), neuropathy (130-132), foot ulcers (133-135), and cardiovascular diseases (136-138).
Due to the long-term health consequences of diabetes, impact of insulin dependence on life quality, and increasing appearance in both young and old populations, understanding the pathophysiology of diabetes and finding a better way to treat diabetes has become a high priority.
Although the underlying mechanisms leading to type 1 diabetes have yet to be fully addressed, accumulating evidence suggests that ER stress plays a critical role in autoimmune-mediated ? cell destruction during the course of type 1 diabetes. ER stress in ? cells can be triggered by either autoimmune responses against ?-cell self-antigens or the increase of compensated insulin synthesis. During the course of type 1 diabetes, autoreactive immune cells secrete copious amount of inflammatory cytokines, leading to excessive production of nitric oxygenand ? cell destruction in an ER stress-dependent pathway. ER stress also regulates the functionality of immune cells with implications in autoimmune progression. The inadequate insulin secretion in patients with type 1 diabetes renders the residual ? cells for compensated insulin secretion to maintain blood glucose homeostasis. This increase in insulin biosynthesis could overwhelm the folding capacity of ER, and exacerbate ? cell dysfunction by inducing ER stress in ? cells.
Although ER stress is a critical factor involved in the pathogenesis of type 1 diabetes, it should be kept in mind that the mechanisms underlying autoimmune-mediated ? cell destruction in type 1 diabetes are complex, and ER stress is unlikely the exclusive mechanism implicated in disease process.
Despite recent significant progress in this area, there are still many questions yet to be addressed.
Are there additional factors inducing ER stress in ? cells during type 1 diabetes development?
Can ER stress be served as a biomarker for ? cell destruction and autoimmune progression in the clinic setting?
Does blockade of ER stress in immune cells attenuate autoimmune progression and protect ? cells?

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    Author: Ocean
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  3. 29.03.2015 at 17:35:29

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