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Results from the Australian Diabetes, Obesity and Life Study, released in April 2001 show that nearly a quarter of Australian adults have either diabetes or impaired glucose metabolism.
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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. The type 2 diabetes symptoms are similar to that of Type 1 and Gestational Diabetes, so to better understand why those things happen to the body, let’s learn what Type 2 Diabetes is and then learn how it is different. When a patient is informed that he has Type-2 diabetes the doctor is saying that the patient’s body is not producing enough insulin or the body cannot use whatever is produced to properly support a healthy immune system. In very severe circumstances a patient who is very ill or has been recently very ill or if the person has become dangerously dehydrated to the point that intravenous rehydration is essential to survival may fall into a diabetic coma, medically referred to as hyperosmolar coma. If other family members have it a person may also develop T-2 through due to shared environment, including dietary habits, or genetic predisposition. Are you considering getting an insulin pump therapy as a way to treat type-1 Diabetes and insulin-dependent type 2 Diabetes? Well, more and more people are wearing insulin pumps to control blood glucose levels and showing excellent results.
One needs to have clear understanding on pros and cons of insulin pump therapy before opting for it.
You may possibly be able to level out the body’s frequent blood glucose swings because you receive constant low dosage of insulin. Your risk of getting infection increases if you do not change the insertion site of cannula for every 2-3 days. You can be at greater risk of developing diabetes ketoacidosis as the pump uses rapid-acting insulin. Wearing an insulin pump at all times can bother an individual as it causes weight gain or results in skin infection. The term diabetes refers to a group of metabolic diseases and is quite prevalent all over the world [2]. Type I Diabetes, in which the body is unable to produce the required amount of the hormone insulin. Type II Diabetes, which is the most common type of diabetes, in which the body cells show resistance to the insulin hormone. Gestational Diabetes is another type of diabetes which is exclusively found in pregnant women. There is also another condition known as Prediabetes which is often diagnosed in individuals. While Type I and Type II Diabetes prove to be chronic and long lasting conditions, both gestational diabetes and prediabetes are reversible conditions which can be treated completely by following adequate remedies and methods of treatment.
Type I Diabetes occurs when body’s own immune system destroys the insulin-producing beta cells of the pancreas. In Type II diabetes, either the body produces insufficient amounts of the hormone insulin, or the body develops a resistance to the action of insulin. Gestational diabetes may be defined as hyperglycemia with its first presentation or onset during pregnancy.
There are a number of symptoms which may help you to diagnose the presence of this metabolic disease.
Increased thirst: Sufferers feel an increased urge of thirst in order to compensate for excessive fluid loss due to urination. Increased hunger: Also known as polyphagia, this condition is also noticed in diabetic patients. Fatigue: Increased tiredness and fatigue are other important symptoms in a diabetic patient. Slow healing: Slow healing of wounds is also an important feature that is seen quite commonly in diabetic patients.
Abnormal sensation: There may be occurrences of numbness or tingling sensation felt in the limbs in diabetic.
Increased risk to infections: A diabetic person is more prone to an infectious disease as compared to a normal person. Miscellaneous: There are some other symptoms of diabetes which may include a blurring of the vision, unexplained loss of weight, lack of interest and concentration while working or studying. Diabetic neuropathy: The excess sugar levels present in the blood stream can prove to cause damage to the blood vessels and capillaries.
Diabetic nephropathy and diabetic ketoacidosis: Damage can be caused to the kidneys due to the excess glucose present in the blood in diabetics.
Diabetic retinopathy: Diabetes can also cause damage to the blood vessels surrounding the retina of the eye.
Cardiovascular or macro vascular diseases like stroke or peripheral vascular disease: The risk of encountering cardiovascular diseases is greatly increased in diabetics. Muscle wasting and weakness: Due to the cells being unable to effectively absorb glucose, diabetic individuals cannot efficiently or effectively use their body muscles. Diabetic coma: While it is known that diabetic patients suffer from increased risk to nerve damage, in some extreme cases, this nerve damage can also lead to a condition of a coma. Others: There are many other complications which can be associated with diabetes and these include damage caused to the limbs, infectious skin diseases and conditions, an impairment of hearing and also the development of Alzheimer’s disease is some individuals. Fasting Plasma Glucose Test: This test measures blood glucose levels after going for at least 8 hours of fasting. Random Plasma Glucose Test: In this test, the doctor checks the blood sugar level without observing to the last meal.
Treatment of diabetes include use of medications [3] or correcting the underlying causes such as diet and exercise [4]. Diet: A diabetic should always take a balanced nutrition to maintain the short-term as well as long-term blood glucose levels under control. Physical activity: It is another important and effective method of treating as well as preventing diabetes especially in Type II Diabetes mellitus caused due to obesity or overweight. Medications: Type I Diabetes can be treated with the insulin therapy where combinations of NPH and regular insulin or synthetic insulin analogues are administered to the patients with diabetes.
Whatever the method of treatment for diabetes may be, care must be taken to periodically monitor the sugar levels in the blood stream of diabetics.
There are also a number of home remedies and lifestyle tips that can be used to provide relief to the symptoms of diabetes. Stress and strain on the body should be considered very seriously as they may adversely affect a diabetic. Regular visits to the doctor and frequent eye checkups are required to be a part of a diabetic’s life. While diabetes cannot be cured completely, following proper medication which is coupled with a healthy lifestyle with lots of physical activity can provide relief to sufferers. Use of this website constitutes acceptance of our [my_terms_of_service_and_privacy_policy]. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide.
We hear a lot about this type of diabetes in today’s media  when they are doing news stories about how America has become an overweight or obese country, but in truth although Type 2 can occur due to being overweight, people who are perceived as being healthy and “thin” can just as likely to develop T-2. Doctor’s refer to this as “Insulin Resistance.” Essentially speaking, the glucose cannot get into the cell tissue and instead builds up in the person’s blood. Insulin forms a complex with the Insulin Receptor (IR) and b chains to form the active signaling complex. All material provided on this website is provided for informational or educational purposes only.
It is a rare form of diabetes and is prevalent in less than 10% of people with diabetes, mainly with children.
In this condition, the glucose levels in the blood prove to be higher than normal, but the levels are not high enough for the condition to be classified under Type II Diabetes.
This results in the body cells being unable to effectively use up glucose, consequently leading to an increased concentration of sugar in the blood stream.
If cases of increased hunger coexist along with above two symptoms in a sufferer, diabetes is said to be diagnosed. This condition affects almost all diabetic individuals and is considered to be one of the easiest ways of diagnosing if diabetes has affected an individual.
This can eventually lead to damage of the nerves and loss of sensation in particular regions of the body such as the fingers and the toes.
There is also a high presence of ketones in the urine which is caused by deamination of some amino acids and also the improper breakdown of fatty acids.
While this may result in some eye conditions such as glaucoma and cataract, over longer periods, it can also lead to permanent blindness. These include potentially serious conditions and diseases such as a heart attack, a stroke, pain in the chest and also a constriction of the arteries in the body. While this causes general fatigue and tiredness, over longer periods it may lead to a gradual wasting of the muscle tissues.
The test should be taken after at least eight hours of fasting and two hours after drinking a glucose containing liquid.
This test helps in assessment of symptoms and for diagnosing diabetes, but it does not diagnose prediabetes. Type II Diabetes can be treated effectively with the use of oral hypoglycemic medication like metformin. While the treatment methods may prove to be effective on their own, diabetes should always ensure to monitor their glucose levels. This is the first and foremost step and sufferers must ensure that they collect as much information about the condition as possible. While regular exercise and diet can help in keeping these in check, measurements need to be taken regularly in order to avoid complications.
Diabetes can have dire consequences on the gums and the teeth and regular brushing and flossing of the teeth should always be done. The recommended limits are one drink of alcohol a day for women and two drinks a day for men. Smokers who also have diabetes have an extremely high risk of developing cardiovascular diseases and the smoking and other forms of tobacco should be stopped at the earliest.
Prolonged stress can prove to be very harmful to the tiny blood vessels and can lead to serious complications such as a stroke. Following an effective treatment plan with a well-maintained lifestyle can help keep symptoms in check and can help diabetics lead a closer to normal life. The other is a hemoglobin test that examines the average sugar levels over a two to three day period. Through recruitment of adaptor molecules and the activation of RAS, the activated IR can cause transcriptional activation.
Diabetes is caused due to an increased level of blood sugar or glucose in the blood stream, which in turn can be caused by a number of different factors, most primarily, the role of the hormone insulin in the body. It is the most prevalent form of diabetes accounting for almost 90% of the total number of people with diabetes. It is suspected that heredity and genes have a major role to play in an individual encountering Type I Diabetes as it is passed on from one generation to another. While this is the most common type of diabetes in individuals, the actual causes of Type II Diabetes are yet to be known. The human placental lactogenic hormone also known as Human Chorionic Somatomammotropin, which is released during the gestational period, reduces the insulin sensitivity in mothers and it may lead to an increased level of blood glucose. There are other medications as well which include angiotensin converting enzyme inhibitors (ACEIs) or the angiotensin receptor blockers (ARBs). This is the most effective way to ensure that targets are being met and that the medications or treatment remedies are proving to be effective. Carbohydrates on the consumptions of excess alcohol can upset the balance that is required in the dietary plan. However, diabetics must make sure to understand the fact that complications related to the disorder can spring up at any time and they need to always maintain a high level of care in order to keep symptoms in check. Use of this website constitutes acceptance of our Terms of Service and Privacy Policy.This website is for informational purposes only.
Insulin injections can be given in syringes, in pens or via insulin pumps where a small plastic catheter continuously releases insulin under the skin (see pictures left). Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. It may also be triggered by environmental factors like diet, viruses, and some specific toxins.
While the body systems of most women counter this by increasing the production of insulin, some women are susceptible to the disorder.
Diabetic sufferers do not have an easy time, but integrating a new lifestyle and adopting healthy measures as daily habits can greatly help in managing the symptoms of this disorder.
Various factors that may trigger Type II Diabetes include dietary habits, lifestyle and genetic susceptibility. 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). HbA1c is a blood test that gives an indication of average glucose level over the past 2-3months.
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. LDL-cholesterol is the 'bad' cholesterol  that leads to deposition of fat in arteries. 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.


Blood vessels at the back of the eyes can also be damaged affected vision (called diabetic retinopathy). Here I will summarize the functional involvement of ER stress in the pathogenesis of type 1 diabetes and the potential underlying mechanisms.2. Nerves can also be damaged, most commonly in the feet which may lead to foot ulcers and rarely to amputations due to unrecognised injury.With careful management of diabetes, many of these complications can be minimised or avoided. 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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