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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. According to World Health Organization database list of top 10 causes of death is arranged in all over the world.
Human factors in accidents include all factors related to drivers and other road users that may contribute to a collision. A 1985 report based on British and American crash data found driver error, intoxication and other human factors contribute wholly or partly to about 93% of crashes. Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.
Type 2 diabetes: results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency.
Gestational diabetes: is when pregnant women, who have never had diabetes before, have a high blood glucose level during pregnancy.
Tuberculosis (TB) is an infection, primarily in the lungs (a pneumonia), caused by bacteria calledMycobacterium tuberculosis. Since many illnesses are manifested by skin rashes, it is a good idea to get diagnosis of the rash. If a bald eagle loses a feather on one wing, it will drop a matching feather on the other side to maintain balance. Commonly, stress rash is what is known as hives or urticaria, and it might occur in greater or lesser amounts under a variety of stressful circumstances.
Many people want to know why stress might result in a rash, and the answers to this are not as clear-cut.
This idea of stress allergy is an interesting one, since some people clearly don’t have and will likely never get a stress rash. Hives sure can be a funny thing, and sometimes people get confused by what they really are.
I have never been one to crumble under pressure, but I recently began to have some very major marital issues.
The condition of gangrene is a serious one, primarily marked by loss of adequate supply of blood to the tissues of the body, ultimately resulting in its necrosis or death.
Injury to the tissues, infection (mostly of bacterial origin) and presence of any underlying health ailment that inflicts damage to the blood carrying vessel structure form the three key underlying mechanisms that are responsible for initiation and development of irreversible tissue damage and life threatening condition of gangrene. As already explained, one of the causes of gangrene in the toes and fingers is linked with damaged blood vessels. High level of blood glucose associated with diabetes mellitus also damages the nerves (known as peripheral neuropathy), especially the nerves in the lower extremities.
The dullness or lack of sensation puts diabetic individuals at an increased risk of injuring the skin of their fingers or feet without having any realization (it mostly goes unnoticed in the feet region). The sore or foot ulcer formed takes an extended time to heal because of both, poor circulation of blood through the injured area as well as lesser number of defence cells. Bacterial infection also forms another causative factor that makes the diabetic individual more prone to developing gangrene. Such type of infection is marked by noticeable skin discolouration and dryness along with the formation of skin blisters. The weakened immune system (seen in diabetes) further raises the risk of incurring serious infection, which later develops, into gangrene.
A link between poverty, low educational attainment and poorer health outcomes with increased morbidity and mortality is well established.
Federal initiatives have acknowledged the importance of the relationship of socioeconomic inequalities to health. Effective health care delivery requires the application of knowledge of cultural health related beliefs, practices and health risks. For example, individuals from specific cultures may require screening for diseases that are more prevalent in that culture, react differently to a medication, or use traditional healing practices. Thus, cultural competence goes beyond awareness and sensitivity by requiring that health care providers apply an understanding and respect for different cultures when working with clients from cultures different from their own. In a study of African American health attitudes, beliefs, and behaviors, 30% believed that their health was dependent upon fate or destiny and only about 50% felt health was a high priority in their life. In another study, caregivers of obese or super-obese children do not always believe the child's weight is a potential health problem. Minorities are far less likely than Whites to have private coverage and far more likely to be uninsured.
When racial and ethnic minorities had insurance, they were more likely to be covered by public rather than private insurance. Among adults 18a€“44 years of age, the percentage with private coverage declined from 72% in 1999 to 62% in 2009, while Medicaid coverage increased from 6% to 10%, resulting in an increase in the percentage of persons 18a€“44 years of age who were uninsured. Minorities face more difficulties obtaining health insurance coverage, especially through employers, than White Americans.
Individuals with low income and educational attainment are less likely to have health insurance. The perceived need for a usual source of care may be low among people who say they seldom or never get sick. Between 1999 and 2009, the percentage of children under 18 years of age with private health insurance declined from 69% to 56%. In 2009, children 6a€“17 years of age were more likely to be uninsured than younger children, and children with a family income below 200% of the poverty level were more likely to be uninsured than children in higher-income families. Contributing factors include parents working in economic sectors that lack employment linked health benefits and multiple and persistent barriers experienced by Latinos in accessing health care. Children under six years of age are more likely to be covered than children age 6-17 years.
Parental education: Children of parents with a higher level of education are most likely to privately insured and least likely to be uninsured. Employment of parents: children living with two employed parents are most likely to be privately insured and least likely to be uninsured.
The Children's Health Insurance Program (CHIP) provides coverage to eligible low-income, uninsured children who do not qualify for Medicaid. The Affordable Care Act of 2010 maintains CHIP eligibility standards in place as of enactment through 2019. Uninsured children are significantly less likely to have a personal doctor or nurse than insured children regardless of race, yet the disparity is larger for black and Hispanic children. Having a usual source of care increases the chance that people receive adequate health services, such as preventive care.
Additionally, for Hispanic children, limited knowledge of English can make it difficult for parents to find a provider with whom they can clearly and comfortably communicate and who understands their knowledge and beliefs about health care. About 30 percent of Hispanic and 20 percent of black Americans lack a usual source of health care compared with less than 16 percent of whites. Hispanic children are nearly three times as likely as non-Hispanic white children to have no usual source of health care. African Americans and Hispanic Americans are far more likely to rely on hospitals or clinics for their usual source of care than are white Americans (16 and 13 percent, respectively, v.
Racial and ethnic disparities are still present after adjusting for differences in health insurance, income, and other individual characteristics. Children with a usual source of health care often face other barriers to receiving needed health care. Four to five million children experience untreated dental disease sufficiently extensive and severe enough to cause chronic dental pain.
Certain children are more vulnerable; In permanent teeth, 80% of all cavities occur in 25% of children. Substantial disparities in the prevalence, severity, and consequence of oral health problems exist among American youth.
Preschoolers living in poverty have twice the odds of having decayed teeth, twice the extent of decay when they have disease, and twice the pain experience of their more affluent peers. Poor adolescents were less likely to have had a dental visit in the past year than near-poor and non-poor adolescents (64% vs. Inadequate numbers of dentists treat Medicaid eligible children (only 10% of dentists participate nationwide). The number and distribution of providers participating in programs to reach underserved children is inadequate to meet the need.
Behavioral and cultural disjunctions between dentists and patients' knowledge and expectations that are expressed as missed appointments or lack of compliance.
According to national data 45% of Whites believe that most Blacks are lazy, 51% that most Blacks are prone to violence, 29% that most Blacks are not intelligent, and 56% that Blacks prefer to live off welfare. Only 17% of Whites indicated that most Blacks are hard-working, 15% that most Blacks are not prone to violence, 21% that most Blacks are intelligent and 12% that most Blacks prefer to be self-supporting. Individuals who perceive themselves experiencing racism are more likely to suffer psychological distress, depressive symptoms, substance use, and physical health problems. In summary, the problem of racial disparities is complex and no one causative factor or magic bullet to resolve the problem can be identified.
Department of Health and Human Services, Office of the Assistant Secretary for Planning and Evaluation. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide. Examples include driver behavior, visual and auditory acuity, decision-making ability, and reaction speed.
This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body.
Death of cell and tissue may target any part of the body, however, it has been typically observed in the extremities, such as the toes, fingers and hands. In both, type 1 and type 2 diabetes, the raised level of sugar is capable of causing damage to the blood vessels and reducing blood supply. Owing to the nerve damage, the transmission of sensation, particularly those of pain to the brain gets impaired. A notorious bacterial organism, Clostridium perfringes is often linked with gas gangrene; after it attacks the site of injury or sometimes, surgical wound.
Heart disease, diabetes, obesity, elevated blood lead level, and low birth weight are more prevalent among individuals with low income and low educational attainment. Health care delivery organizations are legally required to respond to the language and cultural needs of their service area by becoming "linguistically and culturally competent. During this period, Medicaid coverage (which includes the CHIP category) increased from 18% to 35%.
Uninsured black children in 2003 were 35 percent less likely to have a usual source of care than insured black children, and uninsured Hispanic children have an even larger disparity; they are more than 45 percent less likely to have a personal doctor or nurse than insured Hispanic children. Children who have no dental coverage are three-fold more likely to have an unmet dental need than are children with dental coverage. Minorities live in areas of concentrated poverty with poor schools that limit educational and employment opportunities. Most cancers that start in lung, known as primary lung cancers, are carcinomas that derive from epithelial cells. You need to have had chickenpox at one point in your life, as the virus sits dormant in the roots of your nerves for life. In the absence of a continuous supply of nutrient and oxygen rich blood, the cells within the body begin to fail in carrying out their normal function and finally give up. As a result of restricted blood circulation to the extremities, such as the feet, the area becomes deprived of those cells (white blood cells) which aid in fighting off any infection. Yet, because they lack a usual source of care, these people may be at risk for missing preventive care and early diagnosis and treatment of serious diseases. But uninsured white children were only 18 percent less likely to have a usual source of care than insured white children. Thus, nearly half of the 4 million children who obtain their routine health care in community health care centers have no access to dental care in their health center. High paying low skill jobs have followed Whites migration from cities to suburbs resulting in higher rates of job losses for African Americans.
Overview of the Uninsured In the United States: A Summary of the 2011 Current Population Survey.
From Coverage to Care: Exploring Links Between Health Insurance, A Usual Source of Care, and Access. 1.2 Million Children Gain Insurance Since Reauthorization of Children's Health Insurance Program. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. Swelling and inflammation resulting from the infection causes the local temperature of the area involved to be slightly elevated, and also leads to pain. Racial and Ethnic Disparities in Medical and Dental Health, Access to Care, and Use of Services in US Children.
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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