Insulin is an anabolic hormone (a hormone causing storage and growth) secreted by the ? cells of the islets of Langerhans of the pancreas. As mentioned above, the pathophysiology of diabetes mellitus is lack of insulin and therefore one of the best methods of management of diabetes is to replace insulin. In history until 1980’s insulin was manufactured from pancreas of cattle and pigs called bovine and porcine insulin respectively. What is Insulin Resistance?Insulin resistance (IR) is the condition in which normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. 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. Cold temperature-induced hormones cause GLUT1 (green) to be transported to the surface of brown fat cells (left).
A newly identified signaling pathway that stimulates glucose uptake in brown fat cells might be useful for treating type 2 diabetes and obesity, according to a study in The Journal of Cell Biology.
When the body encounters cold temperatures, the sympathetic nervous system activates adrenoceptors on the surface of brown fat cells to stimulate glucose uptake from the bloodstream.
Now, researchers in Sweden reveal that the mTORC2 signaling pathway is the key regulator of adrenoreceptor-stimulated glucose uptake in brown fat tissue in mice. In addition to being an effective tool for controlling blood sugar levels in type 2 diabetes patients, these findings suggest that stimulating the mTORC2 pathway to take advantage of the energy-burning power of brown fat might be effective as a weight loss therapy. Biologists at The Scripps Research Institute (TSRI) have identified a signaling pathway that switches on a powerful calorie-burning process in brown fat cells.
The number of overweight persons is greatly increasing worldwide - and as a result is the risk of suffering a heart attack, stroke, diabetes or Alzheimer's disease. Ethnicity plays a significant role in the likelihood of developing certain diseases, such as diabetes. Indiana University School of Medicine researchers have identified a small protein with a big role in lowering plasma glucose and increasing insulin sensitivity. All's not fair in love and glucose intolerance - overweight men are more prone to get type 2 diabetes than are overweight women. Mitochondria are the engines that drive cellular life, but these complex machines are vulnerable to a wide range of breakdowns, and hundreds of their component parts remain a functional mystery.
A handful of large studies of cancer risk factors have found that working the night shift, as nearly 15 percent of Americans do, boosts the chances of developing cancer. Health experts have long believed that sickle cell gene variants, which occur in about 1 in 13 African-Americans, increase the risk of premature death, even when people carry only a single copy of the variant. For many, a diagnosis of diabetes carries with it a lifelong sentence of glucose monitors and insulin injections.
In type 1 diabetes, the body does not produce sufficient insulin, leading to decreased insulin uptake by cells.
Most people are familiar with type 2 diabetes, a disease associated with poor diet and excess weight. Though researchers and clinicians have expanded their knowledge of the disease in recent decades, options for treatment are still limited.
Herold’s study may foreshadow a new treatment that could change how patients manage their condition.
In the study, two groups of patients, all of whom were within eight weeks of their initial diagnosis, were treated, either with Teplimuzab or with nothing as a control. To understand the answer to this question, it is important to first define responders and non-responders. After discovering this drastic difference, the team was very interested in determining what caused it. The success of the trial has not stopped Herold from looking towards improvements and future applications. In addition to these studies, Herold is enrolling patients for an even more ambitious trial which aims to prevent or delay the onset of type 1 diabetes. About the Author: Grace Cao is a sophomore Molecular, Cellular and Developmental Biology major in Timothy Dwight College. Acknowledgements: The author would like to thank Professor Herold for his time and enthusiasm in explaining his research on type 1 diabetes. Lack of insulin secretion or its action in the target tissue is the pathophysiology of diabetes mellitus and replacement of insulin as a drug is one of the commonest and standard treatments of diabetes.
Being a hexamer secreted in response to glucose or other stimuli like amino acids it has a normal basal level with peaks after each meal.
Being an anabolic hormone it increases glucose uptake, particularly in muscle, liver and adipose tissue (Here the brain is not under the control of insulin dependent glucose uptake). Thus, the uses of insulin are multiple with regard to diabetes.• In Type 1 diabetes it is essential for survival since the synthesis of hormone is reduced• In Type 2 diabetes it may be necessary for control in certain individuals where the response to oral hypoglycaemic agents is poor and at later stage when production of insulin is also law apart from the peripheral resistance to insulin• In gestational diabetes to optimize the outcome insulin is used• Women with diabetes mellitus become pregnant since oral hypoglycaemic agents cannot be used• Rapid-acting insulin is used in hyperglycemic emergencies like diabetic ketoacidosis and hyperosmolar non ketotic coma (HONK)• In late onset autoimmune diabetes mellitus of adult (LADA)• Transiently in type 2 diabetes in special situations such as surgery or infectionWhat are the types of insulin? However, in the present days human insulin, known as insulin analogues is produced by recombinant DNA technology; examples are rapid –acting insulins like Aspart and Lispro and long-acting insulin like Glargine. Insulin resistance in fat cells reduces the effects of insulin and results in elevated hydrolysis of stored triglycerides in the absence of measures which either increase insulin sensitivity or which provide additional insulin. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide.
The pathway, which involves a protein kinase called mTOR, stimulates the transport of a glucose-importing protein called GLUT1 to the surface of brown fat cells. Although the associated technology has improved, the essential nature of treatment has not changed since the discovery and subsequent commercial production of insulin in the 1920s. However, type 1 diabetes is a more severe form of the illness, which is most often diagnosed in children and represents up to ten percent of all diabetes cases.
Diagnosed individuals must carefully and constantly monitor their blood glucose levels, then administer insulin at several points throughout the day. In a clinical trial, patients were treated with the drug Teplizumab, a monoclonal antibody which binds to a specific region of the CD3 receptor. In patients receiving the drug, the average decline in C-peptide was 75 percent less than the control group after two years, meaning their insulin production remained relatively close to constant. According to Herold, the distinction is straightforward: “We looked at the decline in C-peptide in the control group after two years.
He is currently continuing to track the response of patients in the trial to see how long their C-peptide levels remain stable. She is a Copy Editor for the Yale Scientific Magazine and works in Professor Carla Rothlin’s lab in the Immunobiology Department.
Lack of insulin secretion or its action in the target tissue is the pathophysiology of diabetes mellitus and replacement of insulin as a drug is one of the commonest and standard treatments of diabetes (particularly type I).
At the same time insulin suppresses glucose output from liver, glycogenolysis (break down of glycogen in the liver and muscle), gluconeogenesis (synthesis of glucose from amino acids and glycerol).
Increased mobilization of stored lipids in these cells elevates free fatty acids in the blood plasma.
In this condition, immune cells known as T cells attack insulin-producing ? cells in the pancreas, which leads to decreased levels of insulin production.
Furthermore, as Herold explained, since the advent of insulin, “there has never been another treatment that fundamentally changed the natural history of the disease.” Even with appropriate management, a significant fraction of type 1 diabetes patients today develop complications that include kidney failure, blindness, and various neuropathies. This receptor is found on the surface of all T cells, including the ones responsible for ? cell destruction in type 1 diabetes, and helps T cells recognize their target antigen.
Throughout these years, the patients’ insulin production and consequently ? cell function were monitored by measuring levels of C-peptide, a short protein found in a precursor to insulin.
However, not all the treated patients responded similarly, leading to a second critical question: Why did some patients respond better than others?
Drug-treated subjects who had the same level of decline are non-responders, and those with less decline are responders.” Based on this criteria, of the 49 treated subjects who completed the study, 27 were non-responders and 22 were responders. Rather, “the major difference seemed to be that the responders used less insulin going into the trial than the non-responders, and also had better glucose control.” While this initially seemed counterintuitive, as one might expect that responders would end up with lower blood glucose levels rather than the other way around, the team found the same trend when they reevaluated previous trials.
He has also continued to investigate basic immunological questions about type 1 diabetes and Teplimuzab, including defining biomarkers for the disease and investigating the role of the microbiota in regulating the differentiation of regulatory T cells in the gut. Therefore, a thorough knowledge on insulin is crucial for health care professionals to offer a better management to the increasing number of patients suffering from diabetes mellitus. Intermediate acting insulin is made by adding substances to the unmodified insulin thereby slowing the breakdown of the molecule; which has a slower onset, peak and longer duration of action. Insulin resistance in muscle cells reduces glucose uptake (and so local storage of glucose as glycogen), whereas insulin resistance in liver cells results in impaired glycogen synthesis and a failure to suppress glucose production. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades.
However, although insulin-stimulated glucose-uptake is well understood, the mechanisms involved in the adrenoceptor-dependent process have been unclear. Kevan Herold, Yale Professor of Immunobiology and Medicine (Endocrinology), aims to improve treatments for patients with type 1 diabetes. While a concrete cause for type 1 diabetes is unclear, there is evidence for strong genetic and environmental factors. The reason that binding to the CD3 receptor reduces attacks on ? cells is as of yet unknown.
Examining the C-peptide levels over time within these groups revealed that non-responders actually had similar levels of C-peptide as the control group. One potential explanation is that glucose levels may affect immune responses or ? cells directly. By better understanding the disease pathology and interaction with the drug, more effective interventions can be developed. Together with Herold’s other ongoing research, the study represents a long-awaited hope for improved type 1 diabetes treatments. Though this hub is mainly aimed at educating the healthcare professionals and medical students the medical terms have been clarified as much as possible for the interest of the lay community.How does insulin act?
The uptake of amino acids into muscles is promoted and breakdown of muscle (protein catabolism) is reduced.
Long acting insulin has longer duration of action and it is used to maintain the basal levels of insulin. Elevated blood fatty-acid concentrations (associated with insulin resistance and diabetes mellitus Type 2), reduced muscle glucose uptake, and increased liver glucose production all contribute to elevated blood glucose concentration. As the disease progresses and the death of beta cells results in falling insulin levels, patients need to deliver the insulin their body cannot supply through injection or insulin pumps.
Unlike other CD3-targeted antibodies, Teplimuzab does not simply deplete T cells from the body. In patients who responded to the treatment, C-peptide levels remained at or above the initial baseline for an average of 18 months, and the level of C-peptide was almost three times higher than the control group at that time.
Type 1 diabetes mellitus, used to known as juvenile diabetes, is typically developed in children and juveniles.
Research by Herold and Richard Flavell, Sterling Professor and Chair of Immunobiology at Yale, suggests that the drug “causes cells to migrate to the gut, where they may acquire a regulatory function,” said Herold. Although most commonly presented in childhood, type 1 diabetes also accounts for 5-10% cases of adult diabetes (1).
However, prior to the use of insulin as a drug, the dose has to be determined and the type of insulin suitable for each individual should be decided. Recent epidemiologic studies revealed that the incidence for type 1 diabetes in most regions of the world has increased by 2-5% (2). The individual should become aware of the technique of injection and the common adverse effects. 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. In an ''insulin-resistant'' person, normal levels of insulin do not have the same effect on muscle and adipose cells, with the result that glucose levels stay higher than normal. Pancreatic ? cells exhibit exquisite sensitivity to ER stress due to their high development in order to secrete large amounts of insulin.
To compensate for this, the pancreas in an insulin-resistant individual is stimulated to release more 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. The elevated insulin levels have additional effects (see insulin) which cause further biological effects throughout the body.The most common type of insulin resistance is associated with a collection of symptoms known as metabolic syndrome. 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. This is often seen when hyperglycemia develops after a meal, when pancreatic I?-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycemia). The inability of the I?-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to Type 2 diabetes mellitus.Various disease states make the body tissues more resistant to the actions of insulin. 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. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. Blood glucose level is closely regulated in order to provide a homeostatic microenvironment for tissues and organs. Exercise reverses this process in muscle tissue, but if left unchecked, it can spiral into insulin resistance.Elevated blood levels of glucose a€” regardless of cause a€” leads to increased glycation of proteins with changes (only a few of which are understood in any detail) in protein function throughout the body. 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.
With respect to visceral adiposity, a great deal of evidence suggests two strong links with insulin resistance. 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). First, unlike subcutaneous adipose tissue, visceral adipose cells produce significant amounts of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-a), and Interleukins-1 and -6, etc. Pancreatic ? cells produce somatostatin which has a major inhibitory effect, including on pancreatic juice production. In numerous experimental models, these proinfammatory cytokines profoundly disrupt normal insulin action in fat and muscle cells, and may be a major factor in causing the whole-body insulin resistance observed in patients with visceral adiposity.
Pancreatic ? cells secrete pancreatic polypeptide that is responsible for reducing appetite. Second, visceral adiposity is related to an accumulation of fat in the liver, a condition known as nonalcoholic fatty liver disease (NAFLD).
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.
In this case, the production of antibodies against insulin leads to lower-than-expected glucose level reductions (glycemia) after a specific dose of insulin.


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. In vitro and in vivo studies have demonstrated that insulin may modulate the shift of Mg from extracellular to intracellular space. 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.
Intracellular Mg concentration has also been shown to be effective in modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli.
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.
Poor intracellular Mg concentrations, as found in Type 2 diabetes mellitus and in hypertensive patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. In addition, insulin signaling also stimulates the conversion of glucose into glycogen, a process called glycogenesis, in liver. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in noninsulin-dependent diabetic and hypertensive patients.
Therefore, insulin lowers blood glucose level by promoting glycogenesis and glucose uptake by peripheral tissues (7). By contrast, in T2DM patients daily Mg administration, restoring a more appropriate intracellular Mg concentration, contributes to improve insulin-mediated glucose uptake. 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 benefits deriving- from daily Mg supplementation in T2DM patients are further supported by epidemiological studies showing that high daily Mg intake are predictive of a lower incidence of T2DM.
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. An American study has shown that glucosamine (often prescribed for joint problems) may cause insulin resistance.Insulin resistance has also been linked to PCOS (polycystic ovary syndrome) as either causing it or being caused by it. 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. Insulin resistance has certainly risen in step with the increase in sugar consumption and the substantial commercial usage of HFCS since its introduction to the food trades; the effect may also be due to other parallel diet changes however.
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. CellularAt the cellular level, excessive circulating insulin appears to be a contributor to insulin resistance via down-regulation of insulin receptors.
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. Since the usual instances of Type 2 insulin resistance are distinct from pathological over production of insulin, this does not seem to be the typical cause of the insulin resistance leading to Type 2 diabetes mellitus, the largest clinical issue connected with insulin resistance. In response to hyperglycemia, insulin is secreted from a readily available pool in ? cells. The presence of insulin resistance typically precedes the diagnosis of Types 2 diabetes mellitus, however, and as elevated blood glucose levels are the primary stimulus for insulin secretion and production, habitually excessive carbohydrate intake is a likely contributor. Additionally, some Type 2 cases require so much external insulin that this down-regulation contributes to total insulin resistance.Inflammation also seems to be implicated in causing insulin resistance.
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. PKC Theta inhibits Insulin Receptor Substrate (IRS) activation and hence prevents glucose up-take in response to insulin. Preproinsulin is converted to proinsulin by removing the signal peptide forming three disulfide bonds in the ER. MolecularInsulin resistance has been proposed at a molecular level to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as a antioxidant defense mechanism. 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).
It is also based on the finding that insulin resistance can be rapidly reversed by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.GeneticIndividual variability is a cause with an inherited component, as sharply increased rates of insulin resistance and Type 2 diabetes are found in those with close relatives who have developed Type 2 diabetes. DiseaseSub-clinical Cushing's syndrome and hypogonadism (low testosterone levels) seem to be the major insulin resistance causes .Recent research and experimentation has uncovered a non-obesity related connection to insulin resistance and Type 2 diabetes. When the ? cell is appropriately stimulated, insulin is secreted from the cell by exocytosis (11). It has long been observed that patients who have had some kinds of bariatric surgery have increased insulin sensitivity and even remission of Type 2 diabetes. 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). This suggested similar surgery in humans, and early reports in prominent medical journals (January 8) are that the same effect is seen in humans, at least the small number who have participated in the experimental surgical program. In type 1 diabetes, the loss of ? cell increases the burden of insulin secretion on the residual ? cells.
The speculation is that some substance is produced in that portion of the small intestine which signals body cells to become insulin resistant.
If the producing tissue is removed, the signal ceases and body cells revert to normal insulin sensitivity.
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. Both metformin and the thiazolidinediones improve insulin resistance, but are only approved therapies for type 2 diabetes, not insulin resistance, ''per se''. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.Metformin has become one of the more commonly prescribed medications for insulin resistance, and currently a newer drug, exenatide (marketed as Byetta), is being used.
As featured by its name, RER looks bumpy and rough under a microscope due to the ribosomes on the outer surfaces of the cisternae. Exenatide has not been approved except for use in diabetics, but often improves insulin resistance by the same mechanism as it does diabetes. It also has been used to aid in weight loss for diabetics and those with insulin resistance, and is being studied for this use as well as for weight loss in people who have gained weight while on antidepressants.
The newly synthesized proteins are folded into 3-dimensional structure in RER and sent to Golgi complex or membrane via small vesicles. The ''Diabetes Prevention Program'' showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes.Many people with insulin resistance currently follow the lead of some diabetics, and add cinnamon in therapeutic doses to their diet to help control blood sugar.
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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Comments

  1. STRIKE

    Extra about low carbing, making.

    27.03.2015

  2. Vefa

    Wish I had French blood weight at once, and so it is not possible to cut the concern of fats is so deeply ingrained.

    27.03.2015

  3. GuneshLI_YeK

    Sheet from the CDC's National.

    27.03.2015

  4. Love

    Are some examples of good larger than desired amount of starchy foods.

    27.03.2015