The glycemic index is basically a way in which a person can find those foods that are healthy for them to eat and is not going to affect their sugar as bad. There are several lists available that are going to show the food and the GI level that has been assigned to it based on just what types of carbs it offers and the fiber that is offers. Most types of GI’s that are out there are categorizing the foods in conjunction with whether these are safe and good for a person that has blood sugar problems. Through following GI rates, the person will find that they can better control their own blood sugar without the use of insulin or other drugs.
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As the medical care is advancing and the life expectancy is increasing there are now more people who are now elderly and are patients of type 2 diabetes mellitus. The overall goal of management of diabetes in the elderly patients includes maintaining optimal glycemic control as well as managing the associated risk factors due to advanced age. Metformin may be the initial therapy for patients who do not have a renal impairment or severe heart failure. A short acting sulfonylurea like glipizide may be used for patients who have contraindication for metformin. Repaglinide a drug distinct from sulfonylureas maybe used in patients who are allergic to sulfonyureas and also it has possibly a lower risk of hypoglycemia.
Insulin is usually avoided to be used in older patients but sometimes if required a long acting insulin with one or two daily doses can be used after proper assessment and explanation to the care giver. Tanzeum (albiglutide), developed by GlaxoSmithKline (GSK), is a GLP-1 receptor agonist indicated for treatment of type 2 diabetes.
Tanzeum's mechanism of actionTanzeum contains Glucagon-like peptide-1 (GLP-1) receptor agonist, which is a recombinant protein made by combining two tandem copies of modified human GLP-1 genetically merged in tandem with human albumin. The symptoms of type 2 diabetes include frequent urination, constant appetite and excess thirst. 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 Department of Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong, China Davis Heart & Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio, USA1. Espino-Paisan L, Urcelay E, Concha EGdl, Santiago JL: Early and Late Onset Type 1 Diabetes: One and the Same or Two Distinct Genetic Entities? Zhong J, Xu J, Yang P, Liang Y, Wang C-Y: Innate immunity in the recognition of beta-cell antigens in type 1 diabetes.
Schroder,M, Friedl,P: Overexpression of recombinant human antithrombin III in Chinese hamster ovary cells results in malformation and decreased secretion of recombinant protein. Martinez,IM, Chrispeels,MJ: Genomic analysis of the unfolded protein response in Arabidopsis shows its connection to important cellular processes.
The Mediterranean Food Pyramid includes more high glycemic index carbs than most food pyramids.
Living with diabetes can have significant impact on the foods you eat since everything you eat and drink is broken down into glucose, which can affect your diabetes problem. One of the best ways for diabetics to control the quality of their meals is to plan their diabetes menus. Carbohydrates (45%-65%) - Use more low Glycemic Index carbs than highProteins (10%-35%) - Keep it leanUnsaturated fats (20%-35%) - Monounsaturated and polyunsaturated Diabetes menu planning is an also an excellent way to keep track of calories. The average person should consume about 2,000 calories per day to ensure that their body functions properly and they have enough energy to be active. Check out our Nutrition, and Recipes sections for more information about how you can plan your tasty diabetes menus and live a healthy lifestyle by eating well! We intend to do this within local communities, with partnerships and just through word of mouth.
Canagliflozin, when added to metformin and pioglitazone lowered A1C more effectively than placebo.
Dapagliflozin when added to metformin was as effective as DPP-4 inhibitors, thiazolidinediones, sulphonylureas, and GLP-1 antagonists. Empagliflozin was more effective in lowering A1C than glimepiride when added to metformin; when added to insulin and metformin in patients with type 2 diabetes who were obese and had poorly controlled disease, empagliflozin improved glycemic control and reduced weight without increasing the risk of hypoglycemia and with lower insulin requirements.
SGLT2 inhibitors induce glycosuria, improve glycemia, reduce A1C levels, have low risk of hypoglycemia, and modestly reduce weight and blood pressure. SGLT2 inhibitors increase the risk of genital mycotic infections, polyuria, and volume depletion, and may increase the risk of ischemic stroke, especially early in treatment.
The FDA requires post-marketing studies and pharmacovigilance programs of all 3 manufacturers of approved SGLT2 inhibitors. The insulin-independent action of the SGLT2 inhibitors makes their use appropriate at most points in the disease progression of T2DM. This patient with type 1 diabetes noted a painful erosion at the site of tattoo she had gotten several days earlier. Those foods that are higher in sugar are going to lead to the person having high blood sugar, and the like.
Food is rated by a number system that is going to let the person know whether this is something that is going to affect their sugar negatively or not. For the most part, vegetables are going to be the lowest rating on the GI list, making it something that the person can eat quite a bit of without feeling the effects of their sugar levels rising. Those that look at these are going to find that the values in the GI can range from 0 to upwards of 60.
All the material included in here comes from my own experience and is the result of reading a lot about the subject. Although the pharmacological treatment options are almost the same for the older patients as those in the younger adults but the elderly need some specific care and management if they have diabetes.
Educating about the disease: Studies have shown that patients who know their diseases well are able to manage it more properly than those who are not educated about the disease. Preventing and Recognizing Hypoglycemia: The risk of hypoglycemia is much more in the older adults and the symptoms may be missed or confused and so the hypoglycemic episodes are not properly reported in the elderly patients. Care for Proper Nutrition: Senior patients with diabetes should always be helped by a proper dietitian for the nutrition care.
Choosing the Medications: It is important to consider different factors like weight, mobility, kidney function, risk of hypoglycemia, and other co-morbidity before prescribing a medication to an elderly diabetic patient. Monitoring Of Blood Glucose: Monitoring is necessary to achieve glycemic controls and prevent the complications. Retinopathy: The prevalence of retinopathy increases with the increased duration of diabetes and regular eye examinations are extremely important for older diabetic patients. Care for the Foot: The foot problems are at much higher risk in patients who are old and have diabetes. Physical Activity: Although many elderly patients have limited physical activity due to many associated factors like lack of interest in exercise plans, arthritis, nerve damage or vision problems but the primary care physician can guide each individual for the proper physical activity and exercise program that may be helpful. Preventing Osteoporosis and Fractures: Diabetes is a known risk factor for osteoporosis and appropriate majors should be taken to prevent the complications associated with it more so in the elderly patients. Managing the Associated problems: Elderly patients with diabetes are more prone to suffer from depression, urinary incontinence , urinary tract infections, sudden falls and problems with taking the medicine. GSK received approval for Tanzeum from the US Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in April 2014.Albiglutide received marketing authorisation from the European Medicines Agency (EMA) for treatment of type 2 diabetes in adult patients in March 2014. The rate of patients under glycemic control before and after the education of physicians on guidelines on glycemic control with respect to adherence to SEMT guidelines. IntroductionType 2 diabetes is a progressive chronic disease that causes serious complications and decreases the life expectancy. IntroductionAs one of the major health problems in the world, diabetes affects over 346 million people worldwide. Lower you risks for heart disease, stroke, and other problems of diabetes with a diabetic diet plan that includes healthy food choices to help you better control your blood sugar level. Diabetes menu planning means that you create a menu for the day, week, or even month that you stick to.
Obviously, the larger amounts of food and activities start at the bottom suggesting daily use, and gets smaller as you move up (weekly) toward the top which suggest monthly use. A good Diabetes menu plan will not only provide information that is based on careful research 2000-Calorie-Meal-Plan, but we also provide a range of recipes for diabetes (including diabetes snacks, vegetarian recipes, and even diabetes desserts) that are suitable for any healthy diet. We intend for these key elements of sustainable lifestyle change to become pervasive within communities, and within the lives of all of us affected by the disease.
When added to metformin and compared with glimepiride, canagliflozin at low dose was non-inferior to glimeperide and at high dose was more effective. Added to insulin, dapagliflozin decreased A1C vs placebo and avoided the need to raise insulin dose.
The drugs were studied using estimated glomerular filtration rate versus estimated creatinine clearance with the Cockgroft-Gault equation. Primary concerns center on cardiovascular outcomes, risk for bladder cancer, pediatric safety, and animal toxicity studies focused on renal development. Through utilizing the Glycemic Index, a person can be sure that they are eating food that is going to be good for them, yet have no adverse effect on their blood sugar.
For example, taking the soluble fiber away from the total sugars is one way to get a GI rating.
Anything that is considered to be above a 60 is one food to avoid since it means that it is not that healthy for those that have blood sugar problems. Also it is important to take note of the fact that diabetes is not the only disease that may be affecting the patient because elderly people above the age of 70 have more than one chronic diseases that are present at the same time. Even a mild hypoglycemia that caused dizziness may lead do major problems like a fall and resulting fracture that is very difficult to heal due to the age factor. It is usually advised to monitor HbA1c levels twice in a year for elderly patients who are meeting the treatment goals and are stable. The eye examination not only screens for retinopathy but also checks for the cataract and glaucoma that is more common in diabetes as well as with aging.
With advanced age neuropathy increases and the old patients do not take care of the feet as they used to take care at their younger age. It is available in 50mg dose that can be administered through injection for subcutaneous (SC) use.Clinical trials of TanzeumFDA approval for Tanzeum was based on results obtained from comprehensive Phase III study known as Harmony programme that consisted of eight clinical trials, which enrolled more than 5,000 patients and treated more than 2,000 of them with Tanzeum. Physicians’ adherence to SEMT guidelines regarding medical history, physical examination, and laboratory evaluation.
Physicians’ adherence to SEMT guidelines during prospective phase of the study before and after education of physicians on guidelines.
According to 1997-98 population-based survey (TURDEP-I), the prevalence of diabetes was 7.2% in adult population of Turkey . So, it is best to plan a diabetic diet menu that can help you lose excess fat and maintain your ideal weight. A good diabetes menu plan will include diabetes snack options that will help to control your appetite as well as different diabetic meal options so that you don't get bored by eating the same foods over and over again. Bad food choices will raise your blood sugar, that will cause you to use more diabetes drugs, or make you suffer severe diabetes complications. Other people prefer to have a list of GI foods right there for them to look at to know just what they should be looking for and what they should avoid.
Even those that do not have blood sugar problems, the use of the GI can ensure that you are getting healthier food to eat.
Elderly patients may not be able to remember properly about their drugs and doses or may forget about the nutritional care.
The symptoms of the disease include frequent urination, constant appetite and excess thirst. Unfortunately, the therapy of diabetes remains unsatisfied despite of extensive studies in the last decades. The diabetes food guide will teach you what you can eat (all the nutrients you need), how much you should eat, and how often you can enjoy it (while keeping your blood glucose under control).
The patients were randomised to receive Tanzeum 30mg SC once weekly, Tanzeum 30mg SC once weekly uptitrated to 50mg once weekly at Week 12, or placebo.The study results demonstrated that the patients who were treated with Tanzeum 30mg or 50mg showed statistically significant reductions in HbA1c from baseline at Week 52. Early diagnosis, correct and intensive antidiabetes treatment, and effective follow-up were recommended to decrease the risk of complications .
Despite extensive evidence of benefits of tight glycemic control, large proportions of people with diabetes do not achieve target glycemic control.The use of clinical guidelines is the best strategy for the effective control of diabetes. Type 1 diabetes mellitus, used to known as juvenile diabetes, is typically developed in children and juveniles. Other medications available for the treatment of type 2 diabetes include Forxiga (dapagliflozin) developed by AstraZeneca and Bristol-Myers Squibb, and Invokana (canagliflozin) manufactured by Janssen Pharmaceuticals and Mitsubishi Tanabe Pharma Corporation. There are multiple diabetes practice guidelines based on published data or derived from expert consensus and provide specific recommendations to diagnose diabetes and to achieve and maintain glycemic control.
Previous studies reported non-adherence to evidence-based guidelines, which was based on physician factors, patient factors, and organizational factors [8–11].
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).
Therefore, Diabetes Study Group of The Society of Endocrinology and Metabolism of Turkey (SEMT) developed ‘Clinical Practice Guidelines for Diagnosis, Treatment, and Follow-up of Diabetes and Its Complications’ in 2006, which are reviewed and updated biannually [12–14]. 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. In comparison with ‘American Diabetes Association (ADA) Clinical Practice Recommendations’, the SEMT guidelines include more detailed information on diagnosis and follow-up of diabetes and its complications in addition to general information on diabetes. Autoimmune-mediated ? cell death has been considered as the major cause of ?-cell loss in type 1 diabetes. Furthermore, diabetes management on special and co-morbid conditions such as pregnancy, surgery, travel, vaccination, hypertension, hyperlipidemia, coronary artery disease was explained in detail in the SEMT guidelines. 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. If target A1C is not still obtained, basal-bolus insulin is started and MET treatment is retained if possible.The perception and use of SEMT guidelines by physicians in Turkey, however, are unknown. 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. Therefore, we aimed to determine the physicians’ adherence to the SEMT diabetes guidelines in a study entitled “Adherence of physicians to guidelines for the management of type 2 diabetes: The ADMIRE study”.
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.
The main objectives of the ADMIRE study were to evaluate physicians’ adherence to SEMT diabetes guidelines, to determine the factors affecting physicians’ adherence, to evaluate the impact of physicians’ adherence to guidelines on glycemic control in diabetes mellitus, and to prospectively evaluate the impact of education of physicians on the adherence to guidelines.2. 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.
For the retrospective phase, 200 Internal Medicine or Family Medicine physicians who involved in medical care of patients with type 2 diabetes were randomly selected to represent all geographical regions and hospital types.
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). Prospective phaseIn this phase, physicians were educated on the basis of data obtained from retrospective phase. 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).
The educations included one-day comprehensive training coursewith case presentations and distribution of a DVD and booklets on several complications of diabetes mellitus.
After a meal, the digestive system breaks down the carbohydrates to small sugar molecules, mainly glucose. Along with a hard copy of SEMT diabetes guidelines, and online access to education materials for three months.
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. Total duration of prospective phase was 15 months.The change in adherence of physicians to SEMT guidelines and glycemic control with education of physicians was evaluated. Furthermore, the effect of education on the rate of patients with regard to physicians’ adherence to guidelines for treatment of diabetes was determined. 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. Parameters for adherence to guidelinesAdherence to SEMT guidelines was assessed in three domains of medical history, physical examination, and laboratory evaluations; each domain was scored on a 10-point scale (0 for non-adherence, 10 for full adherence). 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. Glycemic control parametersThe relation between the degree of adherence to SEMT guidelines and glycemic control of patients was evaluated.
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.
Statistical analysesStudy data was summarized with descriptive statistics (number, percentages, mean, standard deviation).
Spearman’s simple correlation coefficient (r) was calculated for the correlation of between degree of adherence to guidelines and the levels of A1C, FBG, and PPBG.
Student t test and analysis of variance (ANOVA) followed by post-hoc Tukey test were used to compare continuous data of two and three groups, respectively.
Chi-square test or Mantel-Haenszel chi-square test was used for comparison of discrete data between groups. 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.
Factors affecting physicians’ adherence on retrospective phase Patients’ age, gender, diabetes duration, BMI, presence and number of chronic complications were patient-related factors; type of institution and specialty were physician-related factors whose effects on scores for adherence to guidelines were studied.
Pancreatic ? cells and insulin biosynthesisEither insulin deficiency or insulin inefficiency can cause diabetes. For older patients and males, physicians’ adherence to guidelines was higher for laboratory evaluations.
As the only cell type producing insulin, ? cell plays a critical role in the development of diabetes. All aspects of guideline adherence were poor in patients with short duration (<5 years) of diabetes and in the absence of chronic complications.
In type 1 diabetes, autoimmune-mediated destruction of ? cell leads to insufficient insulin production and inability of cells to take up glucose. Impact of adherence to guidelines on glycemic control on retrospective phase Degree of overall adherence for diagnosis and follow-up procedures to guidelines did not correlate with glycemic control parameters except a negative correlation with FBG levels in visit 2. 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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