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How Are Beta Cells Destroyed In Type 1 Diabetes?

Beta Cells

Beta Cells

Tweet Beta cells are unique cells in the pancreas that produce, store and release the hormone insulin. Located in the area of the pancreas know as the islets of Langerhans (the organ’s endocrine structures), they are one of at least five different types of islet cells that produce and secrete hormones directly into the bloodstream. What is the role of beta cells? The main function of a beta cell is to produce and secrete insulin - the hormone responsible for regulating levels of glucose in the blood. When blood glucose levels start to rise (e.g. during digestion), beta cells quickly respond by secreting some of their stored insulin while at the same time increasing production of the hormone. This quick response to a spike in blood glucose usually takes about ten minutes. In people with diabetes, however, these cells are either attacked and destroyed by the immune system (type 1 diabetes), or are unable to produce a sufficient amount of insulin needed for blood sugar control (type 2 diabetes). Amylin and C-peptide In addition to insulin, beta cells also secrete the hormone Amylin and called C-peptide, a byproduct of insulin production. Amylin slows the rate of glucose entering the bloodstream, making it a more short-term regulator of blood glucose levels. C-peptide is a molecule that helps to prevent neuropathy and other vascular complications by assisting in the repair of the muscular layers of the arteries. It is secreted into the bloodstream in equal quantities (or moles) to insulin. Beta cells in type 1 diabetes In type 1 diabetes, beta cells die from a misguided attack by the body’s immune system. How and why that happens is not clear, but the results of a study published in early 2011 suggest that these pancreatic cells become stressed at the earliest stages of Continue reading >>

Autoimmune Destruction Of Pancreatic Beta Cells

Autoimmune Destruction Of Pancreatic Beta Cells

Type 1 diabetes (T1D) is a chronic autoimmune disease caused by proinflammatory T cell infiltration associated cytokine secretion and reactive oxygen species (ROS) production. In this study, our objective was to determine whether co-delivery of sunitinib, a member of tyrosine kinase inhibitor (TKI) family, and siRNA against Alox15 (siAlox15) could reverse the new-onset of T1D in non-obese diabetic (NOD)/ShiLtJ female mice which spontaneously develop diabetes. A cationic copolymer methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol-graft-tetraethylenepentamine) (mPEG-b-PCC-g-DC-g-TEPA) was used to encapsulate sunitinib with 8.32-9.39% loading efficacy and form complex with siAlox15 at the N/P ratio of 16:1. These micellar formulations exhibited sustained release of sunitinib for around 50% at 24 h and protected siAlox15 from serum degradation for at least 10 h. Further, both sunitinib and siAlox15 inhibited human peripheral blood mononuclear cell (PBMC) proliferation and activation by downregulating the phosphorylation of Akt, platelet-derived growth factor receptor (PDGFR) at protein levels and Alox15 in mRNA levels, respectively. Besides, siAlox15 treatment reversed the cytokine induced ROS upregulation in rat INS-1E cells. Finally, systemic administration of these micelles carrying sunitinib and siAlox15 efficiently reversed T1D in NOD mice as indicated by decreased blood glucose concentration to below 250 mg/dL. The mice showed fast response to high glucose which was determined by intraperitoneal glucose tolerance test and promoted serum insulin production. Tissue staining indicated that sunitinib and siAlox15 combination could inhibit T cell infiltration to mouse islets, thereby promoting islet survival and function. In Continue reading >>

Can Beta Cells Be Healed?

Can Beta Cells Be Healed?

Can Type 2 or Type 1 diabetes be not only reversed, but cured? Can beta cells start producing enough insulin? Can the liver store glucose better, and can body cells learn to handle glucose more efficiently? We always hear that diabetes is incurable, and so far it has been. But people are trying. Diabetes affects so many organs; we’ll have to investigate them one at a time. This week we’ll look at beta cells in the pancreas. If you have Type 1 or 2 diabetes or prediabetes, you have damaged beta cells. So you don’t have enough insulin, and what you have may not be released when it’s needed. If the cells were healed, diabetes would pretty much go away. But is this possible, and how could it be done? In Type 1 diabetes, cells from the immune system attack and destroy beta cells. Type 1.5 diabetes or LADA (latent autoimmune diabetes of adults) probably involves a similar process. So restoring beta cells in Type 1 or 1.5 will probably require changing the immune system. Reducing the need for insulin by eating a healthy diet helps, but I don’t know of any Type 1s or people with LADA who recovered normal beta cell function by diet alone. Many are looking at surgically replacing beta cells. Hundreds of experimental “islet cell transplants” have been done. But the results aren’t great. This approach will only work if we could also “turn off” whatever process is killing beta cells in the first place. But there’s a lot of money in it, so I’m sure the research will continue. Research is going on into drugs that might stop the immune system’s attack. A drug called teplizumab is being studied and shows promise. But as a person with an immune disease of my own, I’m pretty sure this progress will be slow. The immune system is not well understood yet. Beta cel Continue reading >>

Long-sought 'attack' Signal In Type 1 Diabetes Identified

Long-sought 'attack' Signal In Type 1 Diabetes Identified

MORE In people with type 1 diabetes, the body wages a ruthless campaign of destruction against certain cells in the pancreas because it mistakes them for foreign invaders. Now, one of the long-sought triggers of this assault might have been found, according to a new study from Switzerland. The cells that are destroyed, called beta cells, normally produce certain proteins in packages called exosomes. The new study found that, when the cells are in trouble, such as after an infection or other stressful event, these packages are decorated with chemical warning signals that may act as homing beacons that lure immune cells. "When beta cells are subjected to stress, the exosomes are released at higher levels and now contain proteins that signal danger to alert the immune system," said study author Steinunn Baekkeskov, a biochemist at the Swiss Federal Institute of Technology in Lausanne, Switzerland. The new findings could provide a means to shut off the wayward immune system, thereby preventing the development of type 1 diabetes in people who are at very early stages of the disease, the study authors suggested. Mysterious target Normally, beta cells release the hormone insulin, which helps body cells take in sugar from the bloodstream. People with type 1 diabetes, whose beta cells are destroyed, must inject insulin into their bodies, or they will die. Those with the disease constantly monitor their blood sugar and take many doses of insulin each day to regulate their blood sugar. But even with these treatments, blood sugar levels that frequently run too high and too low mean that people with the condition face an increased risk of complications such as kidney failure, heart disease and nerve damage. In an ongoing, decades-long study, scientists have monitored the family memb Continue reading >>

Mediators And Mechanisms Of Pancreatic Beta-cell Death In Type 1 Diabetes

Mediators And Mechanisms Of Pancreatic Beta-cell Death In Type 1 Diabetes

PERSPECTIVA Mecanismos de destruição e morte da célula-beta pancreática no diabetes Pierre Pirot; Alessandra K. Cardozo; Décio L. Eizirik Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium ABSTRACT Type 1 diabetes mellitus (T1D) is characterized by severe insulin deficiency resulting from chronic and progressive destruction of pancreatic beta-cells by the immune system. The triggering of autoimmunity against the beta-cells is probably caused by environmental agent(s) acting in the context of a predisposing genetic background. Once activated, the immune cells invade the islets and mediate their deleterious effects on beta-cells via mechanisms such as Fas/FasL, perforin/granzyme, reactive oxygen and nitrogen species and pro-inflammatory cytokines. Binding of cytokines to their receptors on the beta-cells activates MAP-kinases and the transcription factors STAT-1 and NFk-B, provoking functional impairment, endoplasmic reticulum stress and ultimately apoptosis. This review discusses the potential mediators and mechanisms leading to beta-cell destruction in T1D. Keywords: Pancreatic beta-cell; Diabetes mellitus; Apoptosis; Cytokines; Endoplasmic Reticulum; ER stress RESUMO O diabetes melito tipo 1 (DM1) tem como característica uma grave deficiência de insulina que resulta da destruição da célula-beta, crônica e progressiva, pelo sistema imune. O desencadeamento da autoimunidade contra a célula-beta é causado, provavelmente, por agentes ambientais que atuam quando existe predisposição genética. Uma vez ativadas, células imunes invadem as ilhotas, e os efeitos deletérios sobre as células-beta são mediados por mecanismos relacionados a Fas/FasL, perforina/granzima, espécies reativas de oxigênio e nitrogênio, e a c Continue reading >>

Autoimmune Destruction Of Pancreatic Beta Cells.

Autoimmune Destruction Of Pancreatic Beta Cells.

Abstract Type 1 diabetes results from the destruction of insulin-producing pancreatic beta cells by a beta cell-specific autoimmune process. Beta cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes have been shown to be involved in the pathogenesis of autoimmune diabetes. Beta cell autoantigens are thought to be released from beta cells by cellular turnover or damage and are processed and presented to T helper cells by antigen-presenting cells. Macrophages and dendritic cells are the first cell types to infiltrate the pancreatic islets. Naive CD4+ T cells that circulate in the blood and lymphoid organs, including the pancreatic lymph nodes, may recognize major histocompatibility complex and beta cell peptides presented by dendritic cells and macrophages in the islets. These CD4+ T cells can be activated by interleukin (IL)-12 released from macrophages and dendritic cells. While this process takes place, beta cell antigen-specific CD8+ T cells are activated by IL-2 produced by the activated TH1 CD4+ T cells, differentiate into cytotoxic T cells and are recruited into the pancreatic islets. These activated TH1 CD4+ T cells and CD8+ cytotoxic T cells are involved in the destruction of beta cells. In addition, beta cells can also be damaged by granzymes and perforin released from CD8+ cytotoxic T cells and by soluble mediators such as cytokines and reactive oxygen molecules released from activated macrophages in the islets. Thus, activated macrophages, TH1 CD4+ T cells, and beta cell-cytotoxic CD8+ T cells act synergistically to destroy beta cells, resulting in autoimmune type 1 diabetes. Continue reading >>

Beta Cell Dysfunction

Beta Cell Dysfunction

Beta cells reside in the pancreas, where they do the important job of producing insulin for the body. Beta cells produce insulin, and also secrete insulin when they are signaled to do so by an increase in glucose levels in the blood. Without adequate insulin, blood glucose levels rise too high, a defining characteristic of any type of diabetes. In type 2 diabetes, beta cells churn out a lot of insulin early in the disease process; type 2 is characterized by both high glucose levels, and high insulin levels in the blood. The main problem is that the body's tissues are resistant to insulin, and can't use it properly. As type 2 diabetes progresses over time, however, the beta cells seem to wear out, and eventually produce less insulin. Some people with type 2 diabetes end up having to take insulin because their beta cells are not producing enough of it. In type 1 diabetes, the beta cells do not produce enough insulin. This is generally due to the death of the beta cells. By the time someone is diagnosed with type 1 diabetes, they may have lost 70-80% of their beta cells (it is thought, although more recent studies are testing this number). Beta cell loss occurs gradually over time, beginning before diagnosis, and continuing afterwards, until most beta cells are lost (Cnop et al. 2005). However, new research is also finding that some people with type 1 continue to produce insulin for many years (Davis et al. 2014; Oram et al. 2014), as well as proinsulin (a precursor to insulin) (Steenkamp et al. 2017), and that beta cell dysfunction (not just death) may also be a significant cause of high blood sugar, at least around the time of diagnosis (Pugliese et al. 2014). Further new research suggests that beta cell mass and function is actually maintained until just before diagnosi Continue reading >>

What Is Diabetes Mellitus?

What Is Diabetes Mellitus?

Diabetes is a metabolic disorder that occurs when the body cannot properly use glucose (a form of sugar), the body's main source of fuel. During digestion, most of the carbohydrates we eat are converted to glucose, which passes into the bloodstream where it is available to the cells for use as energy. 80% of the glucose in the blood goes to the muscles. But in order for glucose to enter the cells and be used as energy, insulin, a hormone secreted in the islets of the pancreas, must be present. Without insulin, the body cannot convert food into energy. The cells that produce insulin are called beta cells. They are normally stimulated to produce insulin by the rising level of blood glucose. In that way, the body has a system by which the right amount of insulin is secreted for the right amount of glucose present. Once the glucose has entered the cells, the blood glucose level decreases, and the beta cells stop secreting insulin. Q: What are the different types of diabetes? A: There are basically two types of diabetes. In one type, the beta cells are destroyed by the immune system and no longer secrete insulin. This is called type I diabetes and is characterized by an absolute deficit of insulin. The other type, called type II diabetes, is due to "insulin resistance," an initial resistance of the body's cells to obey the orders of insulin. To overcome this resistance, the beta cells secrete more insulin, and glucose is eventually forced into the cells. Glucose is maintained within normal limits, but at the expense of increased insulin secretion by the beta cells. After many years of such increased secretion, the beta cells become "tired" from working overtime, and the fatigue process begins. This fatigue tends to be progressive, and in time the compensation of insulin resi Continue reading >>

Inflammatory Beta-cell Destruction In Diabetes - Part 1, By Professor Thomas Mandrup-poulsen

Inflammatory Beta-cell Destruction In Diabetes - Part 1, By Professor Thomas Mandrup-poulsen

Diabetes and obesity are growing health problems in rich and poor countries alike. With this course you will get updated on cutting-edge diabetes and obesity research including biological, genetic and clinical aspects as well as prevention and epidemiology of diabetes and obesity. All lectures are provided by high-profile scientists from one the world's leading universities in diabetes research. This course is part of the EIT Health Campus programme.We hope you will enjoy our course.Best Wishes Jens Juul Holst, Signe Srensen Torekov and Nicolai Wewer Albrechtsen Department of Biomedical Sciences Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Inflammatory Beta-cell Destruction in Diabetes Inflammatory beta-cell destruction in diabetes by professor Thomas Mandrup-Poulsen. During this module we Professor Mandrup-Poulsen will guide you through cytokines mediated destruction of the pancreatic beta-cells furthermore their potentiality as drugs targets. Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Welcome to this module on inflammatory beta cell destruction in diabetes. I am Thomas Mandrup-Poulsen of the Department of Biomedical Sciences, So in this module, I'd like to discuss the following topics. I'd like to start off with discussing diabetes And then I'd like to go on with causes of beta cell failure in type 1 and I'll then discuss the innate immune system and beta cell failure. And then inflammatory mediators as a therapeutic targets of type 1 and I'd like to end off with two examples of recent developments from our Continue reading >>

Not All Beta Cells Are Destroyed In Type 1 Diabetes

Not All Beta Cells Are Destroyed In Type 1 Diabetes

For a long time, doctors thought that the onset of type 1 destroyed all beta cells. But recent research coming out of Joslin is suggesting a different story. Susan Bonner-Weir, PhD, Senior Investigator in Islet Cell and Regenerative Biology at Joslin and Professor of Medicine at Harvard Medical School is working on understanding how beta cells can still exist after years of type 1 diabetes. The Joslin Medalist program honors people who have had type 1 diabetes for at least fifty years. Many of the honorees choose to participate in studies being conducted at Joslin that examine their lifestyles and genetic codes for clues to what keeps them living well with this disease for more than five decades. In one branch of this research, Dr. Bonner-Weir studies the pancreases of Medalists who have passed away and donated their organs to furthering diabetes research. “The thing that is quite striking is, I’ve look at over 50 pancreases and every single one of them has some beta cells,” says Dr. Bonner-Weir. “These people had an average of 65 years with type 1 diabetes, but they still have beta cells.” The most peculiar finding, though, is that these beta cells aren’t necessarily found within an islet. They instead crop up here and there throughout the pancreas. It appears that the pancreas can recognize that its ability to create insulin is being hampered by the autoimmune attack and can generate insulin-producing cells in new areas that are as-yet untouched by the autoimmune response. According to Dr. Bonner-Weir, this pattern of beta cell regrowth probably means beta cell destruction isn’t a one-time occurrence. It appears that the body struggles to restore beta cell function while being repeatedly attacked by the autoimmune system.. “My interpretation is that yo Continue reading >>

The Problem Of Not Enough Beta Cells In Type 1 Diabetes

The Problem Of Not Enough Beta Cells In Type 1 Diabetes

Joslin researchers lead in pursuing several strategies to replenish the insulin-producing beta cells destroyed in the disease Here’s how it’s supposed to work: Sprinkled throughout the pancreas, tiny collections of beta cells generate the small amount of insulin needed each day, with their production exquisitely calibrated minute-by-minute with blood glucose levels. But in type 1 diabetes, an autoimmune attack seeks and destroys these important but fragile cells. Joslin scientists are leading the way in the quickly advancing research to find new sources for beta cells—including “progenitor” cells located in the pancreas that can morph into beta cells—and to develop innovative ways to make more copies of surviving cells. Just as critical are efforts to ensure that any newly formed beta cells are fully functional and that they can survive the ordeal of transplantation. An alternate source? Susan Bonner-Weir, Ph.D., and her colleagues have amassed evidence of an important potential source of new beta cells within the pancreas. Her lab showed that in rats and mice that are neonatal or have had pancreatic injury, cells in the nearby pancreatic ducts, which act like pipes for digestive enzymes, can differentiate into beta cells and the other pancreatic cells. “But which cell in the duct tree is the progenitor?” Dr. Bonner-Weir asks. Working with both mice and human cells, her lab is puzzling out exactly which cells can switch, and what signals those cells to make the transition and then proliferate. Replicating success Gordon Weir, M.D., looks at the replication of existing adult human beta cells. In one effort funded by the Juvenile Diabetes Research Foundation, he experiments with human islets that are transplanted into mice whose immune systems have been sh Continue reading >>

Possible Source Of Beta Cell Destruction That Leads To Type 1 Diabetes

Possible Source Of Beta Cell Destruction That Leads To Type 1 Diabetes

Follow all of ScienceDaily's latest research news and top science headlines ! Possible source of beta cell destruction that leads to Type 1 diabetes Doctors have been studying the role of the enzyme 12-Lipoxygenase (12-LO) in the development of Type 1 diabetes. They hope that targeting this enzyme will hold the key to reversing the disease. Doctors at Eastern Virginia Medical School's Strelitz Diabetes Center have been stalking the culprit responsible for Type 1 diabetes. Now, they are one step closer. Members of a research team at the center, led by Jerry Nadler, MD, professor and chair of internal medicine and director of the center, have been studying the role of the enzyme 12-Lipoxygenase (12-LO) in the development of Type 1 diabetes. They hope that targeting this enzyme will hold the key to a cure. Dr. Nadler and several research colleagues in the EVMS Department of Internal Medicine, including Kaiwen Ma, PhD, research instructor; Swarup K. Chakrabarti, PhD, research assistant professor; and David A. Taylor-Fishwick, PhD, associate professor, recently published their findings in the February issue of The Journal of Clinical Endocrinology and Metabolism. Type 1 diabetes is a chronic condition that develops when the pancreas stops generating enough insulin to maintain normal levels of glucose (sugar) in the blood. Insulin moves sugar from the bloodstream to cells so that it can be used to generate energy. In Type 1 diabetes, a person's immune system attacks the insulin-producing beta cells, found only in the pancreas. When the beta cells die, the body no longer can produce enough insulin to regulate blood-glucose levels, and this can lead to serious health complications, even death, without treatment. It is generally understood that inflammation plays a vital role i Continue reading >>

Pathogenic Mechanisms In Type 1 Diabetes: The Islet Is Both Target And Driver Of Disease

Pathogenic Mechanisms In Type 1 Diabetes: The Islet Is Both Target And Driver Of Disease

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease We are experimenting with display styles that make it easier to read articles in PMC. The ePub format uses eBook readers, which have several "ease of reading" features already built in. The ePub format is best viewed in the iBooks reader. You may notice problems with the display of certain parts of an article in other eReaders. Generating an ePub file may take a long time, please be patient. Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease Kate L. Graham, Robyn M. Sutherland, [...], and Thomas W.H. Kay Recent advances in our understanding of the pathogenesis of type 1 diabetes have occurred in all steps of the disease. This review outlines the pathogenic mechanisms utilized by the immune system to mediate destruction of the pancreatic beta-cells. The autoimmune response against beta-cells appears to begin in the pancreatic lymph node where T cells, which have escaped negative selection in the thymus, first meet beta-cell antigens presented by dendritic cells. Proinsulin is an important antigen in early diabetes. T cells migrate to the islets via the circulation and establish insulitis initially around the islets. T cells within insulitis are specific for islet antigens rather than bystanders. Pathogenic CD4+ T cells may recognize peptides from proinsulin which are produced locally within the islet. CD8+ T cells differentiate into effector T cells in islets and then kill beta-cells, primarily via the perforin-granzyme pathway. Cytokines do not appear to be important cytotoxic molecules in vivo. Maturation of the immune response within the islet is now understood to contribute to diabetes, and highlights the islet as both driver and target of t Continue reading >>

Inflammatory Beta-cell Destruction In Diabetes - Part 2, By Professor Thomas-mandrup Poulsen

Inflammatory Beta-cell Destruction In Diabetes - Part 2, By Professor Thomas-mandrup Poulsen

Diabetes and obesity are growing health problems in rich and poor countries alike. With this course you will get updated on cutting-edge diabetes and obesity research including biological, genetic and clinical aspects as well as prevention and epidemiology of diabetes and obesity. All lectures are provided by high-profile scientists from one the world's leading universities in diabetes research. This course is part of the EIT Health Campus programme.We hope you will enjoy our course.Best Wishes Jens Juul Holst, Signe Srensen Torekov and Nicolai Wewer Albrechtsen Department of Biomedical Sciences Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen Inflammatory Beta-cell Destruction in Diabetes Inflammatory beta-cell destruction in diabetes by professor Thomas Mandrup-Poulsen. During this module we Professor Mandrup-Poulsen will guide you through cytokines mediated destruction of the pancreatic beta-cells furthermore their potentiality as drugs targets. Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Department of Biomedical Sciences & NNF Center for Basic Metabolic Research Let us now first consider how inflammatory beta cell destruction comes To understand how the immune system accomplishes this, we first need to discuss how the immune system is activated. The first step in the immune activation is engaging the innate system. And the most important cells here are the dendritic cells and Upon the recognition of dangerous signals, or in case of the release and uptake of antigen, this will activate these cells and they become so called antigen presenting cells. This process involves the uptake of th Continue reading >>

Beta-cell Function And Failure In Type 1 Diabetes

Beta-cell Function And Failure In Type 1 Diabetes

1. Introduction Glucose is an essential energy source for all cells. Therefore, maintaining glucose levels within a normal range is essential for life in vertebrates. Glucose homeostasis in the organism is tightly regulated by insulin, a hormone that acts on the major glucose metabolic tissues such as muscle, liver and adipose tissue. Insulin’s main effects include promoting glucose uptake, glycogen synthesis in the liver and muscle, triglyceride formation to be stored in adipocytes, and protein synthesis. Insulin secretion is held by the pancreatic beta-cells, and it is modulated by glucose levels. Insufficient insulin secretion and consequent impairment of insulin’s actions lead to Diabetes Mellitus. Diabetes is a group of metabolic diseases characterized by hyperglycemia, caused by a defect on insulin production, insulin action or both. Type 1 diabetes in particular is due to an autoimmune destruction of the insulin producing pancreatic beta-cell, which usually leads to absolute insulin deficiency (ADA 2009). This type of diabetes accounts for 5-10% of the total cases of diabetes worldwide, and although its onset is commonly during childhood and adolescence, it can occur at any age, even during late adulthood. As the loss of beta-cells is determinant for the development of overt type 1 diabetes, understanding beta-cell’s normal physiology, namely insulin secretion, and how it may be affected during the progression of this disease is essential. Moreover, the development of new therapeutic interventions for type 1 diabetes, such as islet transplantation, beta cell maintenance and replacement, or stem cell therapy, requires a profound knowledge of how the presence of different nutrients and signals may regulate insulin secretion and beta-cell mass. In this chapter Continue reading >>

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