Let's read! We will often find out this sentence everywhere. When still being a kid, mom used to order us to always read, so did the teacher. Some books are fully read in a week and we need the obligation to support reading. What about now? Do you still love reading? Is reading only for you who have obligation? Absolutely not! We here offer you a new book enPDFd preventing chronic diseases a vital investment to read.

Preventing Chronic Diseases: A Vital Investment

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/15000/15318/JCI0215318.pdf

Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

▪ Abstract Autoimmunity is a complex process that likely results from the summation of multiple defective tolerance mechanisms. The NOD mouse strain is an excellent model of autoimmune disease and an important tool for dissecting tolerance mechanisms. The strength of this mouse strain is that it develops spontaneous autoimmune diabetes, which shares many similarities to autoimmune or type 1a diabetes (T1D) in human subjects, including the presence of pancreas-specific autoantibodies, autoreactive CD4+ and CD8+ T cells, and genetic linkage to disease syntenic to that found in humans. During the past ten years, investigators have used a wide variety of tools to study these mice, including immunological reagents and transgenic and knockout strains; these tools have tremendously enhanced the study of the fundamental disease mechanisms. In addition, investigators have recently developed a number of therapeutic interventions in this animal model that have now been translated into human therapies. In this review...

THE NOD MOUSE: A Model of Immune Dysregulation

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic β cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60–80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

https://www.pnas.org/content/pnas/104/43/17040.full.pdf

The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes

The hallmark of type 1 diabetes is specific destruction of pancreatic islet beta-cells. Apoptosis of beta-cells may be crucial at several points during disease progression, initiating leukocyte invasion of the islets and terminating the production of insulin in islet cells. beta-Cell apoptosis may also be involved in the occasional evolution of type 2 into type 1 diabetes.

β-Cell death during progression to diabetes

In neonatal rodents, the beta-cell mass undergoes a phase of remodeling that includes a wave of apoptosis. Using both mathematical modeling and histochemical detection methods, we have demonstrated that beta-cell apoptosis is significantly increased in neonates as compared with adult rats, peaking at approximately 2 weeks of age. Other tissues, including the kidney and nervous system, also exhibit neonatal waves of apoptosis, suggesting that this is a normal developmental phenomenon. We have demonstrated that increased neonatal beta-cell apoptosis is also present in animal models of autoimmune diabetes, including both the BB rat and NOD mouse. Traditionally, apoptosis has been considered a process that does not induce an immune response. However, recent studies indicate that apoptotic cells can do the following: 1) display autoreactive antigen in their surface blebs; 2) preferentially activate dendritic cells capable of priming tissue-specific cytotoxic T-cells; and 3) induce the formation of autoantibodies. These findings suggest that in some circumstances physiological apoptosis may, in fact, initiate autoimmunity. Initiation of beta-cell-directed autoimmunity in murine models appears to be fixed at approximately 15 days of age, even when diabetes onset is dramatically accelerated. Taken together, these observations have led us to hypothesize that the neonatal wave of beta-cell apoptosis is a trigger for beta-cell-directed autoimmunity.

https://diabetes.diabetesjournals.org/content/diabetes/49/1/1.full.pdf

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Type 1 diabetes is an autoimmune disorder charac-terized by the selective destruction of pancreatic βcells, resulting in insulin deficiency and hyper-glycemia. Studies of both humans (1) and the NODmouse model (2, 3) have shown that βcell destruc-tion is mediated largely by T lymphocytes. Despitethe direct βcell cytotoxic role of T cells during dia-betes progression, prediction of disease in bothhumans and the NOD mouse has been based prima-rily on the presence of circulating autoantibodies toputative T cell antigens (4, 5). Detection and charac-terization of antigen-specific T cells from peripheralblood during the progression of type 1 diabetes, orother autoimmune diseases, has thus far not beenpossible without in vitro manipulation. Conse-quently, little is known regarding the evolution ofautoreactive T cell populations during the naturalhistory of autoimmune diseases.Although the detection of antigen-specific T cellsusing MHC tetramers has permitted careful characteri-zation of T cell responses to many viral and bacterialinfections (6, 7), attempts to elucidate the in vivo dynam-ics of autoreactive T cells during the progression ofautoimmune diseases have been less successful. With asingle exception (8), attempts to visualize autoreactive Tcells in peripheral blood or lymphoid organs ex vivo withMHC tetramers bearing naturally-occurring ligandshave failed (9–14), possibly because of the lower aviditythat T cells have for self versus foreign peptide/MHC lig-ands (15, 16). To overcome this limitation, we have engi-neered high-avidity peptide/MHC tetramers capable ofstably interacting with low-avidity autoreactive T cells,thus facilitating their detection. The visualization of low-avidity T cell populations in peripheral blood would pro-vide a simple, minimally invasive method for assessingthe presence of autoreactive T cells within infiltrated tis-sues and might therefore be useful for predicting thedevelopment of autoimmune disease.The feasibility of employing a high-avidity MHCtetramer to detect relatively low-avidity autoreactive Tcells was investigated using NOD mice, an extensivelystudied model of human type 1 diabetes (3, 17). In thesemice, diabetes develops by 16 to 20 weeks of age inapproximately 80% of females and is preceded by a pro-longed period of mononuclear cell inflammation of the

/pdf/prediction-of-spontaneous-autoimmune-diabetes-in-nod-mice-by-3xyw2sffuy.pdf

Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood

In Vivo Phagocytosis of Apoptotic Cells by Macrophages from NOD Mice Is Reduced

OBJECTIVE To investigate what role family physicians currently play in the management of patients with nutrition-related issues and whether implementation of current nutrition counseling guidelines is feasible in primary care practices. DESIGN Mailed survey. SETTING Family practice offices in British Columbia. PARTICIPANTS A total of 451 Canadian-trained family physicians practising in British Columbia. MAIN OUTCOME MEASURES Respondents’ demographic characteristics; respondents’ attitudes about and perceived barriers to nutrition counseling, as well as their current practices and training in this area. RESULTS Among the 757 physicians surveyed, the response rate was 59.6%. Overall, respondents had positive attitudes about the role of nutrition in patient health, and most physicians (58.1%) believed that more than 60% of their patients would benefit from nutrition counseling. However, there was a considerable gap between the proportion of patients who respondents thought would benefit from nutrition counseling and the proportion of patients who received such counseling either in the family physicians’ offices or through referral to dietitians. Rural physicians referred patients to dietitian services more frequently than urban physicians did (41.7% vs 21.7% made more than 20 referrals to dietitians each year). Nearly all physicians identified lack of time and compensation as the strongest barriers to providing nutrition guidance. Training was not considered to be as strong a barrier to counseling, even though 82.3% of family physicians reported their formal nutrition training in medical school to be inadequate, and only 30% of family physicians reported currently using any nutrition-related resources. CONCLUSION For family physicians, successful implementation of the 2006 Canadian Clinical Practice Guidelines on the Management and Prevention of Obesity requires access to adequate training, compensation, and evidence-based interventions related to nutrition. This study highlights current nutrition counseling practices in family medicine and identifies several obstacles to integrating the current guidelines in primary care settings.

https://www.cfp.ca/content/cfp/56/3/e109.full.pdf

Nutrition in primary care: current practices, attitudes, and barriers.

Autoimmune (type 1) diabetes results from a loss of beta cells that is mediated by self-reactive T cells. Previous studies have shown that a single injection of CFA prevents diabetes in nonobese diabetic (NOD) mice, but the mechanism(s) of protection remain unknown. We show here that NOD mice immunized with CFA have a markedly reduced incidence of diabetes and that this reduced incidence is associated with a decrease in the number of beta cell-specific, autoreactive CTL. In addition, the adoptive transfer of diabetes into syngeneic NOD/SCID recipients was prevented by CFA immunization, and the protective effects of CFA were lost when cells expressing the NK cell marker, asialo GM1, were removed from both donor cells and recipient mice. Returning a population of CD3-DX5+ cells to the adoptive transfer restored the protective effects of CFA. Therefore, NK cells mediate the protective effects of CFA possibly through the down-regulation of autoreactive CTL and stimulation of NK cells represents a novel approach to the prevention of autoimmune diabetes.

/pdf/regulation-of-autoimmune-diabetes-by-complete-freund-s-26ameb019y.pdf

Jacqueline D. Trudeau

Papers

Neonatal beta-cell apoptosis: a trigger for autoimmune diabetes?

Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood

In Vivo Phagocytosis of Apoptotic Cells by Macrophages from NOD Mice Is Reduced

Nutrition in primary care: current practices, attitudes, and barriers.

Regulation of autoimmune diabetes by complete Freund's adjuvant is mediated by NK cells