Destruction Of Pancreatic Beta Cells Research Articles

Myostatin Deletion Preserves Cardio‐Metabolic Function in Type 1 diabetes

Type 1 Diabetes Mellitus (T1DM) is a disease characterized by the destruction of insulin‐secreting pancreatic beta cells and results in hyperglycemia, muscle wasting, and vascular dysfunction. Patients afflicted with T1DM suffer from increased morbidity and early mortality, largely driven by an inability to appropriately maintain glucose homeostasis. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream. The myokine myostatin is a potent negative regulator of muscle growth and is upregulated in T1DM patients but downregulated following regular exercise. Physical exercise is also known to improve cardiovascular health and increase insulin sensitivity of muscle, but many T1DM patients are unable to exercise at a level that conveys benefit due to muscle atrophy. Thus, directly targeting skeletal muscle, independent of exercise, may prove beneficial for T1DM therapy. Our hypothesis is that genetic deletion of myostatin will preserve glucose homeostasis, maintain muscle function, and protect against vascular dysfunction and cardiometabolic effects in a mouse model of T1DM.T1DM was induced via streptozotocin (STZ) in adult male mice with (WT) and without myostatin (MyoKO). Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), fluid dynamics, muscle function (in vivo plantarflexion), and vascular function (ex vivo pressure myography of gracilis arteriole).Myostatin deletion inhibited STZ‐induced increases in plasma glucose, preserved fluid dynamics, and prevented decreases in muscle function, independent of insulin. Further, endothelial function was protected with myostatin deletion. Taken together, this data suggests that myostatin inhibition may be a target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1DM.

Role of NF-kappaB c-Rel O-GlcNAcylation in the regulation of cytotoxic T cell function

Abstract Autoimmunity in type 1 diabetes (T1D) is primarily caused by destruction of insulin producing pancreatic beta cells by cytotoxic T cells, resulting in hyperglycemia. Adverse pathological effects of hyperglycemia include the increased O-GlcNAcylation of cellular proteins. We found that the transcription factor nuclear factor kappaB (NF-kB) subunit c-Rel is a target of O-GlcNAcylation at serine residue 350 in T cells. c-Rel is the major regulator of CD4 and CD8 T cell function and T regulatory cell development that controls autoimmunity and immunosuppression, respectively. c-Rel O GlcNAcylation increases the expression of pro-autoimmune cytokines and decreases the expression of the transcription factor forkhead box P3 (FOXP3) in CD4 T cells. However, the role of c-Rel O-GlcNAcylation in cytotoxic T cells remains unknown. The cell death pathways mediated by Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are major contributors of T cell mediated cytotoxicity. Our preliminary microarray study showed that FasL and TRAIL expressions are dependent on O-GlcNAcylated c-Rel. We also found that hyperglycemia and c-Rel O-GlcNAcylation enhances FasL expression in both CD4 and CD8 T cells. Mechanistically, O-GlcNAcylation enhances and a point mutation at S350 O-GlcNAcylation site prevents c-Rel binding to FasL promoter. Our future studies aim at studying how hyperglycemia-induced c-Rel O-GlcNAcylation enhances cytotoxic ligand expressions in T cells, augmenting their potential to destruct host cells in T1D. This study will define the critical role of c-Rel O-GlcNAcylation in cytotoxic T cell function, revealing a new molecular mechanism that could be targeted to control autoreactive T cell function in T1D. P.R was supported by National Institute of Allergy and Infectious Diseases at National Institute of Health grants R01 AI116730 and R21 AI144264, and National Cancer Institute at National Institute of Health grant R21 CA246194. JTC was supported by National Institute of Health NIH/NEI T32 pre-doctoral training grant T32EY007157.

Dendritic Cells and Their Immunotherapeutic Potential for Treating Type 1 Diabetes.

Type 1 diabetes (T1D) results from the destruction of pancreatic beta cells through a process that is primarily mediated by T cells. Emerging evidence suggests that dendritic cells (DCs) play a crucial role in initiating and developing this debilitating disease. DCs are professional antigen-presenting cells with the ability to integrate signals arising from tissue infection or injury that present processed antigens from these sites to naïve T cells in secondary lymphoid organs, thereby triggering naïve T cells to differentiate and modulate adaptive immune responses. Recent advancements in our knowledge of the various subsets of DCs and their cellular structures and methods of orchestration over time have resulted in a better understanding of how the T cell response is shaped. DCs employ various arsenal to maintain their tolerance, including the induction of effector T cell deletion or unresponsiveness and the generation and expansion of regulatory T cell populations. Therapies that suppress the immunogenic effects of dendritic cells by blocking T cell costimulatory pathways and proinflammatory cytokine production are currently being sought. Moreover, new strategies are being developed that can regulate DC differentiation and development and harness the tolerogenic capacity of these cells. Here, in this report, we focus on recent advances in the field of DC immunology and evaluate the prospects of DC-based therapeutic strategies to treat T1D.

Factors associated with glycemic variability in children with type 1 diabetes mellitus based on flash glucose monitoring system.

Patients with classical type 1 diabetes mellitus (T1DM) require lifelong dependence on exogenous insulin therapy due to pancreatic beta-cell destruction and absolute insulin deficiency. T1DM accounts for about 90% of children with diabetes in China, with a rapid increase in incidence and a younger-age trend. Epidemiological studies have shown that the overall glycated haemoglobin (HbA1c) and compliance rate are low in Chinese children with T1DM. Optimal glucose control is the key for diabetes treatment, and maintaining blood glucose within the target range can prevent or delay chronic vascular complications in patients with T1DM. Therefore, this study aims to investigate the glycemic control of children with T1DM from Hunan and Henan Province with flash glucose monitoring system (FGMS), and to explore factors associated with glycemic variability. A total of 215 children with T1DM under 14 years old were enrolled continuously in 16 hospitals from August 2017 to August 2020. All subjects wore a FGMS device to collect glucose data. Correlation of HbA1c, duration of diabetes, or glucose scan rates with glycemic variability was analyzed. Glucose variability was compared according to the duration of diabetes, HbA1c, glucose scan rates and insulin schema. HbA1c and duration of diabetes were positively correlated with mean blood glucose, standard deviation of glucose, mean amplitude of glucose excursions (MAGE), and coefficient of variation (CV) of glucose (all P<0.01). The glucose scan rates during FGMS wearing was significantly positively correlated with time in range (TIR) (P=0.001) and negatively correlated with MAGE and mean duration of hypoglycemia (all P<0.01). Children with duration ≤1 year had lower time below range (TBR) and MAGE when compared with those with duration >1 year (all P<0.05). TIR and TBR in patients with HbA1c ≤7.5% were higher (TIR: 65% vs 45%, TBR: 5% vs 4%, P<0.05), MAGE was lower (7.0 mmol/L vs 9.4 mmol/L, P<0.001) than those in HbA1c >7.5% group. Compared to the multiple daily insulin injections group, TIR was higher (60% vs 52%, P=0.006), MAGE was lower (P=0.006) in the continuous subcutaneous insulin infusion group. HbA1c was lower in the high scan rates (≥14 times/d) group (7.4% vs 8.0%, P=0.046), TIR was significantly higher (58% vs 47%, P<0.001), and MAGE was lower (P<0.001) than those in the low scan rate (<14 times/d) group. The overall glycemic control of T1DM patients under 14 years old in Hunan and Henan Province is under a high risk of hypoglycemia and great glycemic variability. Shorter duration of diabetes, targeted HbA1c, higher glucose scan rates, and CSII are associated with less glycemic variability.

The Association between 25-(OH)D Level and Metabolic Control Status in Children with Type 1 Diabetes Mellitus at Dr. M. Djamil General Hospital Padang

Background. Type 1 diabetes mellitus (T1DM) is an autoimmune disease causing the destruction of pancreatic beta cells. This is an incurable condition, but with good metabolic control, an optimal quality of life can be achieved. Glycated hemoglobin (HbA1C) is still considered a reliable parameter of metabolic control. Studies showed vitamin D has a role in controlling glycemic homeostasis in children with T1DM. Calcidiol or 25-(OH)D is the best parameter to determine the level of vitamin D in the blood. This study aimed to evaluate the association between 25-(OH)D with metabolic control status in T1DM children at Dr. M. Djamil General Hospital Padang.&#x0D; Methods. A cross-sectional study was conducted on 43 pediatric patients with T1DM from July 2019-January 2021. Serum levels of 25-(OH)D were measured by direct CLIA method and classified into deficiency (≤ 20 ng/mL) and insufficiency (21–30 ng/mL). The HbA1C levels were calculated using the HPLC method and classified into good (&lt;7%), adequate (7-8%), and poor (&gt;8%) control. The Chi-square test and ANOVA were used for data analysis. The P-value of &lt; 0.05 was considered statistically significant.&#x0D; Results. The majority of respondents were girls (53.5%), with 90.7% having a good nutritional status. The mean age at diagnosis was 11.25±2.85 years, and had been known to suffer from T1DM for 2.95±1.74 years. All respondents had abnormal levels of 25-(OH)D (100%), i.e., insufficiency (28%), deficiency (72%), poor (65.1%) metabolic control, and 96.4% of respondents with poor metabolic control had a deficiency of 25-(OH)D. (P-value &lt;0.001).&#x0D; Conclusion. T1DM patients who have poor metabolic control have very low levels of 25-(OH)D.

Unspecific CTL Killing Is Enhanced by High Glucose via TNF-Related Apoptosis-Inducing Ligand.

TNF-related apoptosis inducing ligand (TRAIL) is expressed on cytotoxic T lymphocytes (CTLs) and TRAIL is linked to progression of diabetes. However, the impact of high glucose on TRAIL expression and its related killing function in CTLs still remains largely elusive. Here, we report that TRAIL is substantially up-regulated in CTLs in environments with high glucose (HG) both in vitro and in vivo. Non-mitochondrial reactive oxygen species, NFκB and PI3K/Akt are essential in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of pancreatic beta cell line 1.4E7. Treatment with metformin and vitamin D reduces HG-enhanced expression of TRAIL in CTLs and coherently protects 1.4E7 cells from TRAIL-mediated apoptosis. Our work suggests that HG-induced TRAILhigh CTLs might contribute to the destruction of pancreatic beta cells in a hyperglycemia condition.

Anti-diabetic activity of Carica Papaya Linn in Alloxan-Induced diabetic rats.

Background: Type I Diabetes Mellitus (TIDM) is a disease known to occur in any age group, but most of the people affected are diagnosed in their mid-teenage. It is marked by hyperglycemia due to autoimmune destruction of insulin-producing pancreatic beta cells. Herbal treatment of DM has attracted attention in the last few decades because of its ability to improve diabetic complications such as nephrotic deterioration and oxidative stress. The present research is sought to determine the anti-diabetic potential of Carica Papaya leaf extract in Alloxan-induced diabetic rats.&#x0D; Methodology: For this study, eighteen healthy male Wistar rats weighing 150-200 g were made into three groups (n=6), two of which (Group II and Group III) were induced DM through Alloxan, whereas control (Group I) remained untreated. Group III diabetic rats were treated with 250 mg/kg body weight of papaya leaf extract after confirming hyperglycemia. Animals were sacrificed on the 22nd day for biochemical analysis.&#x0D; Results: This study showed that papaya leaf extract administration caused a significant reduction in the levels of plasma glucose, AST, ALP, ALT, serum urea, blood urea nitrogen (BUN), and creatinine in the papaya-treated group as compared to the Alloxan-treated group. It also increased plasma insulin levels compared to the diabetic-control (Alloxan-treated) group. Activity and concentration of major antioxidant enzymes such as CAT, SOD, and GSH in treated animals were also significantly increased compared to the diabetic (Alloxan-treated) group. &#x0D; Conclusion: Based on the findings, it is concluded that the C. Papaya leaf extract exhibits antidiabetic and antioxidative potential against alloxan-induced TIDM.

Implementing a low-carbohydrate diet in adults to manage type 1 diabetes mellitus: a standard of care protocol

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Type 1 diabetes mellitus is an autoimmune disease characterized by the destruction of pancreatic beta cells and absolute insulin deficiency. After the discovery of insulin, guidelines recommended 50% to 60% of carbohydrate consumption in individuals with diabetes. However, this recommendation is ineffective, since carbohydrate is the macronutrient that causes the greatest increase in blood glucose. The aim of this research is to evaluate the efficacy of a low-carbohydrate diet in adults with type 1 diabetes mellitus.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; The study is a 26 weeks clinical trial. During the first 15 days, participants will receive approximately 130 g of daily carbohydrates, followed by a phase of 7 days, with the consumption of 90 g of daily carbohydrates, and finally, the consumption of 50 g of carbohydrates. The target audience is 20 participants diagnosed with type 1 diabetes mellitus, glycated hemoglobin (HbA1c) &amp;gt;7.0% and aged between 21 and 50 years, in addition to the parameters defined in the established inclusion and exclusion criteria. The primary outcome is HbA1c. Glycemic variability, frequency of hypoglycemia, total daily insulin and improvement in quality of life will also be evaluated.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Despite the evidence that low carbohydrate is effective for treating type 2 diabetes, there is low evidence for the recommendation in people with type 1 diabetes. In order to improve quality of life of this group and guidelines of clinical practice, and to promote development of health care professionals, further well-designed trials are needed.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Trial registration:&lt;/strong&gt; The trial was registered at https://ensaiosclinicos.gov.br/rg/RBR-107jk4tn.&lt;/p&gt;

Fluorine MR Imaging Probes Dynamic Migratory Profiles of Perfluorocarbon-Loaded Dendritic Cells After Streptozotocin-Induced Inflammation

The pathogenesis of type 1 diabetes (T1D) involves presentation of islet-specific self-antigens by dendritic cells (DCs) to autoreactive T cells, resulting in the destruction of insulin-producing pancreatic beta cells. We aimed to study the dynamic homing of diabetes-prone DCs to the pancreas and nearby organs with and without induction of pancreatic stress in a T1D susceptible model of repeated streptozotocin (STZ) injection. In vitro labeling of activated bone marrow-derived DCs (BMDCs) from NOD (Nonobese diabetes) mice was performed using zonyl perfluoro-15-crown-5-ether nanoparticles (ZPFCE-NPs). Internalization of particles was confirmed by confocal microscopy. Two groups of NOD.SCID (nonobese diabetic/severe combined immunodeficiency) mice with (induced by low dose STZ administration) or without pancreatic stress were compared. Diabetogenic BMDCs loaded with BDC2.5 mimotope were pre-labeled with ZPFCE-NPs and adoptively transferred into mice. Longitudinal in vivo fluorine MRI (19F MRI) was performed 24h, 36h and 48h after transfer of BMDCs. For ex vivo quantification of labeled cells, 19F NMR and flow cytometry were performed on dissected tissues to validate in vivo 19F MRI data. In vitro flow cytometry and confocal microscopy confirmed high uptake of nanoparticles in BMDCs during the process of maturation. Migration/homing of activated and ZPFCE-NP- labeled BMDCs to different organs was monitored and quantified longitudinally, showing highest cell density in pancreas at 48-h time-point. Based on 19F MRI, STZ induced mild inflammation in the pancreatic region, as indicated by high accumulation of ZPFCE-NP-labeled BMDCs in the pancreas when compared to the vehicle group. Pancreatic draining lymph nodes showed elevated homing of labeled BMDCs in the vehicle groups in contrast to the STZ group after 72h. The effect of STZ was confirmed by increased blood glucose levels. We showed the potential of 19F MRI for the non-invasive visualization and quantification of migrating immune cells in models for pancreatic inflammation after STZ administration. Without any intrinsic background signal, 19F MRI serves as a highly specific imaging tool to study the migration of diabetic-prone BMDCs in T1D models in vivo. This approach could particularly be of interest for the longitudinal assessment of established or novel anti-inflammatory therapeutic approaches in preclinical models.

Investigation of serum level relationship anti-glutamic acid decarboxylase antibody and inflammatory cytokines (IL1-β, IL-6) with vitamins D in type 2 diabetes.

Various factors are involved in the development and progression of diabetes mellitus, from cytokines and autoimmune destruction of pancreatic beta cells to vitamin D.This study aimed to investigate the association of serum levels of anti-glutamic acid decarboxylase (anti-GAD) and inflammatory cytokines with vitamin D in type 2 diabetes (T2D). This case-control study was performed on 30 patients with T2D and 30 healthy individuals in Mashhad hospitals in 2020. Lipid profile, creatinine, uric acid, FBS, HbA1c, and blood pressure were recorded. All study variables were measured, particularly serum vitamin D, anti-GAD, and inflammatory cytokine levels in diabetic patients, and the data were compared to those from healthy subjects by performing an appropriate statistical analysis. Diabetic patients with a mean age of 52.9 ± 10.4years, including 16 women and healthy individuals with a mean age of 48.5 ± 10.4years, including 16 women, were studied. BMI level (P = 0.002), systolic blood pressure (P = 0.034), HbA1c, insulin, IL-6, IL1-β, anti-GAD levels, and insulin resistance in diabetic patients were significantly higher than the control group (P = 0.001). The vitamin D level in the control group was significantly higher than in the case group (P = 0.0001). The results showed a significant direct relationship between IL-6, IL-1β, and anti-GAD with HbA1c, FBS, insulin, and insulin resistance. However, there was a significant inverse relationship between IL-6, IL-1β, and anti-GAD with vitamin D. Inflammatory cytokines and anti-GAD and vitamin D are associated with diabetes, and thus controlling these factors can help improve T2D.

Generation of a Beta-Cell Transplant Animal Model of Diabetes Using CRISPR Technology.

Since insulin deficiency results from pancreatic beta-cell destruction, all type 1 and most type 2 diabetes patients eventually require life-long insulin injections. Insulin gene synthesis could also be impaired due to insulin gene mutations as observed in diabetic patients with MODY 10. At this point, insulin gene therapy could be very effective to recompense insulin deficiency under these circumstances. For this reason, an HIV-based lentiviral vector carrying the insulin gene under the control of insulin promoter (LentiINS) was generated, and its therapeutic efficacy was tested in a beta-cell transplant model lacking insulin produced by CRISPR/Cas9-mediated genetically engineered pancreatic beta cells. To generate an insulin knockout beta-cell transplant animal model of diabetes, a dual gene knockout plasmid system involving CRISPR/Cas9 was transfected into a mouse pancreatic beta cell line (Min6). Fluorescence microscopy and antibiotic selection were utilized to select the insulin gene knockout clones. Transplantation of the genetically engineered pancreatic beta cells under the kidney capsule of STZ-induced diabetic rats revealed LentiINS- but not LentiLacZ-infected Ins2KO cells transiently reduced hyperglycemia similar to that of MIN6 in diabetic animals. These results suggest LentiINS has the potential to functionally restore insulin production in an insulin knockout beta-cell transplant animal model of diabetes.

Single nucleotide polymorphism rs 2070874 at Interleukin-4 is associated with increased risk of type 1 diabetes mellitus independently of human leukocyte antigens.

IntroductionType 1 diabetes mellitus (T1DM) is characterized by autoimmune destruction of insulin-producing pancreatic beta (β-) cells. Previous studies suggested an imbalance between and pro- and anti-inflammatory cytokines exacerbates T1DM development.ObjectivesWe aimed to test the hypothesis that patients with T1DM carry a higher frequency of regulatory genes associated with low levels of the anti-inflammatory cytokines interleukin-4 (IL-4), its receptor (IL-4R), and interleukin-10 (IL-10).MethodsAccordingly, we compared frequencies of five different single nucleotide polymorphisms (SNPs) in T1DM patients and healthy controls who had been typed for HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes.ResultsThe frequencies of rs2070874 (IL-4) alleles C and T differed between T1DM patients and controls (cp = 0.0065), as did their codominant (cp = 0.026) and recessive (cp = 0.015) models. Increased frequencies were observed in T1DM patients for HLA alleles: DRB1*03 (pc < 0.0013), DRB1*04 (cp = 0.0169), DQA1*03 (cp = 0.0222), DQA1*05 (cp < 0.0006), DQB1*02 (cp = 0.0005), and DQB1*06 (cp < 0.0005). And lower frequencies were observed for: DRB1*07 (cp = 0.0078), DRB1*11 (cp = 0.0013), DRB1*13 (cp < 0.0364), DRB1*15 (cp < 0.0013), DQA1*01 (cp < 0.0006), and DQA1*02 (cp = 0.0348). Certain DRB1: DQA1: DQB1 haplotypes showed greater frequencies, including, 03:05:02 (p < 0.0001) and 04:03:03 (p = 0.0017), whereas others showed lower frequencies, including, 07:02:02 (p = 0.0032), 11:05:03 (p = 0.0007), and 15:01:06 (p = 0.0002). Stratification for the above HLA haplotypes with rs2070874 C/C exhibited no significant differences between T1DM patients overall and controls. However, when stratified for the vulnerable HLA haplotype (03:05:02/04:03:03), young patients in whom T1DM began at ≤13 years had a higher frequency of the SNP (rs2070874 C/C); a gene associated with low IL-4 production (p < 0.024).ConclusionThis study suggests that possession of the rs2070874 C/C genotype, which is associated with low production of IL-4, increases the risk of T1DM in young individuals carrying vulnerable HLA alleles/haplotypes.

In-silico Study for African Plants with Possible Beta-Cell Regeneration Effect through Inhibition of DYRK1A

Background: The continuous destruction of normal insulin-producing pancreatic beta cells is a contributing factor in all common forms of diabetes, due to insufficient production of insulin, especially in type 1 diabetes. There are attempts to betacells transplantation, but the cost and availability of donors pose a great challenge to the process. Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A plays a crucial role in beta-cells destruction. Aims: Our research targets to identify plants for that can be utilized possible alternative approach of beta-cell replacement through a pharmacologically induced regeneration of new beta cells in-silico. Methods and Material: The 3D structure Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A and 6511 phytochemicals were obtained from Protein Databank and African Natural Products Database respectively. They were appropriately prepared for molecular docking simulations. Molecular docking simulations were implemented, after validation of docking protocols, in AutoDock-Vina®, using virtual screening scripts. Phytocompounds with good binding affinities for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A were selected as frontrunners. The compounds were screened for toxicity and Lipinski’s rule confirmation using Datawarrior and then kinase inhibitory bioactivity prediction using Molinspiration. Results: Twelve phytocompounds were found to be predictably highly active in-silico against Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A, druglike based on Lipinski’s rule, non-mutagenic, non-tumorigenic, no reproductive effect and non-irritant, with high bioactivity prediction. Conclusions: In-silico active phytocompounds against Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase A with their plant sources and physicochemical parameters were identified. Further studies will be carried out in-vitro and in-vivo in to validate the results of this study using plants containing the identified phytocompounds.

HLA Allele-Specific Quantitative Profiling of Type 1 Diabetic B Lymphocyte Immunopeptidome.

Peptide ligands presented by human leukocyte antigen (HLA) molecules on the cell surface represent the immunopeptidome that could be utilized for identification of antigenic peptides for immunotherapy and prevention of autoimmune diseases. Although T-cells are well-known key players in the destruction of pancreatic beta-cells in type 1 diabetes (T1D), increasing evidence points toward a role for B-cells in disease pathogenesis. However, as antigen presenting cells, little is known about the comprehensive immunopeptidome of B cells and their changes in the context of T1D. We performed HLA allele-specific quantitative immunopeptidomics using B lymphocytes derived from T1D patients and healthy controls. Hundreds of HLA-I and HLA-II immunopeptides were identified as differentially regulated in T1D per HLA allele for B cells sharing identical HLA alleles. The results were further validated using additional T1D and healthy B cells with partially overlapped HLA alleles. Differentially expressed immunopeptides were confirmed with targeted proteomics and for reactivity using known T-cell assays in the immune epitope database. Considering samples with identical HLA alleles are difficult to obtain for T1D and other similar HLA-restricted diseases, our work represents a viable approach to better understand HLA allele-specific antigen presentation and may facilitate identification of immunopeptides for therapeutic applications in autoimmune diseases. Data are available via ProteomeXchange with identifier PXD026184.

Autophagy Involves in Differentiation of Insulin-Secreting Cells from Adipose Derived Stem Cells.

Objective Destruction of pancreatic beta-cells induces an insulin deficiency and causes type 1 diabetes. The role of autophagy in inducing insulin-secreting cells (ISCs) from adipose-derived mesenchymal stem cells (AMSCs) was investigated in the current study. Materials and Methods In this experimental study, the isolated AMSCs were characterization and exposed to a cocktail differentiation medium (CDM) in the absence or presence of 3-methyladenine (3MA), an autophagy inhibitor. The differentiation of ISCs was confirmed by the evaluation of the expression of beta-cell-specific genes including pancreatic and duodenal homeobox 1 (PDX1), musculoaponeurotic fibrosarcoma oncogene homolog A (MAF-A), Nk class of homeodomain-encoding genes 6.1 and 2.2 (NKX6-1 and NKX2.2), Glucose transporter 2 (GLUT-2) and INSLIN. Using Newport Green (NG), insulin-positive cells were identified. Insulin secretion in response to various glucose concentrations was measured. Autophagy was evaluated by Acridine orange (AO) staining. Also, expression of autophagy-associated genes, including autophagy-related gene 5 (ATG-5), autophagy-related gene 7 (ATG-7), BECLIN-1, and mammalian target of rapamycin (mTOR), was evaluated by Real-time polymerase chain reaction (PCR) method. Results We observed a significant increase of beta-cell specific genes expression in the CDM-treated cells (P<0.01 or P<0.001), whereas the expression of these genes was down-regulated in 3MA-exposed cells. Expression of INSULIN and GLUT-2 genes (P<0.01 and P<0.05, respectively), insulin secretion in response to glucose (P<0.01), and percentage of NG-positive cells (P<0.05) in the 3MA-exposed cells were considerably lower than the cells treated with CDM. The percentage of AO-positive cells (P<0.01) and the expression of autophagy-related genes (P<0.001) was significantly enhanced in the CDM group. These events were significantly prevented by the 3MA. ConclusionOur data showed that autophagy is necessary for beta-cell differentiation, and preventing autophagy by 3MA causes the reduction of beta-cell differentiation and insulin secretion.

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis.

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. Loss of beta-cells leads to insulin insufficiency and hyperglycemia, with patients eventually requiring lifelong insulin therapy to maintain normal glycemic control. Since T1D has been historically defined as a disease of immune system dysregulation, there has been little focus on the state and response of beta-cells and how they may also contribute to their own demise. Major hurdles to identifying a cure for T1D include a limited understanding of disease etiology and how functional and transcriptional beta-cell heterogeneity may be involved in disease progression. Recent studies indicate that the beta-cell response is not simply a passive aspect of T1D pathogenesis, but rather an interplay between the beta-cell and the immune system actively contributing to disease. Here, we comprehensively review the current literature describing beta-cell vulnerability, heterogeneity, and contributions to pathophysiology of T1D, how these responses are influenced by autoimmunity, and describe pathways that can potentially be exploited to delay T1D.

"Awareness and Practice among Parents of Type-1 Diabetic Children and Adolescent and their Glycemic Status"

Diabetes Mellitus (DM) type 1 is a metabolic disorder, characterized by a partial or complete deficiency of the hormone insulin production, resulting from the destruction of pancreatic beta cells, usually caused by the auto immune or idiopathic process..

Schisandrae chinensis Fructus Extract Ameliorates Muscle Atrophy in Streptozotocin-Induced Diabetic Mice by Downregulation of the CREB-KLF15 and Autophagy-Lysosomal Pathways.

Type 1 diabetes mellitus is an autoimmune disease caused by the destruction of pancreatic beta cells. Many patients with type 1 diabetes experience skeletal muscle wasting. Although the link between type 1 diabetes and muscle wasting is not clearly known, insulin insufficiency and hyperglycemia may contribute to decreased muscle mass. In this study, we investigated the therapeutic effect of the ethanolic extract of Schisandrae chinensis Fructus (SFe) on muscle wasting in streptozotocin (STZ)-induced diabetic mice. STZ-diabetic C57BL/6 mice (blood glucose level ≥300 mg/dL) were orally administered SFe (250 or 500 mg/kg/day) for 6 weeks. We observed that SFe administration did not change blood glucose levels but increased gastrocnemius muscle weight, cross-sectional area, and grip strength in STZ-induced diabetic mice. Administration of SFe (500 mg/kg) decreased the expression of atrophic factors, such as MuRF1 and atrogin-1, but did not alter the expression of muscle synthetic factors. Further studies showed that SFe administration decreased the expression of KLF15 and p-CREB, which are upstream molecules of atrophic factors. Examination of the expression of molecules involved in autophagy–lysosomal pathways (e.g., p62/SQSTM1, Atg7, Beclin-1, ULK-1, LC3-I, and LC3-II) revealed that SFe administration significantly decreased the expression of p62/SQSTM1, LC3-I, and LC3-II; however, no changes were observed in the expression of Atg7, Beclin-1, or ULK-1. Our results suggest that SFe ameliorated muscle wasting in STZ-induced diabetic mice by decreasing protein degradation via downregulation of the CREB-KLF15-mediated UPS system and the p62/SQSTM1-mediated autophagy–lysosomal pathway.

Methanolic Extract of Sambucus ebulus Ameliorates Clinical Symptoms in Experimental Type 1 Diabetes through Anti-Inflammatory and Immunomodulatory Actions.

ObjectiveSambucus ebulus (SE), a famous traditional Iranian medicine, is grown in the north of Iran. As a traditional medicine with anti-inflammatory effects, SE has been utilized against inflammatory joint diseases, insect bites, infectious wounds, edema, and eczema. Type1 diabetes, is an autoimmune disease, characterized by the destruction of pancreatic beta cells by the immune system. For the first time, we investigated the effect of methanolic extract of SE on CD4+, CD8+ and regulatory T cells in experimental type 1 diabetes (T1D).Materials and Methods In this experimental study, fifty-six C57BL\\6 mice in 8 groups (G1-G8), were enrolled. Diabetes was induced by a multiple low-dose streptozotocin (MLDS) protocol and mice were daily treated with SE extract at 200 and 400 mg/kg doses, for 35 days. Fasting blood glucose was weekly measured by a glucometer. Islets insulin content was analyzed by immunohistochemistry. Percentage of CD4+, CD8+ and regulatory T cells and cytokines production levels were evaluated by flow cytometer and ELISA, respectively. Results The clinical symptoms of diabetes were significantly alleviated in G2 group mice which received 400 mg/ kg SE extract. Immunohistochemistry analysis showed that the insulin content of islets increased in G2 group mice. Immunophenotyping analysis indicated that the percentage of CD4+ and CD8+ T cells in G2 group mice was significantly decreased. SE extract significantly increased the percentage of regulatory T cells. The extract in G2 and G4 groups mice significantly decreased IFN-γ and IL-17levels. The extract significantly increased IL-10 in G2 group mice. ConclusionThe protective effect of SE extract in MLDS-induced diabetes could be partly due to a decrease of CD4+ and CD8+ T cells and an increase of Treg cells resulting in an inflammation reduction in the pancreatic islets.

Immunogenetic Epidemiology of Type 1 Diabetes in 14 Continental Western European Countries

Human leukocyte antigen (HLA) is widely recognized to influence individual Type 1 diabetes (T1D) risk. Here we utilized an immunogenetic epidemiological approach to evaluate the influence of HLA on T1D at the population level. Specifically, we evaluated the correlations between the population frequencies of 127 HLA Class I and II alleles and the population prevalence of T1D in 14 Continental Western European countries to identify a population-level HLA profile for T1D. The results of these analyses generally corroborated prior findings regarding the influence of HLA on T1D risk and protection and revealed several novel HLA-T1D associations. The findings, discussed within the context of the role of HLA in pathogen elimination and autoimmunity, point to a contributory role of exposure to pathogens in the absence of protective HLA in underlying the autoimmune destruction of pancreatic beta cells in T1D.