Destruction Of Beta Cells Research Articles

Regulation of metabolism by protein modifications in autoimmunity

Abstract In type 1 diabetes (T1D), inflammation and oxidative stress in pancreatic islets amplifies various post-translational modifications (PTMs) of self-proteins. The loss of immune tolerance to islet PTMs triggers an autoreactive T cell response and contributes to the destruction of insulin-producing beta cells in T1D. The major function of beta cells is to secret insulin in response to glucose uptake in order to maintain glucose homeostasis. In this study, we identify autoantibodies against to beta subunit of prolyl-4-hydroxylase (P4Hb; native and carbonylated form) and glucokinase (GK; native and citrullinated form) in both human T1D and murine models. Glucokinase serves as a glucose sensor to initiate glycolysis and insulin signaling in beta cells. P4Hb is required for the accurate folding of insulin. By mass spectrometry, six carbonyl residues and eleven citrulline residues were mapped in oxidative rhP4Hb and PAD-treated rhGK, respectively. Of interest, autoreactive CD4+ T cells to citrullinated GK epitopes are present in the circulation of T1D patients. In regards to glucose metabolism, the carbonylated-P4Hb is amplified in stressed human islets coincident with decreased glucose-stimulated insulin secretion and disturb (increase) proinsulin to insulin ratios. The citrullination alters GK biologic activity (Km) and suppresses glucose-stimulated insulin secretion. Moreover, PAD2/4 inhibitors can partially restore IFNg +IL-1b suppressed glucose stimulated insulin secretion in INS-1E beta cells. Our studies implicate the crucial enzymes, glucokinase and P4Hb, as the biomarkers, providing new insights into creating autoantigens and define the impact of metabolic PTMs on the aberrant beta cell functions of T1D. This research was supported by the Juvenile Diabetes Research Foundation (Innovative Grant to M.J.M., 2-SRA-2018-551-S-B to E.A.J.), and National Institutes of Health (DK104205-01 to K.H. and M.J.M.).

Type 1 Diabetes: A Promising Dialogue between Promiscuous T Cell Receptor and H‐2Db Peptide Complex

Obliteration of the beta cells mediated by CD8 T cells in the islets of Langerhans leads to the development of autoimmune disease, type 1 diabetes (T1D). During the kickoff of T1D, CD8 T cells play a pivotal role in the destruction of these pancreatic beta cells. The CD8 T cell clone AI4, previously isolated from the islets of a young diabetes‐prone NOD mouse, is found to be the most pathogenic among the population of CD8 T cell clones. Multiple natural and synthetic ligands for AI4 have been identified. These ligands include an unusually short seven‐residue peptide derived from the insulin A chain (InsA14‐20) that is recognized by AI4 in the context of H‐2Db but lacks a C‐terminal anchor residue. High diabetogenic activity of AI4 is accredited to the promiscuity, or cross reactivity, of its T cell receptor (TCR). We adopted the structural biology studies for understanding the mechanism of cross‐reactivity of the AI4 TCR with its multiple ligands. Unraveling the three‐dimensional structure of H‐2Db with AI4 ligands will help us to unveil the distinct mechanisms involved in the recognition and the cross‐reactivity of the AI4 TCR. In previous studies, our group has already reported two structures of the H‐2Db peptide complexes recognized by AI4. In our present work we have solved two additional structures of H‐2Db with AI4 ligands and several others are in progress. In addition to these studies, we have cloned, expressed and purified the AI4 TCR in a soluble form, which should allow us to obtain its structure alone and in complex with its multiple ligands. Our approach to study the interaction of promiscuous TCRs with their multiple ligands will allow us to uncover the likely multiple mechanisms that underlie TCR cross‐reactivity in autoimmunity.

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.

Abstract #1185216: Adult-onset autoimmune diabetes revealed in a postpartum female with gestational diabetes

Latent autoimmune diabetes of adulthood (LADA) is an autoimmune disease characterized by adult onset of diabetes due to the presence of circulating autoantibodies. This disease is often challenging to diagnose due to the atypical age of onset. A known risk factor for LADA is a form of gestational diabetes (GDM) known as autoimmune gestational diabetes (AGD). AGD accounts for only 10% of GDM and carries a high risk for the development of LADA after pregnancy as its causative factor is islet cell autoantibodies that lead to the destruction of beta cells in the pancreas.

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.

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.

Review on: Diabetes Mellitus is a Disease

In this review article, an attempt was made to present an overview of diabetes mellitus. Diabetes mellitus (DM) is a group of insulin resistance syndrome characterized by a high blood sugar level over a prolonged period of time. Diabetes is not a contagious disease. We can say Insulin dependent disorder. Nowadays, Diabetes Mellitus detect in many more peoples all over the World. In this report, we all know about Diabetes Mellitus. In that, we include its classification, sign &amp; symptoms, etiology, pathogenesis, diagnosis, treatment etc. It’s had Four types, namely type 1, type 2, gestational Diabetes Mellitus &amp; Other specific types such as, lada, mody. Fatigue Polyphagia, Polydipsia, polyuria, vomiting, dehydration etc., are common signs &amp; symptoms are observed in Diabetes Mellitus. Diabetes Mellitus is mainly caused by the destruction of beta cells in the pancreas. Its cause’s autoimmune disorders such as Addison’s Disease, Hashimoto’s Thyroiditis &amp; Graves’ disease. Some genetic factors, prior family history, environmental factors, autoimmune destruction, high insulin resistance these factors increase the risk of the development of diabetes mellitus. Most of the diabetic patients are older adults. Blood Glucose tests are used to detect diabetes mellitus. Insulin therapy is helpful to prevent or treat diabetes mellitus. For some patients, we used Islet replacement therapy and stem cell therapy used. In diabetes mellitus treatment, some drugs are used, such as miglitol, metformin, nateglinide, pioglitazone, glipizide, dapagliflozin, colestimide, bromocriptine etc. it's known as anti-diabetic drugs. Diabetics patients are more fastly rise in World.

Emerging treatment modalities for the management of diabetes mellitus: A review

This narrative review focussed on Diabetes which has emerged as a significant public health problem after cardiovascular diseases and the sixth leading cause of mortality worldwide. India faces a massive burden of Diabetes, which parallels a similar rise in obesity and metabolic syndrome. (Diabetes mellitus currently had a global prevalence of 6.4%, aged 20-79 years in 2010). Diabetes prevalence among adults over 18 years has increased from 4.7%in 1980 to 8.5 % in 2014 (WHO) and is estimated to be 10.2% by 2030 (IDF). India has the second-largest number of diabetics (about a 61million, i.e., the prevalence of 8.8% and about 77 million, i.e., majority of 8.9%).The number is likely to increase to 101 million (prevalence of 9.9%) by 2030. These rising figures are primarily due to marked transitions leading to unhealthy diets and physical inactivity. That causes problems like retinopathy, cardiomyopathy, nephropathy, and neurodegenerative diseases. Diabetes is the most common progressive heterogeneous endocrine disorder with devastating multi-systemic complications characterized by altered glucose homeostasis and insulin resistance. Diabetes is principally divided into two types Diabetes Insipidus and Diabetes Mellitus (DM). Again, DM is of 2 types — Type 1(Juvenile/Insulin-dependent) and Type-2 (Insulin resistance). Type1-DM is prevalent in the young population, associated with a lack of insulin production due to auto-immune destruction of beta cells of the pancreas. In contrast, Type2-DM is due to the inability of cells/tissues to respond to insulin appropriately. Long-term chronic hyperglycemia leads to organ dysfunction leads to organ failure, especially kidney, eyes, heart, and blood vessels.

Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes.

A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis. Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65 or GAD), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells. Interestingly, bacterial populations within the human gut also express GAD and produce GABA. Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology. Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated. Utilizing in silico analyses, we show that 25 GAD sequences from human gut bacterial sources show sequence and motif similarities to human beta cell GAD65. Our motif analyses determined that most gut GAD sequences contain the pyroxical dependent decarboxylase (PDD) domain of human GAD65, which is important for its enzymatic activity. Additionally, we showed overlap with known human GAD65 T cell receptor epitopes, which may implicate the immune destruction of beta cells. Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system. Due to the notable similarities we found between human and bacterial GAD, these deputized immune cells may then target human beta cells leading to the development of T1D.

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.

Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes

BackgroundAlthough type 1 diabetes (T1D) is typically described as a T cell-mediated autoimmune disease, increasing evidence for a role of B cells has emerged. However, the pivotal disease-relevant B cell subset and its contribution to islet autoimmunity remain elusive.MethodsThe frequencies and phenotypic characteristics of circulating B cell subsets were analyzed using flow cytometry in individuals with new-onset T1D, long-term T1D, type 2 diabetes, and nondiabetic controls, and also in a prospective cohort of patients receiving mesenchymal stromal cell (MSC) transplantation. NOD mice and adoptive transfer assay were used to dissect the role of the certain B cell subset in disease progression. An in-vitro coculture system of islets with immune cells was established to examine the response against islets and the underlying mechanisms.ResultsWe identified that plasmablasts, a B cell subset at the antibody-secreting stage, were significantly increased and correlated with the deterioration of beta cell function in patients with new-onset T1D. Further, a fall of plasmablast number was associated with the preservation of beta cell function in patients who received MSC transplantation after 3 months of follow-up. Meanwhile, a gradual increase of plasmablasts in pancreatic lymph nodes during the natural progression of insulitis was observed in non-obese diabetic (NOD) mice; adoptive transfer of plasmablasts together with T cells from NOD mice accelerated diabetes onset in NOD/SCID recipients.ConclusionsOur study revealed that plasmablasts may function as antigen-presenting cells and promote the activation and proinflammatory response of CD4+ T cells, further contributing to the T cell-mediated beta cell destruction. Our results provide insights into the pathogenic role of plasmablasts in islet autoimmunity and may offer new translational strategies for inhibiting T1D development.

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.

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.

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.

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.