Destruction Of Pancreatic Beta Cells Research Articles

PPARs at the crossroads of T cell differentiation and type 1 diabetes.

T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.

The Current Status of Allogenic Islet Cell Transplantation.

Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell transplantation despite chronic immunosuppression. The Edmonton Protocol, however, remains limited by two obstacles: scarce organ donor availability and risks associated with chronic immunosuppression. To overcome these challenges, the search has begun for an alternative cell source. In 2006, pluripotency genomic factors, coined "Yamanaka Factors," were discovered, which reprogram mature somatic cells back to their embryonic, pluripotent form (iPSC). iPSCs can then be differentiated into specialized cell types, including islet cells. This discovery has opened a gateway to a personalized medicine approach to treating diabetes, circumventing the issues of donor supply and immunosuppression. In this review, we present a brief history of allogenic islet cell transplantation from the early days of pancreatic remnant transplantation to present work on encapsulating stem cell-derived cells. We review data on long-term outcomes and the ongoing challenges of allogenic islet cell and stem cell-derived islet cell transplant.

THU378 Presentation Of Autoimmune Destruction Of Pancreatic Beta Cells By Pembrolizumab In The Setting Of Existing Type 2 Diabetes

Abstract Disclosure: J. Seidenberg: None. M.J. Ansari: None. Background: Prembrolizumab, like other immunotherapies, have become a commonplace treatment for certain cancers. Its method of action is binding of the programmed cell death I receptor that blocks the binding of the programmed cell death ligand 1. PD1-1 receptors have been reported to cause autoimmune endocrinopathies including type 1 diabetes. Many patients who present with the adverse reaction of autoimmune diabetes type 1 present with ketoacidosis. However, patients already diagnosed with diabetes type 2 on insulin could have this strong initial presentation masked. Clinical Case: Patient is a 76 year old female who was recently diagnosed with bladder cancer and started on Pembrolizumab. She presented to the endocrinology clinic due to new onset poor blood sugar control with self-tested glucose levels ranging from 300-400. This patient was previously diagnosed with diabetes type II and was taking metformin, Levemir 18 units daily, Humalog 6 units AC. A C peptide level was obtained during euglycemia, which was undetectable, indicating autoimmune destruction of pancreas. Patient was continued on Pembrolizumab due to her clinical response to it and a low probability of pancreatic beta cells functioning again. Patient’s C peptide continued to be undetectable 1 year after her presentation. Conclusion: Autoimmune destruction of pancreatic beta cells from Pembrolizumab is a rare but important adverse effect. Pembrolizumab has been reported to be associated with autoimmune-related pancreatitis leading to type 1 diabetes in only 0.1% of all patients in clinical trials. We present this patient, who was already being treated with insulin for type 2 diabetes and thus was being tested for elevated glucose regularly. She was able to notice a significant change in glucose control prior to onset of symptoms. All patients who take Pembrolizumab, especially those with underlying diabetes, should be regularly evaluated for interference with pancreatic beta cells with regular glucose labs and if hyperglycemia occurs, with a C peptide level should then be ordered. Presentation: Thursday, June 15, 2023

OR18-05 Interleukin 21 Drives The Development Of Autoimmune Diabetes Mellitus During Immune Checkpoint Inhibitor Cancer Therapy

Abstract Disclosure: J.G. Ortega: None. L.N. Scott: None. S. Wang: None. S. Zhang: None. H. Chen: None. N. Huang: None. M. Lechner: None. Autoimmune diabetes mellitus is a rare but life-threatening side effect of immune checkpoint inhibitor (ICI) cancer therapy. Checkpoint inhibitors increase immune activation by blocking natural regulatory molecules on T cells, including programmed death protein (PD1) and cytotoxic T lymphocyte antigen (CTLA4). As a result of increased immune activation, up to 60% of patients may develop autoimmunity in healthy tissues. Endocrine tissues are among the most often affected by these immune related adverse events (IRAEs). ICI-associated diabetes mellitus (ICI-T1DM) results from autoimmune destruction of insulin-producing pancreatic beta-cells. Patients with ICI-T1DM frequently present in diabetic ketoacidosis and require life-long insulin therapy. Unfortunately, the cause of many IRAEs remains poorly understood. We recently developed a mouse model of IRAEs in which anti-PD1 + anti-CTLA4 antibody treatment of autoimmunity-prone non-obese diabetic mice leads to multi-organ autoimmune infiltrates, including acceleration of insulinitis and DM. ICI-treated mice had increased CD4+ T follicular (Tfh; PD1+ICOS+CXCR5+) and T peripheral helper (Tph; PD1+ICOS+CXCR5-) cells compared to isotype-treated controls. Such Tfh and Tph cells secrete interleukin (IL)-21 and can promote cytotoxic CD8+ T cell function in autoimmunity. Indeed, CD8+ T cells expressing Granzyme B, interferon gamma (IFNγ), and chemokine receptor CXCR6 ("CD8+ autoimmune mediators") were expanded in ICI-treated mice. Furthermore, in vitro, IL21 induced the autoimmune mediator phenotype in CD8+ T cells, with upregulation of IFNγ, cytotoxic and trafficking molecules. Using mice with genetic deletion of T cell receptor alpha (NOD.TCRa-/-), we showed that CD4+ and CD8+ T cells were required for the development of IRAEs in ICI-treated mice. In addition, adoptive transfer of CD4+ and CD8+ T cells into immunodeficient NOD.SCID mice confirmed that these populations were sufficient to cause DM during ICI treatment. Thus, we predicted that IL21 from Tfh and Tph cells contributes to the development of pancreas IRAEs by activating CD8+ autoimmune mediator T cells. Indeed, in our model, mice with genetic blockade of IL21 signaling (IL21R-/-) were protected from developing diabetes. After 4 weeks of ICI treatment, only one of 11 (9.1%) IL21R-/- mice developed DM with onset at day 28, compared to 80% of ICI-treated wild-type (WT) mice, with a median DM-free time of 10 days from start of ICI therapy (p<0.0001, Log Rank test); no isotype-treated WT or IL21R-/- mice developed diabetes. Histologic analyses of pancreatic tissue from ICI-treated mice also showed a significantly lower insulinitis index in IL21R-/- compared to WT mice (mean 0.19±0.06 vs. 0.7±0.14, p<0.01). In summary, we identify IL21+ CD4+ Tfh/Tph cells as drivers of pancreas IRAEs and a potential therapeutic target to prevent ICI-T1DM in cancer patients. Presentation: Saturday, June 17, 2023

Type 2 Diabetes: Molecular mechanism, Understanding and Prevention

Diabetes is a chronic condition that affects millions of people worldwide, with significant implications for individuals, families, and society at large. It is a leading cause of death, disability, and healthcare costs, with serious complications such as blindness, kidney disease, nerve damage, and cardiovascular disease. Furthermore, the prevalence of diabetes is increasing globally, highlighting the need for effective prevention and management strategies. This increase in prevalence is due to various factors such as changes in diet, sedentary lifestyles, and an aging population. Additionally, there are social determinants of health, such as poverty and inequality, that disproportionately affect vulnerable populations and contribute to the diabetes burden. This research aims to provide a comprehensive overview of the importance of diabetes by situating it in a larger context, defining the condition, and exploring its impact on day-to-day lives. Type 1 diabetes is an autoimmune disorder characterized by the destruction of pancreatic beta cells, resulting in a lack of insulin production. On the other hand, Type 2 diabetes is a metabolic disorder characterized by insulin resistance, where the body's cells become less responsive to insulin. The prevention of Type 1 diabetes involves reducing exposure to environmental triggers and maintaining a healthy lifestyle. In contrast, the prevention of Type 2 diabetes involves lifestyle modifications such as diet and exercise, as well as medication management. The molecular mechanisms underlying the pathogenesis of Type 1 and Type 2 diabetes involve complex interactions between genetic and environmental factors, leading to dysfunction in insulin secretion and insulin action pathways. Situating diabetes in a larger context also involves understanding the economic impact of the disease. The costs associated with diabetes are significant, including direct costs such as medical expenses and indirect costs such as loss of productivity and decreased quality of life. These costs place a considerable burden on healthcare systems, governments, and individuals.

Antibodies to Glutamic Acid Decarboxylase-65 is Associated with Total Daily Dose of Insulin Requirement in Children with Type 1 Diabetes

BACKGROUND: Type 1 diabetes (T1D) mostly occurs due to the destruction of pancreatic beta cells due to autoimmune processes. Diagnosis of T1D can be established by examining the c-peptide levels and the markers of pancreatic autoantibodies, including glutamic acid decarboxylase 65 autoantibodies (GAD-65). However, the association between c-peptide and anti-GAD-65 toward patients’ clinical manifestations needs to be further explored. Hence, the aim of current study was to identify the association of anti-GAD65 with c-peptide and clinical characteristics in children with T1D.METHODS: Case-control study involving 47 T1D children (T1D group) and 41 healthy children (control group) younger than 18 years old was conducted. Secondary data regarding subjects’ demographic characteristics and medical history were collected from subjects, and serum blood was drawn from each subject for the anti-GAD65 and c-peptide measurement. Anti-GAD65 and c-peptide levels were measured using an Enzyme-Linked Immunosorbent Assay (ELISA) methods.RESULTS: Anti-GAD65 antibody was detected in 78.7% T1D group, while only 2.43% were detected in control group subject (p=0.0000). The c-peptide level of T1D group was 0.07±0.19 nmol/L and control group was 1.5±0.77 nmol/L (p=0.0000). The total daily dose of insulin in subjects with positive anti-GAD65 was greater than in the negative anti-GAD65 (p=0.012). The sensitivity and specificity of the anti-GAD65 were 85.4% was 66.7%, respectively.CONCLUSION: The results of this study show that anti-GAD65 was associated with total daily dose of insulin requirement in children with T1D.KEYWORDS: diabetes mellitus, type 1 diabetes, anti-GAD65, c-peptide

Human A2-CAR T Cells Reject HLA-A2 + Human Islets Transplanted Into Mice Without Inducing Graft-versus-host Disease.

Type 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include the use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD). We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4 + and CD8 + T cells and tested their ability to reject HLA-A2 + islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T-cell engraftment, islet function, and xGVHD were assessed longitudinally. The speed and consistency of A2-CAR T-cell-mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of coinjected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, coinjection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2 + human islets within 1 wk and without xGVHD for 12 wk. Injection of A2-CAR T cells can be used to study rejection of human insulin-producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of islet-replacement therapies.

Elevated glucose metabolism driving pro-inflammatory response in B cells contributes to the progression of type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune system's failure to maintain self-tolerance, resulting in the autoimmune destruction of pancreatic beta cells. Although T1D has conventionally been viewed as a T-cell-dominant disease, recent research has emphasized the contribution of B cells in the onset of the disease. However, the mechanism underlying aberrant B cell responses remains unknown. B cell metabolism is a crucial prerequisite for B cell function and the development of adaptive immune responses. Here, we investigated the metabolic features of B cells, first in a cross-sectional cohort and subsequently in non-obese diabetic (NOD) mice, and revealed that there is an increased frequency of high-glucose-avidity (2-NBDGhigh) B cell population that may contribute to T1D progression. Further characterization of the metabolic, transcriptional and functional phenotype of B cells in NOD mice found that elevated glucose avidity is associated with a greater capacity for co-stimulation, proliferation and inflammatory cytokine production. Mechanistically, elevated Myc signaling orchestrated the glucose metabolism and the pro-inflammatory response of B cells in T1D. In vitro experiments demonstrated that pharmacological inhibition of glucose metabolism using metformin and 2-DG reduced pro-inflammatory cytokine production and B cell proliferation. Moreover, the combination of these inhibitors successfully delayed insulitis development, onset of diabetes, and improved high blood glucose levels in streptozotocin (STZ)-induced diabetic mice model. Taken together, our work has uncovered these high-glucose-avidity B cells as novel adjuvant diagnostic and therapeutic targets for T1D.

RNF20/RNF40 ameliorates streptozotocin-induced type 1 diabetes by activating vitamin D receptors in vivo.

Type 1 diabetes is one of the chronic autoimmune diseases. Its features include the immune-triggered pancreatic beta-cells destruction. Ubiquitin ligases RNF20 and RNF40 have been discovered to participate into beta cells gene expression, insulin secretion, and expression of vitamin D receptors (VDRs). However, no reports about the role of RNF20/RNF40 in type 1 diabetes are known till now. The aim of this study was to clarify the role of RNF20/RNF40 in type 1 diabetes and explore the mechanism. In this study, streptozotocin (STZ)-induced mice type 1 diabetes model was used. The protein expressions of genes were examined through Western blot analysis. Fasting blood glucose was detected through glucose meter. The plasma insulin was tested through the commercial kit. Hematoxylin and eosin staining was utilized to observe pathological changes of pancreatic tissues. Immunofluorescence assay was performed to evaluate the level of insulin. The levels of pro-inflammatory cytokines in serum were assessed by enzyme-linked-immunosorbent serologic assay. The cell apoptosis was measured through terminal deoxynucleotidyl transferase dUTP nick end labelling assay. STZ was used to stimulate mice model for type 1 diabetes. At first, both RNF20 and RNF40 expressions were down-regulated in STZ-mediated type 1 diabetes. Additionally, RNF20/RNF40 improved hyperglycemia in STZ-stimulated mice. Moreover, RNF20/RNF40 relieved pancreatic tissue injury in STZ-induced mice. Further experiments found that RNF20/RNF40 rescued the strengthened inflammation mediated by STZ treatment. The cell apoptosis was enhanced in the pancreatic tissues of STZ-triggered mice, but this effect was weakened by overexpression of RNF20/RNF40. Besides, the VDR expression was positively regulated by RNF20/RNF40. Finally, VDR knockdown reversed improved hyperglycemia, inflammation, and cell apoptosis stimulated by overexpression of RNF20/RNF40. Our findings proved that RNF20/RNF40 activated VDR to relieve type 1 diabetes. This work might highlight the functioning of RNF20/RNF40 in the treatment of type 1 diabetes.

Frequency of Celiac Disease among Children with Type I Diabetes Mellitus

Background: Type 1 diabetes mellitus (T1DM) is a metabolic condition of chronic hyperglycemia due to a lack of insulin resulting from the autoimmune destruction of pancreatic beta cells. T1DM is associated with many autoimmune conditions, especially hypothyroidism and celiac disease (CD). Objective: To determine the frequency of celiac disease among children and adolescents with type 1 diabetes mellitus. Study Design: Prospective cross-sectional study. Settings: Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Child Health Sciences, The Children’s Hospital, Lahore Pakistan. Duration: October 2019 to January 2022. Methods: A total of 150 children and adolescents with T1DM were included in this study. Patients already diagnosed with CD, patients with concomitant autoimmune disease, patients with Down syndrome, and patients who refused to participate and who lost follow-up were excluded from the study. All patients underwent a celiac screen, and those with positive or borderline serology had an endoscopic biopsy of the distal duodenum. Biopsy reporting was done as per Modified Marsh Classification. The patient's data and laboratory findings were recorded through a predesigned proforma and analyzed using SPSS version 20. Results: The mean age of participants was 8.08 ± 2.95 years, including 79 (52.7%) male and 71 (47.3%) female patients. A total of 19 (12.7%) had positive serology for celiac disease, and 8 (5.3%) had biopsy findings confirming celiac disease. Conclusion: Children and adolescents with T1DM have an increased tendency for CD, warranting earlier screening for timely detection and management.

Investigating immune profile by CyTOF in individuals with long-standing type 1 diabetes

Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of pancreatic beta cells. Eosinophils are found in pancreatic tissue from individuals with T1D. Eosinophilic suppression of T cells is dependent of the protein galectin-10. Little is known when it comes to the role of eosinophil granulocytes in type 1 diabetes. Here we show that individuals with long-standing T1D had lower levels of galectin-10hi eosinophils and a subgroup of galectin-10hi eosinophils were entirely absent in all T1D patients. In addition, 7% immature eosinophils were present in the circulation of T1D patients whereas 0.8% in healthy individuals. Furthermore, higher levels of CD4+CD8+ T cells and Th17 cells were observed in patients with T1D. Blood samples from 12 adult individuals with long-standing T1D and 12 healthy individuals were compared using cytometry by time-of-flight. Lower levels of galectin-10hi eosinophils, which are potent T cell suppressors, in individuals with T1D could indicate that activated T cells are enabled to unrestrictedly kill the insulin producing beta cells. This is the first study showing absence of galectin-10hi eosinophilic subgroup in individuals with T1D compared with healthy controls. This study is a first important step toward unraveling the role of the eosinophils in patients with T1D.

Islet Autoantibodies to Pancreatic Insulin-Producing Beta Cells in Adolescent and Adults with Type 1 Diabetes Mellitus: A Cross-Sectional Study.

(1) Background: Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of pancreatic insulin-producing beta cells. T1D is one of the most common endocrine and metabolic disorders occurring in children. Autoantibodies against pancreatic insulin-producing beta cells are important immunological and serological markers of T1D. Zinc transporter 8 autoantibody (ZnT8) is a recently identified autoantibody in T1D; however, no data on ZnT8 autoantibody in the Saudi Arabian population have been reported. Thus, we aimed to investigate the prevalence of islet autoantibodies (IA-2 and ZnT8) in adolescents and adults with T1D according to age and disease duration. (2) Methods: In total, 270 patients were enrolled in this cross-sectional study. After meeting the study's inclusion and exclusion criteria, 108 patients with T1D (50 men and 58 women) were assessed for T1D autoantibody levels. Serum ZnT8 and IA-2 autoantibodies were measured using commercial enzyme-linked immunosorbent assay kits. (3) Results: IA-2 and ZnT8 autoantibodies were present in 67.6% and 54.6% of patients with T1D, respectively. Autoantibody positivity was found in 79.6% of the patients with T1D. Both the IA-2 and ZnT8 autoantibodies were frequently observed in adolescents. The prevalence of IA-2 and ZnT8 autoantibodies in patients with a disease duration < 1 year was 100% and 62.5%, respectively, which declined with an increase in disease duration (p < 0.020). Logistic regression analysis revealed a significant relationship between age and autoantibodies (p < 0.004). (4) Conclusions: The prevalence of IA-2 and ZnT8 autoantibodies in the Saudi Arabian T1D population appears to be higher in adolescents. The current study also showed that the prevalence of autoantibodies decreased with disease duration and age. IA-2 and ZnT8 autoantibodies are important immunological and serological markers for T1D diagnosis in the Saudi Arabian population.

Teplizumab Therapy to Delay the Onset of Type 1 Diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results in the destruction of insulin-producing pancreatic beta cells. The incidence and prevalence of T1DM are increasing, making this one of the most common diseases of childhood. The disease is associated with significant morbidity and mortality with patients experiencing reduced quality of life and decreased life expectancy compared with the general population. Patients become dependent on exogenous insulin which has been the primary treatment since its first clinical use over 100 years ago. Although there have been advancements in glucose monitoring technology and insulin delivery devices, most patients fail to meet glycemic targets. Research has therefore focused on different treatment options to delay or prevent disease progression. Monoclonal antibodies have previously been utilized to suppress the immune response following an organ transplant and were subsequently studied for their ability to treat autoimmune diseases. Teplizumab, a monoclonal antibody (manufactured by Provention Bio and marketed as Tzield), was recently approved by the Food and Drug Administration as the first preventative treatment for T1DM. The approval came after a 3-decade history of research and development. This article provides an overview of the discovery and mechanism of action of teplizumab, as well as the clinical trials that led to its approval.

Deletion of Vβ3 +CD4 +T-cells by endogenous mouse mammary tumor virus 3 prevents type 1 diabetes induction by autoreactive CD8 +T-cells

Abstract In both humans and NOD mice, type 1 diabetes (T1D) develops from the autoimmune destruction of pancreatic beta cells by T-cells. Interactions between both helper CD4 +and cytotoxic CD8 +T-cells are essential for T1D development in NOD mice. Previous work has indicated that pathogenic T-cells arise from deleterious interactions between relatively common genes which regulate aspects of T-cell activation/effector function (Ctla-4, Tnfrsf9, Il2/Il21), peptide presentation (H2-A g7, B2m), and T-cell receptor signaling (Ptpn22). In this study, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded Mtv3 provirus as a genetic element affecting CD4 +/CD8 +T-cell interactions through an additional mechanism, altering the T-cell receptor (TCR) repertoire. Mtv3 encodes a superantigen that deletes the majority of Vβ3 +thymocytes in NOD mice. Ablating Mtv3 and restoring Vβ3 +T-cells has no effect on spontaneous T1D development in NOD mice. However, transferring Mtv3 to C57BL/6 (B6) mice congenic for the NOD H2 g7MHC haplotype (B6.H2 g7) completely blocks their normal susceptibility to T1D mediated by transferred CD8 +T-cells transgenically expressing AI4 or NY8.3 TCRs. The entire genetic effect is manifest by Vβ3 +CD4 +T-cells, which unless deleted by Mtv3, accumulate in insulitic lesions and trigger in B6 background mice the pathogenic activation of diabetogenic CD8 +T-cells. Our findings provide evidence that endogenous Mtv superantigens can influence autoimmune responses. Furthermore, since most common mouse strains have gaps in their TCR Vβ repertoire due to Mtvs, it raises questions about the role of Mtvs in other mouse models designed to reflect human disorders. Supported by grants from the American Diabetes Association (1-14-BS-051) and NIH (AI130656)

Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based JAK inhibitor Treatment that Involves Anergy Formation

Abstract Type 1 diabetes is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. The inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of this disease. To improve on drug bioavailability and reduce deleterious systemic exposure, we identified a lipid nanoparticle (LNp) formulation with favorable Tofa encapsulation efficiency and negligible cellular toxicity. Live animal imaging indicated these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Spectral flow analysis revealed that multiple immune cells, like dendritic cells, T cells, and B cells, uptake the particles in these tissues. Short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of disease onset. Importantly, the therapeutic effect was associated with a profound increase in anergic CD4 T cells in the draining sites of LNp. Anergic cells have been known to form following stimulation in absence of co-stimulation, however, additional in vitro stimulation assays suggest a distinctive path of anergy induction promoted by blocking cytokine signaling. Overall, our results suggest an unexpected and novel immunomodulatory effect of JAK inhibition that warrants further investigation for the development of an effective treatment of type 1 diabetes.

Prolonged remission in latent autoimmune diabetes of adults (LADA): Is insulin resistance a major influence?

Abstract Introduction Type 1 diabetes mellitus (T1DM) is a chronic inflammatory disease that courses with high serum glucose levels as a result of pancreatic beta cell destruction and subsequent insulinopenia. LADA is a type of autoimmune diabetes where damage to the beta cell occurs much slower. The natural history of type 1 diabetes is very heterogeneous and variable. This is especially true for LADA with several possible different clinical courses due to a wider variety of pancreatic cell destruction and insulin resistance. Clinically overt diabetes ensues when more than 80% of pancreatic cell mass is loss. After treatment initiation partial disease remission is common, especially in children. However complete remission is rare, and remission lasting for over a year is even rarer, with few reports published in literature. Some agents such as vitamin D and DPP4 inhibitors have been presented has having potential immunomodulatory effects. Clinical Case A 36-year-old man with grade 1 obesity (BMI 33 kg/m2) presented at the emergency department with symptoms of insulinopenia (polyuria and polydipsia in the previous 3 months) and hyperglycemia (capillary blood glucose &amp;gt;500mg/dL). Ketonemia was negative and pH was normal on blood gas analysis The diagnosis of diabetes mellitus was made and insulin therapy was instituted on a basal-bolus regimen. At the first follow-up appointment, due to his morphotype and familiar history of type 2 diabetes (mother diagnosed at 52 years of age), he stopped short-acting insulin and was started on metformin and SGLT2 inhibitor. A week later he was admitted in the hospital in euglycemic ketoacidosis. Initial workup revealed positive anti-GAD 41.8 U/mL, HbA1C 9.8%, C-peptide 1.83 ng/mL, serum insuline 17.4 uU/mL. Consequently, metformin and SGLT2 inhibitor therapy was stopped, and the patient resumed basal bolus insulin regimen. He then remained under a basal insulin without need of meal-time insulin bolus, progressively lowering the basal insulin dose until suspension four months later. Simultaneously, lifestyle changes were implemented with significant weigh loss (BMI 33 &amp;gt; 26.4 kg/m2 at the time of insulin suspension). After 3 years of follow-up the patient remains without need of antidiabetic therapy, with normal Hba1c 5.3%. Anti-GAD antibodies remain positive (39.4 U/mL) but C-peptide and serum insulin are within the reference range (1.69 ng/mL [1.1–4–4], 6.9uU/mL [2.6–25], respectively). Conclusion Prolonged disease remission in type 1 diabetes is rare. This case highlights an especially long “honeymoon” period in a patient with LADA. Obesity and insulin resistance probably played a role in the initial patient presentation, and its improvement probably helps to justify this prolonged remission. In spite of the family history of diabetes, other types of diabetes seem unlikely due to positive antibodies and SGLT2 inhibitor associated euglycemic ketoacidosis.

Cellular Metabolism in B Cells in Type 1 Diabetes

Background/Objective: Type 1 diabetes (T1D) is an immune-mediated disease that results in the destruction of pancreatic beta cells. While beta cell destruction is classically considered T cell mediated, autoreactive B cells play important roles in disease progression. B cell depletion prevents disease in non-obese diabetic (NOD) mice, and B cell depletion temporarily slows disease progression in individuals with new-onset T1D. However, mechanisms of autoreactive B cell function in T1D are not fully known. Cellular metabolism has been shown to drive autoimmune B cell development in other mouse models. We hypothesize that metabolic characteristics of B cells from NOD mice are distinct from metabolic characteristics of B cells from non-autoimmune C57BL/6J (B6) mice; therefore, making cellular metabolic pathways viable targets for therapeutic intervention.&#x0D; Methods: Lymphocytes from spleen, pancreas, pancreatic lymph nodes, and mesenteric/lumbar lymph nodes were processed into single-cell suspensions. Glucose uptake was measured using fluorescent glucose analog 2-NBDG. Mitochondrial polarity was measured using fluorescent probes for mass and membrane potential. Cells were stained for surface markers and analyzed on an Attune Nxt flow cytometer.&#x0D; Results: No statistically significant differences in glucose uptake or mitochondrial polarity for lymphocyte subsets in the spleen or PLNs of NOD and B6 mice were identified. In NOD mice, polarity was significantly higher in B cells in the pancreas compared to the spleen and PLNs. Polarity was also higher in B cells in PLNs compared to non-specific lymph nodes in NOD mice.&#x0D; Conclusions/Impact: While no differences in glucose uptake or polarity in lymphocytes from NOD and B6 mice ex vivo were identified, future studies are needed to determine whether their activation drives metabolic alterations. Differences in polarity in the pancreas in NOD mice suggest that cellular metabolism is influenced by the islet microenvironment and has the potential to influence their function at the site of autoimmune attack.

Immunologic Desensitisation of Allergens and its Impact on Insulin Use in Type 1 Diabetes Mellitus: A Case Report

Type1 diabetes mellitus, also known as juvenile diabetes is an autoimmune disorder. It is a chronic condition in which there is a destruction of pancreatic beta cells by autoimmune response. Here, a case of a 13-year-old girl, weighing 32 kg and with a Body Mass index (BMI) of 13.9 kg/m2 was reported to the family medicine clinic with complaints of weakness, increased appetite and thirst, and increased frequency of micturition for the past two months. Personal history revealed a consistent weight loss over the past six months with the problem of lice in the hair from the past two months. A family history of diabetes, hypertension, and allergies was present. General physical examination reveals no abnormality and vitals were within normal limits. Blood investigations revealed increased levels of random blood sugar levels, glycated Haemoglobin (HbA1c) and Immunoglobulin (Ig)E. Hormonal assay was within normal limits, and skin prick test result revealed strong positive reactions to some allergens. The treatment included subcutaneous insulin, regular physical exercise and immunologic desensitisation of food allergens through Sublingual Immunotherapy (SLIT). The treatment resulted in controlled blood glucose levels with a reduction in insulin dose, a decrease in HbA1c levels, increased body weight and an improved BMI.

The effect of pregnant serum, cord blood serum and hCG on jurkat T-cell IL-2 secretion

Type 1 diabetes mellitus (T1DM) results in autoimmune destruction of insulin producing pancreatic beta cells. Although thought to be terminally differentiated, beta cells may undergo expansion during pregnancy. As pregnancy creates a state of immune tolerance, exploring this finding may offer insights to possible therapies for T1DM. We investigated whether circulating factors in serum from pregnant women could reduce the degree of immune activation of human T cells specific for beta cell antigens by measuring interleukin-2 (IL-2).

Monogenic diabetes : a pioneer in precision medicine management

Diabetes mellitus in children is subdivided into several categories depending on the underlying pathological mechanism. Type 1 diabetes is due to the autoimmune destruction of pancreatic beta-cells, type 2 diabetes to progressive impairment in insulin secretion or insulin sensitivity, and monogenic diabetes due to genetic abnormalities, impairing insulin secretion. In monogenic diabetes, genetic defects result in pancreatic or beta-cell defects (abnormal function or destruction), resulting in neonatal or MODY (Maturity-Onset Diabetes of the Young) diabetes, depending on the age of onset. The identification of monogenic diabetes is crucial as it allows the initiation of targeted and personalized treatment.