Destruction Of Pancreatic Beta Cells Research Articles

Enrichment of Bioactive Lipids in Urinary Extracellular Vesicles and Evidence of Apoptosis in Kidneys of Hypertensive Diabetic Cathepsin B Knockout Mice after Streptozotocin Treatment

Cathepsin B (CtsB) is a ubiquitously expressed cysteine protease that plays important roles in health and disease. Urinary extracellular vesicles (uEVs) are released from cells associated with urinary organs. The antibiotic streptozotocin (STZ) is known to induce pancreatic islet beta cell destruction, diabetic nephropathy, and hypertension. We hypothesized that streptozotocin-induced diabetic kidney disease and hypertension result in the release of bioactive lipids from kidney cells that induce oxidative stress and renal cell death. Lipidomics was performed on uEVs isolated from CtsB knockout mice treated with or without STZ, and their kidneys were used to investigate changes in proteins associated with cell death. Lysophosphatidylethanolamine (LPE) (18:1), lysophosphatidylserine (LPS) (22:6), and lysophosphatidylglycerol (LPG) (22:5) were among the bioactive lipids enriched in uEVs from CtsB knockout mice treated with STZ compared to untreated CtsB mice (n = 3 uEV preparations per group). Anti-oxidant programming was activated in the kidneys of the CtsB knockout mice treated with STZ, as indicated by increased expression of glutathione peroxidase 4 (GPX4) and the cystine/glutamate antiporter SLC7A11 (XCT) (n = 4 mice per group), which was supported by a higher reactivity to 4-hydroxy-2-nonenal (4-HNE), a marker for oxidative stress (n = 3 mice per group). Apoptosis but not ferroptosis was the ongoing form of cell death in these kidneys as cleaved caspase-3 levels were significantly elevated in the STZ-treated CtsB knockout mice (n = 4 mice per group). There were no appreciable differences in the pro-ferroptosis enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) or the inflammatory marker CD93 in the kidneys (n = 3 mice per group), which further supports apoptosis as the prevalent mechanism of pathology. These data suggest that STZ treatment leads to oxidative stress, inducing apoptotic injury in the kidneys during the development of diabetic kidney disease and hypertension.

Nutritional Management of Athletes with Type 1 Diabetes: A Narrative Review.

Type 1 diabetes mellitus (T1DM) represents a complex clinical challenge for health systems. The autoimmune destruction of pancreatic beta cells leads to a complete lack of insulin production, exposing people to a lifelong risk of acute (DKA, coma) and chronic complications (macro and microvascular). Physical activity (PA) has widely demonstrated its efficacy in helping diabetes treatment. Nutritional management of people living with T1DM is particularly difficult. Balancing macronutrients, their effects on glycemic control, and insulin treatment represents a complex clinical challenge for the diabetologist. The effects of PA on glycemic control are largely unpredictable depending on many individual factors, such as intensity, nutrient co-ingestion, and many others. Due to this clinical complexity, we have reviewed the actual scientific literature in depth to help diabetologists, sport medicine doctors, nutritionists, and all the health figures involved in diabetes care to ameliorate both glycemic control and the nutritional status of T1DM people engaging in PA. Two electronic databases (PubMed and Scopus) were searched from their inception to January 2024. The main recommendations for carbohydrate and protein ingestion before, during, and immediately after PA are explained. Glycemic management during such activity is widely reviewed. Micronutrient needs and nutritional supplement effects are also highlighted in this paper.

An updated review on diabetes mellitus: Exploring its etiology, pathophysiology, complications and treatment approach

Diabetes mellitus, a prevalent chronic metabolic disorder, encompasses types like Type 1 (T1DM), Type 2 (T2DM), and gestational diabetes, marked by elevated blood sugar levels. T1DM, an autoimmune disease, entails genetic susceptibility triggering pancreatic beta cell destruction, necessitating insulin replacement. T2DM, linked to metabolic syndrome and insulin resistance, is influenced by genetics, obesity, inactivity, and ethnicity. Gestational Diabetes Mellitus (GDM) in pregnancy elevates offspring obesity and T2DM risk. Diagnosis involves fasting glucose, oral glucose tolerance, HbA1c tests, and specific antibody assessments. Chronic complications include atherosclerosis, retinopathy, neuropathy, nephropathy, and osmotic cell death, emphasizing glycaemic control. Treatment strategies differ, with T1DM requiring insulin therapy and T2DM involving lifestyle changes, medication, and potential insulin use, underscoring the need to understand diabetes for effective management and improved quality of life.

Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21.

Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear. To explore how SASP is transcriptionally regulated in beta cells, we used the NOD beta cell line NIT-1 to model beta cell SASP and identified binding partners of BET protein Brd4 and explored the role of the cyclin-dependent kinase inhibitor p21. Brd4 interacted with a variety of proteins in senescent NIT-1 cells including subunits of the Ino80 chromatin remodeling complex, which was expressed in beta cells during T1D progression in NOD mice and in human beta cells of control, autoantibody-positive, and T1D donors as determined from single-cell RNA-seq data. RNAi knockdown of p21 during senescence in NIT-1 cells did not significantly impact viability or SASP. Taken together, these results suggest that Brd4 interacts with several protein partners during senescence in NIT-1 cells, some of which may play roles in SASP gene activation and that p21 is dispensable for the SASP in this beta cell model.

Evidence for C-peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes.

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic beta cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of beta cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of beta cell function have established a predictive relationship between stimulated C-peptide as a measure of beta cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of beta cell function, but also as a specific, sensitive, feasible, and clinically meaningful outcome defining beta cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes.

A novel subpopulation of monocytes with a strong interferon signature indicated by SIGLEC-1 is present in patients with in recent-onset type 1 diabetes.

Type 1 diabetes is a T cell-mediated autoimmune disease characterised by pancreatic beta cell destruction. In this study, we explored the pathogenic immune responses in initiation of type 1 diabetes and new immunological targets for type 1 diabetes prevention and treatment. We obtained peripheral blood samples from four individuals with newly diagnosed latent autoimmune diabetes in adults (LADA) and from four healthy control participants. Single-cell RNA-sequencing (scRNA-seq) was performed on peripheral blood mononuclear cells to uncover transcriptomic profiles of early LADA. Validation was performed through flow cytometry in a cohort comprising 54 LADA, 17 adult-onset type 2 diabetes, and 26 healthy adults, matched using propensity score matching (PSM) based on age and sex. A similar PSM method matched 15 paediatric type 1 diabetes patients with 15 healthy children. Further flow cytometry analysis was performed in both peripheral blood and pancreatic tissues of non-obese diabetic (NOD) mice. Additionally, cell adoptive transfer and clearance assays were performed in NOD mice to explore the role of this monocyte subset in islet inflammation and onset of type 1 diabetes. The scRNA-seq data showed that upregulated genes in peripheral T cells and monocytes from early-onset LADA patients were primarily enriched in the IFN signalling pathway. A new cluster of classical monocytes (cluster4) was identified, and the proportion of this cluster was significantly increased in individuals with LADA compared with healthy control individuals (11.93% vs 5.93%, p=0.017) and that exhibited a strong IFN signature marked by SIGLEC-1 (encoding sialoadhesin). These SIGLEC-1+ monocytes expressed high levels of genes encoding C-C chemokine receptors 1 or 2, as well as genes for chemoattractants for T cells and natural killer cells. They also showed relatively low levels of genes for co-stimulatory and HLA molecules. Flow cytometry analysis verified the elevated levels of SIGLEC-1+ monocytes in the peripheral blood of participants with LADA and paediatric type 1 diabetes compared with healthy control participants and those with type 2 diabetes. Interestingly, the proportion of SIGLEC-1+ monocytes positively correlated with disease activity and negatively with disease duration in the LADA patients. In NOD mice, the proportion of SIGLEC-1+ monocytes in the peripheral blood was highest at the age of 6 weeks (16.88%), while the peak occurred at 12 weeks in pancreatic tissues (23.65%). Adoptive transfer experiments revealed a significant acceleration in diabetes onset in the SIGLEC-1+ group compared with the SIGLEC-1- or saline control group. Our study identified a novel group of SIGLEC-1+ monocytes that may serve as an important indicator for early diagnosis, activity assessment and monitoring of therapeutic efficacy in type 1 diabetes, and may also be a novel target for preventing and treating type 1 diabetes. RNA-seq data have been deposited in the GSA human database ( https://ngdc.cncb.ac.cn/gsa-human/ ) under accession number HRA003649.

Approaches to Measuring Beta Cell Reserve and Defining Partial Clinical Remission in Paediatric Type 1 Diabetes.

Type 1 diabetes (T1D) results from the autoimmune T-cell mediated destruction of pancreatic beta cells leading to insufficient insulin secretion. At the time of diagnosis of T1D, there is residual beta cell function that declines over the subsequent months to years. Recent interventions have been approved to preserve beta cell function in evolving T1D. The aim of this review is to summarise the approaches used to assess residual beta cell function in evolving T1D, and to highlight potential future directions. Studies including subjects aged 0 to 18 years were included in this review. The following search terms were used; "(type 1 diabetes) and (partial remission)" and "(type 1 diabetes) and (honeymoon)". References of included studies were reviewed to determine if additional relevant studies were eligible. There are numerous approaches to quantifying beta cell reserve in evolving T1D. These include c-peptide measurement after a mixed meal or glucagon stimuli, fasting c-peptide, the urinary c-peptide/creatinine ratio, insulin dose-adjusted haemoglobin A1c, and other clinical models to estimate beta cell function. Other biomarkers may have a role, including the proinsulin/c-peptide ratio, cytokines, and microRNA. Studies using thresholds to determine if residual beta cell function is present often differ in values used to define remission. As interventions are approved to preserve beta cell function, it will become increasingly necessary to quantify residual beta cell function in research and clinical contexts. In this report, we have highlighted the strengths and limitations of the current approaches.

Exploring the underlying mechanism of ethyl acetate extract of Annona muricata leaves via the NRF2 and NF-ΚB pathway in type 1 diabetic Wistar rats

Type 1 diabetes mellitus is an autoimmune disorder characterized by the destruction of pancreatic beta cells, leading to impaired insulin production and regulation. Recent research has shown that medicinal plants with antioxidant and anti-inflammatory properties hold promise as potential therapeutic agents for managing complications of the disease. The aim of this study is to investigate the anti-diabetic, antioxidant, and anti-inflammatory effect of ethyl acetate extract of Annona muricata leaves in streptozotocin (STZ)-induced diabetes in Wistar rats. Thirty five (35) male Wistar rats weighing 150-180g were used for this experiment. Group 1 (Normal control), Group 2 (STZ 40 mg/kg only Diabetic control), Group 3 (STZ+ metformin 500mg/kg bw), Group 4 (STZ + ethyl acetate extract 250 mg/kg bw), Group 5 (STZ + ethyl acetate extract (500 mg/kg bw). Fasting blood samples were collected by cardiac puncture for glucose estimation and liver tissues excised for both biochemical and molecular studies. The study demonstrated the extract's ability to modulate the NF-κB pathway, leading to the suppression of inflammatory responses in diabetic rats. These findings suggest that the ethyl acetate extract of A. muricata leaves may ameliorate type 1 diabetes by promoting antioxidant defense and reducing inflammatory processes through the NRF2 and NF-κB pathways. This research sheds light on the potential of natural compounds as adjunct therapies for type 1 diabetes and provides a foundation for further investigations into the development of novel treatments targeting oxidative stress and inflammation in autoimmune diabetes.

Impact of Living with Stigma in Persons with Type 1 Diabetes: A Patient-Physician Perspective.

Type 1 diabetes mellitus (T1D) is an autoimmune disorder characterized by a complete deficiency in insulin due to the destruction of pancreatic beta cells. Globally, T1D accounts for nearly 5-10% of the total diabetes cases. Living with this life-long condition has a significant emotional, psychological, physical, mental, and social impact. Despite extensive research characterizing the underlying physiology of T1D, additional work is needed to address the psychosocial aspects associated with the condition and its effect on the quality of life (QoL) of people living with T1D. One area that warrants further exploration is the stigma-related stereotypes and prejudice of people living with T1D experience in real-life settings. Despite the acknowledgment of stigma for conditions such as obesity, mental illness, and epilepsy, its association with T1D and ensuing psychological distress remains relatively under-investigated. Health-related stigma is a huge barrier to seeking appropriate, timely support for enhanced healthcare management and engagement in such patients. Here, we provide the perspectives of an adult with over 33years of living with T1D and an expert endocrinologist who details their experience of T1D-related stigma. The self-reported factors explored by the person living with T1D include (but are not limited to) blame, mockery of the condition/person, diabetes-related shame, exclusion, rejection, negative judgments, fear, stereotyping, and discrimination. The lived experience supported by the clinical insights of the endocrinologist highlights the urgent need to decipher the severity, extent, nature, determinants, and consequences of stigma faced by a person living with T1D. Raising societal awareness, increasing education for caregivers, access to counseling for people living with diabetes, and engaging in shared decision-making remain the path forward.

Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children

Aims/hypothesisType 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb+) children to identify molecules related to type 1 diabetes progression.MethodsWe measured the levels of 14 sICM in the sera of AAb+ children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb+ children were followed up and divided based on their progression to type 1 diabetes (AAbP) or not (AAbNP) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAbP children.ResultsWe found that AAb+ children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb+ children who progressed to type 1 diabetes (AAbP) had higher sICM concentrations than non-progressors (AAbNP). Further, sICM levels decreased in AAbP children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007).Conclusions/interpretationThis study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.Graphical

A Quick Look at The Present and Immediate Future of Diabetes Mellitus Type 1

Type 1 diabetes (T1DM) is a hyperglycaemic syndrome that results from the autoimmune destruction of pancreatic beta cells. To achieve good metabolic control, for which we have an excellent technological tool, continuous interstitial glucose monitoring (CGM), which should be used in all pediatric patients from diagnosis. Positive results of delay in the diagnosis of DM1 and lengthening of the remission phase have been obtained with the use of monoclonal antibodies. Without a doubt, the greatest current advances in the treatment of DM1 come from the use of technology, together with regulated/structured and continued diabetes education, this being a fundamental piece to improve control, adherence to treatment and quality. of patient’s lives [1,2] . Despite all the advances in general, the objectives advocated by international societies for this age (American Diabetes Association [ADA], International Society for Pediatric and Adolescent Diabetes [ISPAD]) have not been achieved, leading to the search for other systems that lead to greater adherence to treatment.

Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease that destroys insulin-producing pancreatic β-cells. Insulin replacement therapy is currently the mainstay of treatment for T1DM; however, treatment with insulin does not ameliorate disease progression, as dysregulated immune response and inflammation continue to cause further pancreatic β-cell degradation. Therefore, shifting therapeutic strategies toward immunomodulating approaches could be effective to prevent and reverse disease progression. Different immune-modulatory therapies could be used, e.g., monoclonal-based immunotherapy, mesenchymal stem cell, and immune cell therapy. Since immune-modulatory approaches could have a systemic effect on the immune system and cause toxicity, more specific treatment options should target the immune response against pancreatic β-cells. In this regard, chimeric antigen receptor (CAR)-based immunotherapy could be a promising candidate for modulation of dysregulated immune function in T1DM. CAR-based therapy has previously been approved for a number of hematologic malignancies. Nevertheless, there is renewed interest in CAR T cells' " off-the-shelf " treatment for T1DM. Several pre-clinical studies demonstrated that redirecting antigen-specific CAR T cells, especially regulatory CAR T cells (CAR Tregs), toward the pancreatic β-cells, could prevent diabetes onset and progression in diabetic mice models. Here, we aim to review the current progress of CAR-based immune-cell therapy for T1DM and the corresponding challenges, with a special focus on designing CAR-based immunomodulatory strategies to improve its efficacy in the treatment of T1DM.

Integrating multi-omics data to analyze the potential pathogenic mechanism of CTSH gene involved in type 1 diabetes in the exocrine pancreas.

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-producing pancreatic islet beta cells. Despite significant advancements, the precise pathogenesis of the disease remains unknown. This work integrated data from expression quantitative trait locus (eQTL) studies with Genome wide association study (GWAS) summary data of T1D and single-cell transcriptome data to investigate the potential pathogenic mechanisms of the CTSH gene involved in T1D in exocrine pancreas. Using the summary data-based Mendelian randomization (SMR) approach, we obtained four potential causative genes associated with T1D: BTN3A2, PGAP3, SMARCE1 and CTSH. To further investigate these genes'roles in T1D development, we validated them using a scRNA-seq dataset from pancreatic tissues of both T1D patients and healthy controls. The analysis showed a significantly high expression of the CTSH gene in T1D acinar cells, whereas the other three genes showed no significant changes in the scRNA-seq data. Moreover, single-cell WGCNA analysis revealed the strongest positive correlation between the module containing CTSH and T1D. In addition, we found cellular ligand-receptor interactions between the acinar cells and different cell types, especially ductal cells. Finally, based on functional enrichment analysis, we hypothesized that the CTSH gene in the exocrine pancreas enhances the antiviral response, leading to the overexpression of pro-inflammatory cytokines and the development of an inflammatory microenvironment. This process promotes β cells injury and ultimately the development of T1D. Our findings offer insights into the underlying pathogenic mechanisms of T1D.

Biomarkers and Inflammatory Pathways in Diabetes Mellitus Progression

With the rapidly increasing prevalence of diabetes in the global population, an early diagnosis of both type 1 diabetes mellitus and type 2 diabetes mellitus is critical to preventing long-term complications. Two potential components of unlocking a consistent early diagnosis of diabetes are understanding biological inflammatory pathways and identifying more sensitive biomarkers of diabetes. Novel biomarkers, such as interleukin, assist in monitoring the destruction of pancreatic beta cells, while inflammatory pathways can help explain the underpinnings of the insulin resistance found in both types of diabetes. In addition, research into 5-methoxytryptamine and 20-Hydroxy-leukotriene B4 would prove useful as a result of their heightened levels in patients with normal glucose levels.

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

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 (Ctla4, Tnfrsf9, Il2/Il21), peptide presentation (H2-A g7, B2m), and T cell receptor (TCR) signaling (Ptpn22). Here, we used a combination of subcongenic mapping and a CRISPR/Cas9 screen to identify the NOD-encoded mammary tumor virus (Mtv)3 provirus as a genetic element affecting CD4+/CD8+ T cell interactions through an additional mechanism, altering the TCR repertoire. Mtv3 encodes a superantigen (SAg) 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 g7 MHC 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 manifested by Vβ3+CD4+ T cells, which unless deleted by Mtv3, accumulate in insulitic lesions triggering in B6 background mice the pathogenic activation of diabetogenic CD8+ T cells. Our findings provide evidence that endogenous Mtv SAgs 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 immune disorders.

NADH intraperitoneal injection prevents massive pancreatic beta cell destruction in a streptozotocin-induced diabetes in rats.

Diabetes mellitus is a chronic metabolic disease characterized by persistent hyperglycemia, revealing a decrease in insulin efficiency. The sustained glucotoxic pancreatic microenvironment increases reactive oxygen species generation, resulting in chronic oxidative stress responsible for massive DNA damage. This triggers PARP-1 activation with both NAD+ and ATP depletion, affecting drastically pancreatic beta cells' energy storage and leading to their dysfunction and death. The aim of the present study is to highlight the main histological changes observed in pancreatic islets pre-treated with a unique NADH intraperitoneal injection in a streptozotocin-(STZ)-induced diabetes model. In order to adjust NADH doses, a preliminary study with three different doses, 500mg/kg, 300mg/kg, and 150mg/kg, respectively, was conducted. Subsequently, and on the basis of the results of the aforementioned study, Wistar rats were randomly divided into four groups: non-diabetic control group, diabetics (STZ 45mg/kg), NADH-treated group (150mg/kg) 15min before STZ administration, and NADH-treated group (150mg/kg) 15min after STZ administration. The effect of NADH was assessed by blood glucose level, TUNEL staining, histo-morphological analysis, and immunohistochemistry. The optimum protective dose of NADH was 150mg/kg. NADH effectively decreased hyperglycemia and reduced diabetes induced by STZ. Histologically, NADH pre-treatment revealed a decrease in beta cell death favoring apoptosis over necrosis and therefore preventing inflammation with further beta cell destruction. Our data clearly demonstrate that NADH prior or post-treatment could effectively prevent the deleterious loss of beta cell mass in STZ-induced diabetes in rats and preserve the normal pancreatic islet's function.

Effect of macrophage polarization on parasitic protection against type 1 diabetes mellitus

Type 1 diabetes mellitus is a chronic disease caused by the destruction of pancreatic beta cells. Based on the hygiene hypothesis, a growing body of evidence suggests a negative association between parasitic infections and diabetes in humans and animal models. The mechanism of parasite-mediated prevention of type 1 diabetes mellitus may be related to the adaptive and innate immune systems. Macrophage polarization is a new paradigm for the treatment of type 1 diabetes mellitus, and different host macrophage subsets play various roles during parasite infection. Proinflammatory cytokines are released by M1 macrophages, which are important in the development of type 1 diabetes mellitus. Parasite-activated M2 macrophages prevent the development of type 1 diabetes mellitus and can influence the development of adaptive immune responses through several mechanisms, including Th2 cells and regulatory T cells. Here, we review the role and mechanism of macrophage polarization in parasitic protection against type 1 diabetes mellitus.

A Review on Latent Autoimmune Diabetes in Adults.

Latent autoimmune diabetes (LADA) is an unique form of diabetes that has characteristics of both type 1 and type 2 diabetes. Type 1.5 diabetes also known as LADA is occasionally confused for type 2 diabetes becausethere isdelayinpresenting featuresand early insulin independence. LADA, on the other hand, is an autoimmune disorder that differs from type 2 diabetes in that autoantibodies against pancreatic beta cells are what characterise it. Insulin production eventually diminishes due to the autoimmune destruction of pancreatic beta cells as a result of the pathophysiology of LADA. Autoantibodies to glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2), and insulin are frequently detected in LADA patients. These autoantibodies have important implications for therapy strategies and are essential in differentiating LADA from type 2 diabetes. LADA clinical management is very challenging. The aim of this article is to view the characteristics, disease presentation, diagnostic challenges, progression and treatment modalities of LADA.

Genetic association of PTPN22 polymorphisms with Type 1 diabetes in Pakistani children

ObjectiveType 1 diabetes, a multigenic autoimmune disorder, is caused by the destruction of pancreatic beta-cells leads to insufficient insulin production and hyperglycemia, resulting in early morbidities and mortality. This study was designed to explore the genetic association of PTPN22 gene polymorphisms with T1D susceptibility among Pakistani children. MethodsBlood samples of T1D patients were obtained from the Department of Diabetes and Endocrinology of Children Hospital & University of Child Health Sciences, Lahore. Genotyping of rs2476601, rs1310182, and rs1217414of the PTPN22 gene was performed by Tetra ARMS-PCR assay. Statistically, binary logistic regression was applied to determine variation in genotype distribution and association of PTPN22 gene polymorphism with T1D. ResultsGenetic analysis showed that the A allele of rs2476601 (OR = 0.53, 95 % CI = 0.31–0.90; P < 0.02) and T allele of rs1310182 was found to be risk allele for T1D development (OR = 0.51, 95 % CI = 0.36–0.76; P < 0.01) while the A allele of rs1217414 was a protective allele against T1D (OR = 1.19, 95 % CI = 0.80–1.77; P = 0.36). Genetic models revealed that GG genotypes of rs2476601 (OR = 2.01, 95 % CI = 1.13–3.58; P < 0.01), and AA genotypes of rs1310182 in the dominant model (OR = 1.83, 95 % CI = 1.03–3.24; P < 0.03) showed significant risk association with T1D. ConclusionFrom the results, it is concluded that PTPN22gene has a strong genetic association with SNP rs2476601andrs1310182with T1D in Pakistani children.

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.