Role In Pathogenesis Of Type 1 Diabetes Research Articles

Elevated Serum IgA at Onset of Type 1 Diabetes in Children

Background. Elevated serum IgA levels have been observed in various autoimmune conditions, including type 1 diabetes (T1D). However, whether children with T1D and elevated serum IgA have unique features has not been studied. We aimed to evaluate the prevalence and characteristics associated with elevated serum IgA at the onset of pediatric T1D. Materials and Methods. We analyzed demographic, clinical, and laboratory data retrospectively collected from 631 racially diverse children (6 months–18 years of age) with T1D who had serum IgA levels measured within 90 days of T1D diagnosis. Univariable and multivariable logistic regression models were used to identify characteristics that were significantly associated with elevated versus normal IgA. Results. Elevated serum IgA was present in 20.3% (128/631) of the children with newly diagnosed T1D. After adjusting for other variables, A1c level (p=0.029), positive insulin autoantibodies (IAA) (p=0.041), negative glutamic acid decarboxylase autoantibodies (GADA) (p=0.005) and Hispanic ethnicity (p <0.001) were significantly associated with elevated serum IgA. After adjustment for confounders, the odds of elevated serum IgA were significantly increased with positive IAA (OR 1.653, 95% CI 1.019–2.679), higher HbA1c (OR 1.132, 95% CI 1.014–1.268) and Hispanic ethnicity (OR 3.279, 95% CI 2.003–5.359) but decreased with GADA positivity (OR 0.474, 95% CI 0.281–0.805). Conclusions. Elevated serum IgA is present in 20.3% of the children at T1D onset and is associated with specific demographic and clinical characteristics, suggesting a unique pathogenesis in a subset of individuals. Further studies are warranted to investigate the IgA response, its role in T1D pathogenesis, and whether these associations persist over time.

Beta-Cell Tipe1 Orchestrates Insulin Secretion and Cell Proliferation by Promoting Gαs/cAMP Signaling via USP5.

Inadequate β-cell mass and insulin secretion are essential for the development of type 2 diabetes (T2D). TNF-α-induced protein 8-like 1 (Tipe1) plays a crucial role in multiple diseases, however, a specific role in T2D pathogenesis remains largely unexplored. Herein, Tipe1 as a key regulator in T2D, contributing to the maintenance of β cell homeostasis is identified. The results show that the β-cell-specific knockout of Tipe1 (termed Ins2-Tipe1BKO) aggravated diabetic phenotypes in db/db mice or in mice with high-fat diet-induced diabetes. Notably, Tipe1 improves β cell mass and function, a process that depends on Gαs, the α subunit of the G-stimulating protein. Mechanistically, Tipe1 inhibited the K48-linked ubiquitination degradation of Gαs by recruiting the deubiquitinase USP5. Consequently, Gαs or cAMP agonists almost completely restored the dysfunction of β cells observed in Ins2-Tipe1BKO mice. The findings characterize Tipe1 as a regulator of β cell function through the Gαs/cAMP pathway, suggesting that Tipe1 may emerge as a novel target for T2D intervention.

Autoimmune diseases: targets, biology, and drug discovery.

Autoimmune diseases (AIDs) arise from a breakdown in immunological self-tolerance, wherein the adaptive immune system mistakenly attacks healthy cells, tissues and organs. AIDs impose excessive treatment costs and currently rely on non-specific and universal immunosuppression, which only offer symptomatic relief without addressing the underlying causes. AIDs are driven by autoantigens, targeting the autoantigens holds great promise in transforming the treatment of these diseases. To achieve this goal, a comprehensive understanding of the pathogenic mechanisms underlying different AIDs and the identification of specific autoantigens are critical. In this review, we categorize AIDs based on their underlying causes and compile information on autoantigens implicated in each disease, providing a roadmap for the development of novel immunotherapy regimens. We will focus on type 1 diabetes (T1D), which is an autoimmune disease characterized by irreversible destruction of insulin-producing β cells in the Langerhans islets of the pancreas. We will discuss insulin as possible autoantigen of T1D and its role in T1D pathogenesis. Finally, we will review current treatments of TID and propose a potentially effective immunotherapy targeting autoantigens.

Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children.

Type 1 diabetes (T1D) is a complex autoimmune disorder that is highly prevalent globally. The interactions between genetic and environmental factors may trigger T1D in susceptible individuals. HLA genes play a significant role in T1D pathogenesis, and specific haplotypes are associated with an increased risk of developing the disease. Identifying risk haplotypes can greatly improve the genetic scoring for early diagnosis of T1D in difficult to rank subgroups. This study employed next-generation sequencing to evaluate the association between HLA class II alleles, haplotypes, and amino acids and T1D, by recruiting 95 children with T1D and 150 controls in the Kuwaiti population. Significant associations were identified for alleles at the HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci, including DRB1*03:01:01, DQA1*05:01:01, and DQB1*02:01:01, which conferred high risk, and DRB1*11:04:01, DQA1*05:05:01, and DQB1*03:01:01, which were protective. The DRB1*03:01:01~DQA1*05:01:01~DQB1*02:01:01 haplotype was most strongly associated with the risk of developing T1D, while DRB1*11:04-DQA1*05:05-DQB1*03:01 was the only haplotype that rendered protection against T1D. We also identified 66 amino acid positions across the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes that were significantly associated with T1D, including novel associations. These results validate and extend our knowledge on the associations between HLA genes and T1D in Kuwaiti children. The identified risk alleles, haplotypes, and amino acid variations may influence disease development through effects on HLA structure and function and may allow early intervention via population-based screening efforts.

825-P: Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

Studies in several animal models and of humans with type 1 diabetes (T1D) have suggested that Qa-1/HLA-E restricted CD8+ T regulatory cells (Tregs) are important in maintaining self-tolerance and a defect thereof playing a key role in T1D pathogenesis. To evaluate the safety and efficacy of targeting this pathway in T1D we undertook a first in human, phase 1/2 study of AVT001, an investigational autologous dendritic cell-based vaccine designed to address this immunologic mechanism. This double-blind, randomized (2:1 treated vs placebo) trial enrolled individuals (n=25) who were 16 years and older, within 1 year of clinical diagnosis of T1D, and with an ex-vivo correctable defect in the function of HLA-E-restricted CD8+ Tregs. All participants underwent leukapheresis, the first step in the generation of AVT001. AVT001 treatment (n=16) or placebo (n=9) was delivered as a series of three-monthly intravenous infusions. The primary endpoint of the study was safety/tolerability at day 150. AVT001 was safe and well tolerated with all participants completing treatment, no peri-infusion reactions noted, and adverse events reported as being mild or moderate in the AVT001 treated group, with rates similar to placebo. A pre-specified efficacy endpoint was change from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal tolerance test utilizing a mixed-effect model for repeated measurements (MMRM). The baseline mean (SD) AUCs were treated 0.531 (0.363) and placebo 0.611 (0.178) nmol/L. At day 150, the C-peptide AUCs were significantly different between groups, namely 0.518 (0.430) and 0.472 (0.134) respectively. Per MMRM, the least square mean difference between AVT001 and placebo at day 150, is estimated to be 0.172 (p=<.0001). There was an increase in AUC or no change for 6 (37.5%) in the AVT001 treated group and 1 (11.1%) in the placebo group. These results indicate that AVT001 treatment was safe and well tolerated with evidence of significant preservation of endogenous insulin secretion. Disclosure J.L.Gaglia: Advisory Panel; Dompé, Consultant; Vertex Pharmaceuticals Incorporated, Abata Therapeutics, Avotres Inc., Current Health, Research Support; Avotres Inc., Dompé, Imcyse, Stock/Shareholder; Vertex Pharmaceuticals Incorporated. J.Ritz: Advisory Panel; Novartis, Taleris, AvroBio, Clade Therapeutics, LifeVault Bio, Smart Immune, Garuda, Tscan, Research Support; Gilead Sciences, Inc., Novartis. H.Jiang: Employee; Avotres Inc. M.Mackey: None. H.L.Daley: None. N.Bryant: None. D.Y.Kim: None. T.Dong: Employee; Avotres Inc., Novartis. E.E.Fan: None. J.Vora: Other Relationship; Avotres Inc., Glyscend Inc. J.S.Skyler: Advisory Panel; Adocia, Altheia Sciences, Arecor, Avotres Inc., Bayer Inc., COUR Pharmaceuticals, Dance Biopharm/Aerami, Diasome, Enthera, Immnomolecular Therapeutics, Kriya Therapeutics, Oramed Pharmaceuticals, Orgenesis Inc., Precigen, Inc., ViaCyte, Inc., Board Member; Applied Therapeutics Inc., Dexcom, Inc., Consultant; Novo Nordisk, Sanofi, Signos, 4Immune, Other Relationship; Imcyse, Provention Bio, Inc. Funding Avotres Inc.

Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients.

Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations.

Glucagon in type 2 diabetes: Friend or foe?

Hyperglucagonemia is one of the 'ominous' eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homoeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signalling pathways has rekindled the interest in this hormone beyond its classic effect on glycaemia. Glucagon can promote weight loss by regulating food intake, energy expenditure, and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease, while few studies postulated its favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarise the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signalling modulation with new antidiabetic drugs.

Multi-omic interactions in the gut of children at the onset of islet autoimmunity

BackgroundThe gastrointestinal ecosystem is a highly complex environment with a profound influence on human health. Inflammation in the gut, linked to an altered gut microbiome, has been associated with the development of multiple human conditions including type 1 diabetes (T1D). Viruses infecting the gastrointestinal tract, especially enteroviruses, are also thought to play an important role in T1D pathogenesis possibly via overlapping mechanisms. However, it is not known whether the microbiome and virome act together or which risk factor may be of greater importance at the time when islet autoimmunity is initiated.ResultsHere, we apply an integrative approach to combine comprehensive fecal virome, microbiome, and metaproteome data sampled before and at the onset of islet autoimmunity in 40 children at increased risk of T1D. We show strong age-related effects, with microbial and metaproteome diversity increasing with age while host antibody number and abundance declined with age. Mastadenovirus, which has been associated with a reduced risk of T1D, was associated with profound changes in the metaproteome indicating a functional shift in the microbiota. Multi-omic factor analysis modeling revealed a cluster of proteins associated with carbohydrate transport from the genus Faecalibacterium were associated with islet autoimmunity.ConclusionsThese findings demonstrate the interrelatedness of the gut microbiota, metaproteome and virome in young children. We show a functional remodeling of the gut microbiota accompanies both islet autoimmunity and viral infection with a switch in function in Faecalibacterium occurring at the onset of islet autoimmunity.E8v6si3w2ZwgkjoJioDRP1Video

1024-P: Identification of Sex-Specific Cytokine and Viral Infection Profiles in Type 1 Diabetes Patients

Type 1 Diabetes (T1D) is an autoimmune disease caused by the destruction of beta cells. Because both viral infections and cytokines are suggested to play a role in T1D pathogenesis, we analyzed the viral infection and cytokine profiles of T1D patients compared to age and sex-matched healthy controls. The median age in years of T1D patients was 16.9 ± 1.14 (mean ± SEM) and 17.88 ± 0.78 for the healthy subjects. The disease duration in years was 8 ± 1.1 (n=25, 13 females, 12 males) . We first assessed the viral infection history using a PepSeq-based highly multiplexed serological assay. This assay covers the full proteomes of human viruses and determines serum immunoglobulin-G (IgG) reactivity to 30mer viral peptides. We showed that enterovirus (EV) seropositivity were distinct between the two groups, with more EV-C and EV-D positives in the T1D samples and more EV-A and EV-B positives in the controls. The trends for the viruses showing higher seropositivity were primarily driven by the female patients. To determine the cytokine profiles, we measured the serum levels of 48 cytokines, chemokines and growth factors. Interestingly, we only observed significant sex-specific differences. For example, anti-inflammatory cytokines interleukin-4 (IL-4) , IL-13, IL-22, and pro-inflammatory cytokines IL-17E and tumor necrosis factor-β were significantly lower in female patients as compared to female controls. Male patients had increased levels of epidermal growth factor and platelet-derived growth factor compared to healthy males. IL-22 was unique, unlike the decrease in female patients, it increased in the male patients compared to healthy males. Altogether, we identified sex-dependent alterations in the cytokine profiles and observed a difference in EV exposure profiles between T1D patients and healthy subjects. Determining sex-specific cytokine profiles and the potential role of viral infections in T1D pathogenesis will help us to gain deeper insight into the pathogenesis of the disease. Disclosure K.Girdhar: n/a. A.Pina: None. J.Momirov: None. M.A.Atkinson: None. J.Ladner: None. E.Altindis: None. Funding NIH NIDDK 1K01DK117967-G. Harold & Leila Y. Mathers Foundation grants to EA

Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets.

The mechanisms underlying type 1 diabetes (T1D) pathogenesis remain largely unknown. While autoantibodies to pancreatic beta-cell antigens are often the first biological response and thereby a useful biomarker for identifying individuals in early stages of T1D, their role in T1D pathogenesis is not well understood. Recognition of these antigenic targets by autoreactive T-cells plays a pathological role in T1D development. Recently, several beta-cell neoantigens have been described, indicating that both neoantigens and known T1D antigens escape central or peripheral tolerance. Several questions regarding the mechanisms by which tolerance is broken in T1D remain unanswered. Further delineating the timing and nature of antigenic responses could allow their use as biomarkers to improve staging, as targets for therapeutic intervention, and lead to a better understanding of the mechanisms leading to loss of tolerance. Multiple factors that contribute to cellular stress may result in the generation of beta-cell derived neoepitopes and contribute to autoimmunity. Understanding the cellular mechanisms that induce beta-cells to produce neoantigens has direct implications on development of therapies to intercept T1D disease progression. In this perspective, we will discuss evidence for the role of neoantigens in the pathogenesis of T1D, including antigenic responses and cellular mechanisms. We will additionally discuss the pathways leading to neoepitope formation and the cross talk between the immune system and the beta-cells in this regard. Ultimately, delineating the timing of neoepitope generation in T1D pathogenesis will determine their role as biomarkers as well as therapeutic targets.

A Triple Threat? The Role of Diet, Nutrition, and the Microbiota in T1D Pathogenesis.

In recent years the role of the intestinal microbiota in health and disease has come to the forefront of medical research. Alterations in the intestinal microbiota and several of its features have been linked to numerous diseases, including type 1 diabetes (T1D). To date, studies in animal models of T1D, as well as studies in human subjects, have linked several intestinal microbiota alterations with T1D pathogenesis. Features that are most often linked with T1D pathogenesis include decreased microbial diversity, the relative abundance of specific strains of individual microbes, and altered metabolite production. Alterations in these features as well as others have provided insight into T1D pathogenesis and shed light on the potential mechanism by which the microbiota plays a role in T1D pathogenesis, yet the underlying factors leading to these alterations remains unknown. One potential mechanism for alteration of the microbiota is through diet and nutrition. Previous studies have shown associations of diet with islet autoimmunity, but a direct contributing factor has yet to be identified. Diet, through introduction of antigens and alteration of the composition and function of the microbiota, may elicit the immune system to produce autoreactive responses that result in the destruction of the beta cells. Here, we review the evidence associating diet induced changes in the intestinal microbiota and their contribution to T1D pathogenesis. We further provide a roadmap for determining the effect of diet and other modifiable factors on the entire microbiota ecosystem, including its impact on both immune and beta cell function, as it relates to T1D. A greater understanding of the complex interactions between the intestinal microbiota and several interacting systems in the body (immune, intestinal integrity and function, metabolism, beta cell function, etc.) may provide scientifically rational approaches to prevent development of T1D and other childhood immune and allergic diseases and biomarkers to evaluate the efficacy of interventions.

Modulation of hyaluronan synthases and involvement of T cell-derived hyaluronan in autoimmune responses to transplanted islets

The extracellular matrix glycosaminoglycan hyaluronan (HA) accumulates in human and mouse islets during the onset of autoimmune type 1 diabetes (T1D). HA plays a critical role in T1D pathogenesis, as spontaneous disease is blocked in mice fed the HA synthesis inhibitor 4-methylumbelliferone (4MU). The present study demonstrates the involvement of HA in T cell-mediated autoimmune responses to transplanted islets and in in vivo and in vitro T cell activation. Scaffolded islet implants (SIs) loaded with RIP-mOVA mouse islets expressing chicken ovalbumin (OVA) on their β cells were grafted into T and B cell-deficient RIP-mOVA mice, which subsequently received CD4+ T cells from DO11.10 transgenic mice bearing OVA peptide-specific T cell receptors (TcRs), followed by injection of OVA peptide to induce an immune response to the OVA-expressing islets. By affinity histochemistry (AHC), HA was greatly increased in grafted islets with T cell infiltrates (compared to islets grafted into mice lacking T cells) and a portion of this HA co-localized with the infiltrating T cells. Transferred T cells underwent HA synthase (HAS) isoform switching – T cells isolated from the SI grafts strongly upregulated HAS1 and HAS2 mRNAs and downregulated HAS3 mRNA, in contrast to T cells from graft-draining mesenteric lymph nodes, which expressed HAS3 mRNA only. Expression of HAS1 and HAS2 proteins by T cells in SI infiltrates was confirmed by immunohistochemistry (IHC). DO11.10 mice fed 4MU had suppressed in vivo T cell immune priming (measured as a reduced recall response to OVA peptide) compared to T cells from control mice fed a normal diet. In co-cultures of naïve DO11.10 T cells and OVA peptide-loaded antigen-presenting cells (APCs), pre-exposure of the T cells (but not pre-exposure of APCs) to 4MU inhibited early T cell activation (CD69 expression). In addition, T cells exposed to 4MU during activation in vitro with anti-CD3/CD28 antibodies had inhibited phosphorylation of the CD3ζ subunit of the TcR, a very early event in TcR signaling. Collectively, our results demonstrate that T cell-derived HA plays a significant role in T cell immune responses, and that expression of T cell HAS isoforms changes in a locale-specific manner during in vivo priming and functional phases of the T cell response.

Epigenetic Effects of Gut Metabolites: Exploring the Path of Dietary Prevention of Type 1 Diabetes.

Type 1 diabetes (T1D) has increased over the past half century and has now become the second most frequent autoimmune disease in childhood and one of major public health concern worldwide. Evidence suggests that modern lifestyles and rapid environmental changes are driving factors that underlie this increase. The integration of these two factors brings about changes in food intake. This, in turn, alters epigenetic regulations of the genome and intestinal microbiota composition, which may ultimately play a role in pathogenesis of T1D. Recent evidence shows that dysbiosis of the gut microbiota is closely associated with T1D and that a dietary intervention can influence epigenetic changes associated with this disease and may modify gene expression patterns through epigenetic mechanisms. In this review focus on how a diet can shape the gut microbiome, its effect on the epigenome in T1D, and the future of T1D management by microbiome therapy.

A newly discovered dual expresser lymphocyte that clonally expanded in Type 1 diabetes (T1D) patients secretes a public antibody that recognize public TCR in T1D

Abstract PURPOSE We have recently discovered a new lymphocyte that co-express BCR and TCR (Ahmed et al, Cell, 2019: 177:11583) and referred as X cell to denote its crossover phenotype. Importantly, X cells express a public BCR that also encodes a potent autoantigen in its CDR3 sequence that is 10 fold more potent than native insulin peptide (InsB:9–23) in binding to DQ8 and activating autologous CD4 T cells. The x-autoantigen cross-activate insulin specific CD4 T cells as a peptide in the context of HLA-DQ8 molecules or as a soluble intact mAb (x-mAb). The goal of this study is to characterize autoreactive CD4 T cells that are responsive to x-mAb to determine their phenotype, cytokine profile and TCR repertoire and whether they express public TCRs. METHODS We used EBV-lymphoblastoid X cell clone as a source of x-mAb (IgM) and FACS based protocol to identify IgM reactive CD4 T cells (referred as IgMpos) and their functional properties. ImmunoSEQ assay used to characterize TCR repertoires. RESULTS Preliminary data show that frequency of IgMpos CD4 T cells is significantly higher in T1D as compared to Healthy subjects. In addition, IgMpos CD4 T cells exhibit an activated phenotype as compared to autologous IgMneg CD4 T cells, including expression of CD45RO, CD44, and CD69. Analysis of TCRVβ repertoire shows that IgMpos CD4 T cells are enriched for public clonally expanded TCRs as compared to IgMneg counterparts. CONCLUSIONS X cells in T1D patients are predominated by a single public BCR and that the secreted version of this BCR (x-mAb) is autoreactive against a specific subset of CD4 T cells that predominated by few clonotypes that express public TCRs. Our results are revealing previously unknown mechanism that appears to be a play critical role in pathogenesis of T1D.

The Role of Gut Microbiota and Environmental Factors in Type 1 Diabetes Pathogenesis.

Type 1 Diabetes (T1D) is regarded as an autoimmune disease characterized by insulin deficiency resulting from destruction of pancreatic β-cells. The incidence rates of T1D have increased worldwide. Over the past decades, progress has been made in understanding the complexity of the immune response and its role in T1D pathogenesis, however, the trigger of T1D autoimmunity remains unclear. The increasing incidence rates, immigrant studies, and twin studies suggest that environmental factors play an important role and the trigger cannot simply be explained by genetic predisposition. Several research initiatives have identified environmental factors that potentially contribute to the onset of T1D autoimmunity and the progression of disease in children/young adults. More recently, the interplay between gut microbiota and the immune system has been implicated as an important factor in T1D pathogenesis. Although results often vary between studies, broad compositional and diversity patterns have emerged from both longitudinal and cross-sectional human studies. T1D patients have a less diverse gut microbiota, an increased prevalence of Bacteriodetes taxa and an aberrant metabolomic profile compared to healthy controls. In this comprehensive review, we present the data obtained from both animal and human studies focusing on the large longitudinal human studies. These studies are particularly valuable in elucidating the environmental factors that lead to aberrant gut microbiota composition and potentially contribute to T1D. We also discuss how environmental factors, such as birth mode, diet, and antibiotic use modulate gut microbiota and how this potentially contributes to T1D. In the final section, we focus on existing recent literature on microbiota-produced metabolites, proteins, and gut virome function as potential protectants or triggers of T1D onset. Overall, current results indicate that higher levels of diversity along with the presence of beneficial microbes and the resulting microbial-produced metabolites can act as protectors against T1D onset. However, the specifics of the interplay between host and microbes are yet to be discovered.

Altered Insulin Signaling in Alzheimer's Disease Brain - Special Emphasis on PI3K-Akt Pathway.

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two to fourfold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid, and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-β and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in vivo in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.

Ameliorating gut microenvironment through staphylococcal nuclease-mediated intestinal NETs degradation for prevention of type 1 diabetes in NOD mice

AimsRecent studies have revealed that neutrophil extracellular traps (NETs) provide negative feedback in the progression to chronic inflammation and contribute to the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). In addition, accumulating evidences suggest that gut immunity play a key role in T1D pathogenesis. Our study aimed to evaluate whether staphylococcal nuclease (SNase) targeting intestinal NETs can ameliorate the intestinal inflammatory environment and protect against T1D development in non-obese diabetic(NOD) mice. Main methodsDegradation of NETs with SNase in vitro was examined using SYTOX green assay. NOD/LtJ mice were oral administration of Lactococcus lactisl (L. lactis) pCYT: SNase and blood glucose levels were monitored weekly. Several biomarkers of NETs formation, gut leakage and inflammation were determined using a commercial ELISA kit. T Cell phenotypes in peripheral immune system were analyzed in flow cytometry and fecal samples were isolated to investigate intestinal microbiota. Key findingsThe oral delivery of SNase by L. lactis can decrease the NETs levels and ameliorate inflammation both in the intestine and pancreatic islets and finally effectively regulate the blood glucose levels of NOD mice. Meanwhile, zonulin and lipopolysaccharide levels also reduced in SNase-fed NOD mice, suggesting SNase could improve gut barrier function via intestinal NETs degradation. Furthermore, the abundances of the intestinal microbiota and butyrate-producing gut bacteria were also increased with SNase treatment. SignificanceSNase shows potential for intestinal NETs to prevent T1D based on the gut-pancreas axis.

Developmental exposure to DEHP alters hepatic glucose uptake and transcriptional regulation of GLUT2 in rat male offspring

Type-2-diabetes (T2D) is a long term metabolic disorder characterized by high blood glucose and insulin resistance. It has become an alarming issue globally due to tremendous increase in number of new subjects every year. Apart from the classical factors, there are few non-classical factors such as environmental pollutants, endocrine disrupting chemicals (EDCs) which also play a major role in pathogenesis of T2D. Di-(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer which is an endocrine disrupting chemical. It is used in the plastic industry to give flexibility and durability. Its widespread use resulted in constant presence in the environment and human are under high risk of exposure to this compound. There are literature available stating that DEHP has an impact on glucose homeostasis. Glucose transporter 2 (GLUT2) is a principal transporter of glucose in liver and it is a bi-directional transporter. We investigated whether DEHP exposure during gestation and lactation alters transcriptional regulation of GLUT2 and epigenetics changes in the rat F1 male offspring at adulthood. Pregnant rats were divided into three groups and administered with DEHP (10 and 100 mg /kg /day) or olive oil from gestational day (GD) 9– to postnatal day (PND) 21 through oral gavage. DEHP treated rats showed decreased glucose uptake and oxidation, decreased mRNA levels of insulin receptor (IR), GLUT2 and reduced GLUT2 protein in cytosol but unaltered level in plasma membrane. There are three main transcription factors (SREBP1c, HNF3β and HNF1α) involved in the regulation of GLUT2 gene and all these proteins were reduced in DEHP exposed groups. A weak interaction of the transcription factors (SREBP1c & HNF1α) with GLUT2 gene promoter was observed in DEHP-treated groups. Hyper- methylation of IR and GLUT2 gene promoter was observed in both the DEHP-exposed groups compared to control. The present study reveals that DEHP exposure alters transcriptional regulation of GLUT2 and imposes epigenetic alteration in IR and GLUT2 gene promoters which plays a significant role in the development of metabolic abnormality in F1 male offspring at adulthood.

Immunoglobulin M gene association with autoantibody reactivity and type 1 diabetes

Several lines of evidence show that autoimmune responses evolving in type 1 diabetes (T1D) patients include the generation of multi-reactive autoantibody (AutoAb) repertoires, but their role in T1D pathogenesis remains elusive. We tested the hypothesis that variants at the immunoglobulin heavy chain (IGH) locus are genetic determinants of AutoAbs against pancreatic antigens and contribute to T1D susceptibility. With this aim, two independent study designs were used: a case-control study and a family-based cohort comprising a total of 240 T1D patients, 172 first-degree relatives (mother and/or father), and 130 unrelated healthy controls living in Portugal. We found that three SNPs in the IGH locus show suggestive association with T1D with the highest nominal association at rs1950942 (in the IGHM-IGHJ gene region) in both the case-control study (P = 9.35E−03) and the family-based cohort (P = 3.08E−03). These SNPs were also associated with IgG AutoAbs against pancreatic antigens and with AutoAb multi-reactivity in T1D patients. Notably, we found that the SNP with the highest association with T1D susceptibility and IgG autoantibody reactivity (rs1950942) was also associated with anti-GAD IgM reactivity in T1D patients (P = 5.98E−03) and in non-affected parents (P = 4.17E−03). This finding implies that IGH association with autoreactive IgM is detectable irrespective of disease status.These results suggest that genetic variants at the IgM gene region of the IGH locus contribute to antibody autoreactivity and are associated with T1D. We propose that the control of autoantibody generation by IGH polymorphisms is a component of the complex architecture of T1D genetic susceptibility.

PTPN22 and islet-specific autoimmunity: What have the mouse models taught us?

An allelic variant of the protein tyrosin phosphatase non-receptor 22 (PTPN22) gene, PTPN22 R620W, constitutes the strongest non-HLA genetic risk factor for the development of type 1 diabetes (T1D). A number of studies using mouse models have addressed how PTPN22 predisposes to T1D. PTPN22 downmodulation, overexpression or expression of the variant gene in genetically manipulated mice has generated controversial results. These discrepancies probably derive from the fact that PTPN22 has differential effects on innate and adaptive immune responses. Moreover, the effects of PTPN22 are dependent on other genetic variables. Here we discuss these findings and try to explain the discrepancies. Exploring the mechanism by which PTPN22 contributes to islet-specific autoimmunity could help us understand its role in T1D pathogenesis and exploit it as a potential therapeutic target to prevent the disease.