Occurrence Of Type 1 Diabetes Research Articles

The Effect of COVID-19 on Type 1 Diabetes Occurrence among Children and Adolescents: A Multicenter Prospective Observational Cohort Study in Israel

Aim. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the pediatric occurrence of type 1 diabetes (T1D) is inconclusive. We aimed to assess associations between seroprevalences of the distinct anti-SARS-CoV-2 antibodies and T1D occurrence in children and adolescents. Methods. This multicenter prospective observational cohort comprised children diagnosed with T1D between October 2020 and July 2022 and unrelated children who performed endocrine tests (control group) in a 1 : 3 ratio. Anti-SARS-CoV-2 antibodies, including anti-S, anti-N, and neutralizing antibodies, were assessed in each group. Results. The cohort included 51 children with T1D and 182 children in the control group. The median (interquartile range) age was 11.4 (8.2, 13.3) years, with 45% being female. Increases were not observed in the seroprevalence of any of the anti-SARS-CoV-2 antibodies among the children with new-onset T1D compared to the control group. Among the T1D group, anti-S seroprevalence was higher among those without diabetic ketoacidosis (DKA) than in those with DKA upon T1D diagnosis (72% vs. 42%, p = 0.035 ). After adjustment to vaccination status, this difference was not statistically significant. Additionally, anti-N antibodies and neutralizing antibodies did not differ between the DKA and the non-DKA groups. None of the anti-SARS-CoV-2 antibodies were associated with any of the glycemic parameters. Conclusions. This study is the first to assess several distinct anti-SARS-CoV-2 antibodies in new-onset T1D, and our findings do not support an association between SARS-CoV-2 infection and the occurrence of T1D in children and adolescents. Since autoimmunity may emerge years after a viral infection, we recommend conducting follow-up epidemiological studies to assess whether there is a change in the incidence of T1D following the SARS-CoV-2 pandemic.

Type 1 Diabetes in Children: Challenges, Effective Treatment and Complication

Type 1 diabetes (T1D) in children is a growing global concern. It's an autoimmune condition where the immune system attacks insulin-producing beta cells in the pancreas. The development of T1D is influenced by genetic factors, such as HLA genotypes, and environmental triggers, including infections and dietary factors. Understanding these patterns is vital for public health interventions. Symptoms in children typically include increased urination, excessive thirst, and weight loss. Ongoing research aims to better understand the interaction between genetics and environment in the development of T1D. Recognizing the increasing occurrence of T1D in children, the study highlights the interaction between genetic susceptibility and environmental triggers in its development. The clinical signs range from urination and unexplained weight loss to changes posing challenges for early detection with diabetic ketoacidosis often being the first observable symptom. The discussion then shifts to contemporary management approaches for T1D, where insulin therapy plays a role. Technological advancements such as insulin pumps and continuous glucose monitoring systems redefine precision in administering insulin. A comprehensive management approach includes monitoring of blood glucose levels, dietary interventions, physical activity recommendations, psychological support and education that empower children and their families to manage the condition actively.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Diabetic ketoacidosis due to Simultaneous Acute-Onset Type 1 Diabetes and Graves’ Disease

An 18-year old Japanese woman with thirst, weight loss and palpitations for a few weeks’ duration was admitted. Her diagnosis was diabetic ketoacidosis with acute-onset type 1 diabetes (T1D) and Graves’ disease (GD) (autoimmune polyglandular syndrome type 3 variant; APS3v). She was treated with intensification therapy with insulin and anti-thyroid drugs. Human leukocyte antigen testing revealed that her HLA type was HLA- DRB1*08:02-DQA1*03:01-DQB1*03:02 haplotype, which was vulnerable not only to APS3v, but also to both acute-onset T1D and GD. This genetic factor probably contributes to the simultaneous occurrence of T1D and GD.

Simultaneous Occurrence of Type 1 Diabetes Mellitus and Graves' Disease: A Report of Two Cases and a Review of the Literature

Two unrelated Japanese women, 41 and 27 years of age, were admitted with histories of thirst, weight loss and palpitations of a few weeks' duration. Both were diagnosed to have diabetic ketosis or ketoacidosis with acute-onset type 1 diabetes (T1D) and Graves' disease (GD) (autoimmune polyglandular syndrome type 3 variant; APS3v), and were treated with intensive insulin therapy and anti-thyroid drugs. Human leukocyte antigen examinations showed that both cases had the HLA-A2, A24, B54, and DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype, which made them susceptible not only to APS3v, but also to both acute-onset T1D and GD. The genetic background of patients strongly contributes to the simultaneous occurrence of T1D and GD.

The metabolic progression to type 1 diabetes as indicated by serial oral glucose tolerance testing in the Diabetes Prevention Trial-type 1.

Type 1 diabetes (T1D) is often first recognized when signs and symptoms occur, yet the pathogenetic development of T1D usually begins years before that. Pancreatic autoantibodies commonly become elevated long before diagnosis (1). Although data indicate that the first-phase insulin response (FPIR) is also abnormal well before diagnosis (2–5), the development and progression of metabolic abnormalities had not been well characterized until the recent performance of T1D prevention trials (6–8). The unique designs of these trials provided the opportunity to perform longitudinal studies that have yielded new insights into metabolic changes that occur during the progression to T1D. This review will describe what we have learned about the metabolic natural history of T1D from the Diabetes Prevention Trial–Type 1 (DPT-1). ### A description of DPT-1. DPT-1 included two separate trials, the parenteral and oral insulin trials (6,7). The objective of both trials was to delay or prevent the occurrence of T1D by interfering with the immunologic processes that result in the disorder. The parenteral insulin trial consisted of an intervention group that received subcutaneous ultralente insulin at a dose of 0.125 units/kg twice daily and a control group that received no insulin. The intervention group was admitted annually to a unit for 4 days during which a continuous infusion of recombinant human regular insulin was administered. The oral insulin trial included an intervention group, which received a once-daily dose of 7.5 mg recombinant human insulin crystals, and a placebo control group. In both trials, individuals were required to be nondiabetic, aged 1–45 years, and first- or second-degree relatives of T1D patients. Two phases determined further eligibility for the trials. In the screening phase, the relatives were tested for islet cell autoantibody (ICA) positivity. Those positive then participated in a risk assessment phase. This included an intravenous glucose tolerance test …

Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population

Polymorphic variants of the IL2RA gene, which encodes high-affinity alpha subunit (CD25) of the interleukin-2 receptor, were recently found to affect the risk of several autoimmune disorders. This study was aimed to investigate the association of selected IL2RA polymorphisms (rs11594656, rs3118470, rs2104286 and rs7093069) with type 1 diabetes (T1D) in a Polish cohort comprising 445 patients and 671 healthy control subjects. The minor A allele at rs11594656 was found significantly less frequently among T1D subjects, compared with the control group [P = 0.011; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.629-0.942]. In contrast, the minor C allele at rs3118470 appeared to be significantly associated with the occurrence of T1D (P = 0.003; OR = 1.30; 95% CI = 1.094-1.550). Two other IL2RA single nucleotide polymorphisms (SNPs) did not show significant differences among investigated groups. In conclusion, the study confirms the association of the IL2RA locus with T1D in the Polish population.

Protection against or triggering of Type 1 diabetes? Different roles for viral infections

The emergence of autoreactivity that ultimately destroys insulin-producing β-cells and causes Type 1 diabetes (T1D) is a result of genetic susceptibility and environmental factors, such as viral infections. The ability to induce strong cellular immune responses and to cause inflammation in the target organ makes viral infections prime candidates for the initiation of islet autoreactivity. Indeed, certain viruses have been linked to the occurrence of T1D based on epidemiological, serological and histological findings; and several rodent studies clearly demonstrate that viral infections can trigger autoimmunity. However, viruses have also been shown to efficiently prevent autoimmunity, which underlines the beneficial aspects of exposure to microbial agents as suggested by the hygiene hypothesis. Here, we will try to untangle some aspects of the complex interplay between viruses and the immune system and we will recapitulate by what rationale certain viruses have been associated with T1D.

Influence of Maternal Hyperglycaemia on Cord Blood Mononuclear Cells in Response to Diabetes‐associated Autoantigens

Perfect maternal diabetes compensation is crucial for the outcome of the baby. However, little is known how hyperglycaemia influences the specific immune response. Furthermore, babies of type 1 diabetes (T1D) mothers have less risk of development T1D than babies with a T1D father. This study aimed to analyze the effect of maternal hyperglycaemia on newborns with focus on the response to diabetes-associated autoantigens. (1) Newborns of T1D mothers split into groups according to maternal diabetes compensation during the 3rd trimester: perfect (n = 15) or acceptable (n = 25) compensation. (2) newborns with T1D father (n = 12) (3) newborns with a mother treated for either gestational or type 2 diabetes (n = 10) (4) control newborns (n = 25). Spontaneous as well as diabetes-associated autoantigen-stimulated production of 23 cytokines and chemokines were tested using protein microarray. In addition, the influence of glucose on cytokine and chemokine responsiveness was analyzed in vitro. The study groups differed in their spontaneous as well as stimulated cytokine and chemokine spectra. A prominent Th1 response (high IFN-gamma) from autoantigen stimulation was observed especially in babies of T1D fathers (P = 0.001) and also in mothers with perfect diabetes compensation during the 3rd trimester (P = 0.016) in comparison with control newborns. By contrast, cord blood mononuclear cells cultivated in vitro in high glucose concentration decreased the diabetogenic stimulated Th1 cytokine response. Maternal 'sweet' as well as 'autoimmune environment' may both lead to lower occurrence of T1D within their offspring. Further studies will reveal the exact immunological mechanism of this observation.

The Use of Idd Congenic Mice to Identify Checkpoints of Peripheral Tolerance to Islet Antigen

Type 1 diabetes (T1D) occurs because of lack of T cell tolerance to islet antigens. We hypothesized that critical genetic susceptibility loci that control progression to T1D, designated as insulin-dependent diabetes (Idd) loci, would be responsible for preventing CD8 T cell tolerance. To test this hypothesis, we have used two different congenic non-obese diabetic (NOD) mice that are highly protected from the occurrence of T1D because they express protective alleles at Idd3 and Idd5.1, 5.2, 5.3 (Idd3/5 mice), or at Idd9.1, 9.2, and 9.3 (Idd9 mice). By examining the CD8 T response to two different islet-expressed antigens, we have determined that CD8 T tolerance is restored in both strains of mice. However, tolerance occurs at different checkpoints in each strain. In Idd3/5 mice, islet-antigen-specific CD8 T cells are eliminated in the pancreatic lymph nodes, where they are first activated by cross-presented islet antigens. In contrast, in Idd9 mice autoreactive CD8 T cells accumulate at this site and are not tolerized until after they enter the pancreas. We are currently identifying the cell types and mechanisms that are critical for tolerance induction at each checkpoint.

793. Induction of Molecular Chimerism in NOD Mice Is Resistant to the Occurrence of Type I Diabetes Induced by Blockade of the Programmed Death-1 Pathway

Top of pageAbstract Introduction: We have recently shown that induction of molecular chimerism by reconstitution of NOD mice with autologous bone marrow cells reconstituted with retrovirus carrying genes encoding MHC class II |[beta]| chains (either IA|[beta]|d or IA|[beta]|k) from protective haplotypes can induce central deletion of auto-reactive T cells and prevent occurrence of type 1 diabetes (T1D) in NOD mice. Studies have also shown that blockade of programmed death (PD-1) pathway using anti-PD-L1 monoclonal antibody results in precipitated occurrence of T1D in na|[iuml]|ve NOD mice. Here we show that induction of molecular chimerism in NOD mice is resistant to the occurrence of T1D induced by anti-PD-L1 antibody treatment. Methods: Bone marrow cells were harvested from 4-week old NOD mice treated with 5-fluorouracil (150mg/kg) 7 days prior and then transduced with retrovirus carrying genes encoding either a protective MHC class II |[beta]| chain or GFP alone as a control. 4 weeks old recipient NOD mice were lethally irradiated and reconstituted the following day with either IA|[beta]|d-GFP or GFP transduced bone marrow. 4 weeks after reconstitution, recipient mice were treated with anti-PD-L1 monoclonal antibody or rat IgG as a control. Results: 75% of the mice reconstituted with control GFP transduced bone marrow and treated with anti-PD-L1 antibody developed diabetes by 85 days after antibody treatment (Median onset time (MOT) = 32 days), while 67% of the mice reconstituted with control GFP transduced bone marrow and treated with control rat IgG developed diabetes by 134 days (MOT = 129 days, p<0.001), suggesting that anti-PD-L1 treatment precipitates the occurrence of T1D in NOD mice reconstituted with control GFP transduced bone marrow. In contrast, all the mice that reconstituted with IA|[beta]|d-GFP transduced bone marrow and treated with control rat IgG remained normoglycemic 180 days after reconstitution at which time point our experiments terminated. Only 1 out of 12 mice reconstituted with IA|[beta]|d-GFP transduced bone marrow and treated with anti-PD-L1 treatment developed diabetes. Conclusion: Induction of molecular chimerism in NOD mice is resistant to the occurrence of T1D induced by anti-PD-L1 treatment.

Type-2 diabetes family history delays the onset of type-1 diabetes.

Type-1 diabetes (T1D) is an autoimmune disease leading to insulin deficiency. Its occurrence is influenced by genetic and environmental factors. The human leukocyte antigen (HLA) region on chromosome 6 accounts for 45% of the genetic susceptibility for the disease, mainly the HLA-DQB1*0201 and HLA-DQB1*0302 alleles. Among the environmental factors involved, early exposure to cow's milk seems to be a trigger. In this study, we investigated the occurrence of T1D in 253 Lebanese Caucasian patients, in relation to HLA-DQB1*0201, HLA-DQB1*0302, HLA-DQB1*0602, gender, and early exposure to cow's milk, as well as to family history of T1D and type-2 diabetes (T2D). Our genetic analysis results show that in the patients studied, 77% and 40% were positive for BQ1*0201 and BQ1*0302, respectively. As for BQ1*0602, only 0.8% of patients were positive for this T1D protective allele, compared with 24% among the controls. Furthermore, our results did not show any gender preference of the disease or any effects of early intake of cow's milk on the age at onset of T1D. When family history of T2D or T1D was studied, our results show a novel finding whereby an immediate family history of T2D, but not T1D, delays the age at onset of T1D.