Regulatory T cells (Tregs) constitute an attractive therapeutic target given their essential role in controlling autoimmunity. However, recent animal studies provide evidence for functional ...heterogeneity and lineage plasticity within the Treg compartment. To understand better the plasticity of human Tregs in the context of type 1 diabetes, we characterized an IFN-γ-competent subset of human CD4(+)CD127(lo/-)CD25(+) Tregs. We measured the frequency of Tregs in the peripheral blood of patients with type 1 diabetes by epigenetic analysis of the Treg-specific demethylated region (TSDR) and the frequency of the IFN-γ(+) subset by flow cytometry. Purified IFN-γ(+) Tregs were assessed for suppressive function, degree of TSDR demethylation, and expression of Treg lineage markers FOXP3 and Helios. The frequency of Tregs in peripheral blood was comparable but the FOXP3(+)IFN-γ(+) fraction was significantly increased in patients with type 1 diabetes compared to healthy controls. Purified IFN-γ(+) Tregs expressed FOXP3 and possessed suppressive activity but lacked Helios expression and were predominately methylated at the TSDR, characteristics of an adaptive Treg. Naive Tregs were capable of upregulating expression of Th1-associated T-bet, CXCR3, and IFN-γ in response to IL-12. Notably, naive, thymic-derived natural Tregs also demonstrated the capacity for Th1 differentiation without concomitant loss of Helios expression or TSDR demethylation.
We previously demonstrated that diabetes exacerbates stroke-induced brain injury, and that this correlates with brain methylglyoxal (MG)-to-glutathione (GSH) status. Cerebral injury was reversed by ...N-acetylcysteine (NAC). Here we tested if the pro-thrombotic phenotype seen in the systemic circulation and brain during diabetes was associated with increased MG-glycation of proteins, and if NAC could reverse this.
The streptozotocin (STZ)-induced mouse model of type 1 diabetes was used. Thrombus formation in venules and arterioles (pial circulation) was determined by intravital videomicroscopy using the light-dye method. Circulating blood platelet-leukocyte aggregates (PLAs) were analyzed by flow cytometry 1 wk before other measurements. GSH and MG levels in platelets were measured by HPLC. MG-modified proteins, glutathione peroxidase-1 (GPx-1), and superoxide dismutase-1 (SOD1) levels were detected in platelets by western blot at 20 weeks. Proteins involved in coagulation were quantified by ELISA. NAC (2mM) was given in drinking water for 3 weeks before the terminal experiment.
Thrombus development was accelerated by diabetes in a time-dependent manner. % PLAs were significantly elevated by diabetes. Plasma activated plasminogen activator inhibitor type 1 levels were progressively increased with diabetes duration, with tail bleeding time reduced by 20 wks diabetes. Diabetes lowered platelet GSH levels, GPx-1 and SOD-1 expression. This was associated with higher MG levels, and increased MG-adduct formation in platelets. NAC treatment partly or completely reversed the effects of diabetes.
Collectively, these results show that the diabetic blood and brain become progressively more susceptible to platelet activation and thrombosis. NAC, given after the establishment of diabetes, may offer protection against the risk for stroke by altering both systemic and vascular prothrombotic responses via enhancing platelet GSH, and GSH-dependent MG elimination, as well as correcting levels of antioxidants such as SOD1 and GPx-1.
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•Diabetes elevates dicarbonyl stress leading to enhanced thrombosis in the brain.•Glutathione levels decrease leading to impaired elimination of methylglyoxal in platelets during diabetes.•Platelet proteins are glycated and platelets form aggregates with leukocytes in diabetes.•Diabetes increases circulating levels of plasminogen activator inhibitor-1.•NAC, via GSH synthesis, reverses the platelet activation, protein glycation and pro-coagulation responses & protects against thrombosis in the diabetic brain.
Debate exists as to whether the higher hemoglobin A1c (HbA1c) levels observed in black persons than in white persons are due to worse glycemic control or racial differences in the glycation of ...hemoglobin.
To determine whether a racial difference exists in the relationship of mean glucose and HbA1c.
Prospective, 12-week observational study.
10 diabetes centers in the United States.
104 black persons and 104 white persons aged 8 years or older who had had type 1 diabetes for at least 2 years and had an HbA1c level of 6.0% to 12.0%.
Mean glucose concentration, measured by using continuous glucose monitoring and compared by race with HbA1c, glycated albumin, and fructosamine values.
The mean HbA1c level was 9.1% in black persons and 8.3% in white persons. For a given HbA1c level, the mean glucose concentration was significantly lower in black persons than in white persons (P = 0.013), which was reflected in mean HbA1c values in black persons being 0.4 percentage points (95% CI, 0.2 to 0.6 percentage points) higher than those in white persons for a given mean glucose concentration. In contrast, no significant racial differences were found in the relationship of glycated albumin and fructosamine levels with the mean glucose concentration (P > 0.20 for both comparisons).
There were too few participants with HbA1c levels less than 6.5% to generalize the results to such individuals.
On average, HbA1c levels overestimate the mean glucose concentration in black persons compared with white persons, possibly owing to racial differences in the glycation of hemoglobin. However, because race only partially explains the observed HbA1c differences between black persons and white persons, future research should focus on identifying and modifying barriers impeding improved glycemic control in black persons with diabetes.
Helmsley Charitable Trust.
Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic β-cell death. Multiple approaches for induction of ...anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of regulatory immune cells, we orally introduced microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and transforming growth factor-β (TGF-β) to C57BL/6 mice treated with multiple low doses of streptozotocin (MLDS) for T1D induction. Disease incidence was significantly lower in ATRA/TGF-β MPs-treated mice, as was the degree of immune cell infiltration into the pancreatic islets. In Peyer's patches (PP), ATRA/TGF-β MPs up-regulated tolerogenic dendritic cells (tolDCs) (CD11c+CD11b-CD103+), while the proportion of mature dendritic cells was not altered. This was accompanied by reduced Th1 and Th17 proportions and up-regulation of regulatory T cells (Tregs - CD4+CD25highFoxP3+). The immune cell composition in the pancreatic lymph nodes was similar to PP. Further, the proportion of effector Tbet+CD25med cells was decreased, while the proportion of Tbet+ Treg cells that specifically inhibit Th1 response was increased. Moreover, ATRA/TGF-β MPs treatment resulted in increased Treg proliferation and frequency of CTLA-4+PD1+ and CD39+IL-10+ Tregs, suggestive of their higher suppressive capacity. Reduced pancreatic infiltration may have been a consequence of lower cell capacity for matrix degradation. In conclusion, oral application of ATRA/TGF-β MPs ameliorated T1D through potentiation of tolDCs and Tregs, inhibition of Th1 response and prevention of the immune cell entrance into the islets.
Type 1 diabetes (T1DM) is a chronic autoimmune disease characterized by T-cell-mediated destruction of insulin-producing beta cells. Evidence shows that patients with T1DM and mice used in specific ...diabetic models both exhibit changes in their intestinal microbiota and dysregulated microbiota contributes to the pathogenesis of T1DM. Islet transplantation (Tx) is poised to play an important role in the treatment of T1DM. However, whether treatment of T1DM with islet Tx can rescue dysregulated microbiota remains unclear.
In this study, we induced diabetic C57BL/6 mice with streptozotocin. Then treatment with either insulin administration, or homogenic or allogenic islet Tx was performed to the diabetic mice. Total DNA was isolated from fecal pellets and high-throughput 16S rRNA sequencing was used to investigate intestinal microbiota composition.
The overall microbial diversity was comparable between control (nonstreptozotocin treated) and diabetic mice. Our results showed the ratio of the Bacteroidetes: Firmicutes between nondiabetic and diabetic mice was significant different. Treatment with islet Tx or insulin partially corrects the dysregulated bacterial composition. At the genus level, Bacteroides, Odoribacter, and Alistipes were associated with the progression and treatment efficacy of the disease, which may be used as a biomarker to predict curative effect of treatment for patients with T1DM.
Collectively, our results indicate that diabetic mice show changed microbiota composition and that treatment with insulin and islet Tx can partially correct the dysregulated microbiota.
The objective of the study was to report on the measurement properties of the revised and updated Pediatric Quality of Life Inventory (PedsQL) 3.2 Diabetes Module for children, adolescents, and young ...adults with type 1 diabetes.
The 33-item PedsQL 3.2 Diabetes Module and PedsQL Generic Core Scales were completed in a 10-site national field test study by 656 families of patients ages 2-25 years with type 1 diabetes.
The 15-item Diabetes Symptoms Summary Score and 18-item Diabetes Management Summary Score were derived from the factor analysis of the items. The Diabetes Symptoms and Diabetes Management Summary Scores evidenced excellent reliability (patient self-report α = 0.88-0.90; parent proxy report α = 0.89-0.90). The Diabetes Symptoms and Diabetes Management Summary Scores demonstrated construct validity through medium to large effect size correlations with the Generic Core Scales Total Scale Score (
= 0.43-0.67,
< 0.001). HbA
was significantly correlated with the Diabetes Symptoms and Diabetes Management Summary Scores (
= -0.21 to -0.29,
< 0.001). Minimal clinically important difference scores ranged from 5.05 to 5.55.
The PedsQL 3.2 Diabetes Module Diabetes Symptoms and Diabetes Management Summary Scores demonstrated excellent measurement properties and may be useful as standardized patient-reported outcomes of diabetes symptoms and diabetes management in clinical research, clinical trials, and practice in children, adolescents, and young adults with type 1 diabetes.
Aims/hypothesis
The aim of this study was to investigate the effect of childhood-onset type 1 diabetes on the risk of subsequent neurodevelopmental disorders, and the role of glycaemic control in ...this association. We hypothesised that individuals with poor glycaemic control may be at a higher risk of neurodevelopmental disorders compared with the general population, as well as compared with individuals with type 1 diabetes with adequate glycaemic control.
Methods
This Swedish population-based cohort study was conducted using data from health registers from 1973 to 2013. We identified 8430 patients with childhood-onset type 1 diabetes (diagnosed before age 18 years) with a median age of diabetes onset of 9.6 (IQR 5.9–12.9) and 84,300 reference individuals from the general population, matched for sex, birth year and birth county. Cox models were used to estimate the effect of HbA
1c
on the risk of subsequent neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability.
Results
During a median follow-up period of 5.6 years, 398 (4.7%) individuals with type 1 diabetes received a diagnosis of any neurodevelopmental disorder compared with 3066 (3.6%) in the general population, corresponding to an adjusted HR (HR
adjusted
) of 1.31 (95% CI 1.18, 1.46) after additionally adjusting for other psychiatric morbidity prior to inclusion, parental psychiatric morbidity and parental highest education level. The risk of any neurodevelopmental disorder increased with HbA
1c
levels and the highest risk was observed in patients with mean HbA
1c
>8.6% (>70 mmol/mol) (HR
adjusted
1.90 95% CI 1.51, 2.37) compared with reference individuals without type 1 diabetes. In addition, when compared with patients with diabetes with HbA
1c
<7.5% (<58 mmol/mol), patients with HbA
1c
>8.6% (>70 mmol/mol) had the highest risk of any neurodevelopmental disorder (HR
adjusted
3.71 95% CI 2.75, 5.02) and of specific neurodevelopmental disorders including ADHD (HR
adjusted
4.16 95% CI 2.92, 5.94), ASD (HR
adjusted
2.84 95% CI 1.52, 5.28) and intellectual disability (HR
adjusted
3.93 95% CI 1.38, 11.22).
Conclusions/interpretation
Childhood-onset type 1 diabetes is associated with an increased risk of neurodevelopmental disorders, with the highest risk seen in individuals with poor glycaemic control. Routine neurodevelopmental follow-up visits should be considered in type 1 diabetes, especially in patients with poor glycaemic control.
Graphical abstract
Type 1 (T1D) and Type 2 diabetes (T2D) represent a demanding set of biopsychosocial challenges for patients and their families, whether the age of disease onset occurs in childhood, adolescence, or ...adulthood. Psychological conditions, defined as syndromes, disorders, and diabetes-specific psychological issues affect a larger proportion of individuals with T1D and T2D compared to the general population. In this review, we summarize the prevalence, impact and psychological treatments associated with the primary categories of psychological conditions that affect adults with T1D and T2D: depressive symptoms and syndromes, anxiety disorders, eating behaviors and disorders and serious mental illness. The implications of the literature for psychologists are discussed, and priorities for future research to advance the science of psychological conditions for adults with T1D and T2D are identified.
Abstract Purpose To evaluate the psychosocial burden of adolescents with diabetes, determine the trajectory of psychosocial burden, and examine the interdependent relationships between psychosocial ...burden and glycemic control across the first 6 years of diabetes. Methods Data from SEARCH for Diabetes in Youth, an observational study of U.S. children diagnosed with diabetes before the age of 20, were collected during study visits conducted at baseline and then at 12, 24, and 60 months after baseline. Blood was drawn, clinical and demographic information was collected, and psychosocial burden was evaluated using standardized depression and generic and diabetes-specific health-related quality of life (QOL) surveys. Results Among the 1,307 adolescents (mean age, 14.1±2.5 years) with baseline data, 1,026 had type 1 diabetes and 281 had type 2 diabetes. For those with a 60-month follow-up visit, glycated hemoglobin (A1c ) values rose 1.5% from baseline (type 1, 7.7%–9.3% and type 2, 7.3%–8.8%). Adolescents with type 2 diabetes reported more depression and poorer QOL than adolescents with type 1 diabetes. For each diabetes type, there were similar baseline risk factors for higher A1c values: longer diabetes duration, ethnic minority status, and declining diabetes QOL ( p < .05). However, youth with type 2 diabetes had higher A1c values with increasing generic QOL, an unexpected finding. Younger adolescents with type 1 diabetes had higher A1c values at the end of the study. Conclusions Significant deterioration in glycemic control marks the first 6 years of diabetes for adolescents. Psychosocial burden, particularly poor diabetes-specific QOL, is a contributor to suboptimal glycemic outcomes.
To assess whether the detection of enterovirus RNA in blood predicts the development of clinical type 1 diabetes in a prospective birth cohort study. Further, to study the role of enteroviruses in ...both the initiation of the process and the progression to type 1 diabetes.
This was a nested case-control study where all case children (N = 38) have progressed to clinical type 1 diabetes. Nondiabetic control children (N = 140) were pairwise matched for sex, date of birth, hospital district, and HLA-DQ-conferred genetic susceptibility to type 1 diabetes. Serum samples, drawn at 3- to 12-month intervals, were screened for enterovirus RNA using RT-PCR.
Enterovirus RNA-positive samples were more frequent among the case subjects than among the control subjects. A total of 5.1% of the samples (17 of 333) in the case group were enterovirus RNA-positive compared with 1.9% of the samples (19 of 993) in the control group (P < 0.01). The strongest risk for type 1 diabetes was related to enterovirus RNA positivity during the 6-month period preceding the first autoantibody-positive sample (odds ratio 7.7 95% CI 1.9-31.5). This risk effect was stronger in boys than in girls.
The present study supports the hypothesis that enteroviruses play a role in the pathogenesis of type 1 diabetes, especially in the initiation of the β-cell damaging process. The enterovirus-associated risk for type 1 diabetes may be stronger in boys than in girls.
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