Immunity to self co-generates regulatory T cells

Immune responses to self are kept in check by tolerance mechanisms, including suppression by regulatory T cells (Tregs). The defective generation of Tregs specific for self-antigens may lead to autoimmune disease. We identified a novel population of human CD4^+^ Tregs, characterized by high surface expression of CD52, which is co-generated in response to autoantigen. Blood CD4^+^CD52^hi^ T cells were generated preferentially in response to low-dose autoantigen and suppressed proliferation and interferon-[gamma] production by other T cells. Depletion of resting CD4^+^CD52^hi^ T cells enhanced the T-cell response to autoantigen. CD4^+^CD52^hi^ Tregs were neither derived from nor distinguished by markers of conventional resting CD4^+^CD25^+^ Tregs. In response to the pancreatic islet autoantigens glutamic acid decarboxylase, the generation of CD4^+^CD52^hi^ Tregs was impaired in individuals with and at-risk for type 1 diabetes, compared to healthy controls and individuals with type 2 diabetes. CD4^+^CD52^hi^ Tregs co-generated to self-antigen may therefore contribute to immune homeostasis and protect against autoimmune disease

The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades

Prevalence and Clinical Characteristics of Recently Diagnosed Type 2 Diabetes Patients with Positive Anti-Glutamic Acid Decarboxylase Antibody

BackgroundLatent autoimmune diabetes in adults (LADA) refers to a specific type of diabetes characterized by adult onset, presence of islet auto-antibodies, insulin independence at the time of diagnosis, and rapid decline in β-cell function. The prevalence of LADA among patients with type 2 diabetes varies from 2% to 20% according to the study population. Since most studies on the prevalence of LADA performed in Korea were conducted in patients who had been tested for anti-glutamic acid decarboxylase antibody (GADAb), a selection bias could not be excluded. In this study, we examined the prevalence and clinical characteristics of LADA among adult patients recently diagnosed with type 2 diabetes.MethodsWe included 462 patients who were diagnosed with type 2 diabetes within 5 years from the time this study was performed. We measured GADAb, fasting insulin level, fasting C-peptide level, fasting plasma glucose level, HbA1c, and serum lipid profiles and collected data on clinical characteristics.ResultsThe prevalence of LADA was 4.3% (20/462) among adult patients with newly diagnosed type 2 diabetes. Compared with the GADAb-negative patients, the GADAb-positive patients had lower fasting C-peptide levels (1.2±0.8 ng/mL vs. 2.0±1.2 ng/mL, P=0.004). Other metabolic features were not significantly different between the two groups.ConclusionThe prevalence of LADA is 4.3% among Korean adult patients with recently diagnosed type 2 diabetes. The Korean LADA patients exhibited decreased insulin secretory capacity as reflected by lower C-peptide levels

Evidence That Nasal Insulin Induces Immune Tolerance to Insulin in Adults With Autoimmune Diabetes

OBJECTIVE: Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment. RESEARCH DESIGN AND METHODS: We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin. RESULTS: β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. CONCLUSIONS: Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals

Identification of a distinct phenotype of elderly latent autoimmune diabetes in adults: LADA China Study 8.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) exhibits significant clinical heterogeneity, but the underlying causes remain unclear. The aim of this study was to investigate whether age of onset of LADA contributes to the observed clinical heterogeneity by comparing the clinical, metabolic, and immunogenetic characteristics between elderly and young LADA patients. METHODS: The cross-sectional study included a total of 579 patients with LADA which was further divided into elderly LADA (E-LADA) group (n = 135, age of onset ≥60 years) and young LADA (Y-LADA) group (n = 444, age of onset <60 years). Age-matched subjects with type 2 diabetes were served as control (E-T2D group, n = 622). Clinical characteristics, serum autoantibodies, and HLA-DQ haplotypes were compared among these groups. RESULTS: Compared with patients with Y-LADA, patients with E-LADA have better residual beta-cell function and higher level of insulin resistance (both P < .01), more metabolic syndrome characteristics, similar proportion of islet autoantibody positivity, and strikingly different HLA-DQ genetic background. In comparison with E-T2D patients, E-LADA patients tend to have similar metabolic syndrome prevalence, comparable C-peptide levels, and insulin resistance levels and share similar HLA-DQ genetic characteristics. CONCLUSIONS: Elderly LADA differs phenotypically and genetically from Y-LADA but has a clinical and genetic profile more similar to that of E-T2D. These distinct phenotypes could potentially help physicians better manage patients with E-LADA

GAD65 Autoantibody Responses in Japanese Latent Autoimmune Diabetes in Adult Patients

OBJECTIVE—To determine whether development of insulin requirement in patients with latent autoimmune diabetes in adults (LADA) is accompanied with the emergence of a type 1 diabetes–like autoimmune response

Levels of C-peptide, body mass index and age, and their usefulness in classification of diabetes in relation to autoimmunity, in adults with newly diagnosed diabetes in Kronoberg, Sweden

Objective: C-peptide is a main outcome measure in treatment trials of diabetes. C-peptide also has a role in the classification of diabetes, which is often difficult in adults and this is also increasingly recognised in adolescents and elders. Aim: We aimed to describe the levels of C-peptide in relation to age and body mass index (BMI) in a large population-based cohort of adults with newly diagnosed diabetes and compare the capabilities of C-peptide, age and BMI to discriminate between autoimmune and non-autoimmune diabetes. Subjects and methods: Blood samples from 1180 patients were analysed regarding islet cell antibody, glutamic acid decarboxylase antibody and fasting C-peptide (FCP). Receiver operating characteristics (ROC) curves were analysed to check the ability of age, BMI and C-peptide to discriminate between autoantibody-positive (Ab(+)) and -negative (Ab(-)) diabetes. Results: Mean FCP was 0.73 +/- 0.5 (range 0.13-1.80) nmol/l in the Ab(+) and 1.42 +/- 0.9 (range 0.13-8.30) nmol/l in the Ab(-). FCP was 0.02 nmol/l higher per year increase in age at diagnosis of diabetes. Mean BMI was 26.0 +/- 4.8 (range 18.0-39.0) kg/m(2) in the Ab(+) and 28.9 +/- 5.3 (range 15.5-62.6) kg/m(2) in the Ab(-). FCP increased with age also within each BMI group. The highest area under the curve (AUC) in the ROC analysis was found for C-peptide, followed by age and BMI (0.78, 0.68 and 0.66 respectively). Conclusions: At diagnosis of diabetes, C-peptide was superior to age and BMI in discriminating between autoimmune and non-autoimmune diabetes. C-peptide increased significantly with BMI and age, latter also within each BMI group. Most of the adults had normal or high levels of C-peptide at presentation of diabetes among the autoimmune patients

Weight Gain in Early Life Predicts Risk of Islet Autoimmunity in Children With a First-Degree Relative With Type 1 Diabetes

OBJECTIVE—In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity

Incidence of insulin-requiring diabetes in the US military

The aim of the study was to determine age- and race-related, and overall incidence rates of insulin-requiring diabetes in adults in the US military. Electronic records for admissions to US military and Tricare hospitals during 1990–2005 and visits to military clinics during 2000–2005 were identified using the Career History Archival Medical and Personnel System at the Naval Health Research Center, San Diego, CA, USA. Population data were obtained from the Defense Manpower Data Center and Defense Medical Epidemiology Database. In men there were 2,918 new cases of insulin-requiring diabetes in 20,427,038 person-years at ages 18–44 years (median age 28 years) for a total age-adjusted incidence rate of 17.5 per 100,000 person-years (95% CI 16.4–18.6). Incidence rates were twice as high in black men as in white men (31.5 vs 14.5 per 100,000, p &lt; 0.001). In women there were 414 new cases in 3,285,000 person-years at ages 18–44 years (median age 27 years), for a total age-adjusted incidence rate of 13.6 per 100,000 (95% CI 12.4–14.9). Incidence rates were twice as high in black women as in white women (21.8 vs 9.7 per 100,000, p &lt; 0.001). In a regression model, incidence of insulin-requiring diabetes peaked annually in the winter–spring season (OR 1.46, p &lt; 0.01). Race and seasonal differences persisted in the multivariate analysis. Differences in incidence rates by race and season suggest a need for further research into possible reasons, including the possibility of a contribution from vitamin D deficiency. Cohort studies using prediagnostic serum 25-hydroxyvitamin D should be conducted to further evaluate this relationship