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

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

Obesity is associated with retinopathy and macrovascular disease in type 1 diabetes

Excessive body weight is increasingly seen in type 1 diabetes but its impact is debated. To address this uncertainty, we aimed to determine the association between excess body weight and the macro- and microvascular complications of type 1 diabetes. We identified 501 adults with type 1 diabetes attending an Australian hospital clinic and extracted their clinical and biochemical data from our patient management database. In both men and women, obesity (BMI > 30 kg/m2) was the predominant risk factor for retinopathy and cardiovascular disease despite similar HbA1c and increased use of cardioprotective drugs compared to non-obese patients. Obesity was associated with albuminuria in women, but not renal impairment or neuropathy in either sex. We conclude that obesity in type 1 diabetes may promote retinopathy and macrovascular disease. Future trials to determine the effect of weight loss on type 1 diabetes in obese people are needed

The Need to Prioritize Education and Resources to Support Exercise in Type 1 Diabetes:Results of an Australian Survey of Adults With Type 1 Diabetes and Health Providers

Objectives Regular exercise is recommended for people with type 1 diabetes (PWD) to improve their health, but many do not meet recommended exercise targets. Educational resources supporting PWD to exercise exist, but their value is unclear. To determine the need for improved exercise resources in Australia, we surveyed adult PWD and health providers (HPs) about their confidence in managing type 1 diabetes (T1D) around exercise, barriers to exercise, and the adequacy of current resources. Methods Australian adult PWD and HPs completed surveys to rate the importance of exercise in T1D management, confidence in managing T1D around exercise, barriers to giving and receiving education, resources used, and what form new resources should take. Results Responses were received from 128 PWD and 122 HPs. Both groups considered exercise to be important for diabetes management. PWD cited time constraints (57%) and concern about dysglycemia (43%) as barriers to exercise, and many lacked confidence in managing T1D around exercise. HPs were more confident, but experienced barriers to providing advice, and PWD did not tend to rely on this advice. Instead, 72% of PWD found continuous glucose monitoring most helpful. Both groups desired better resources to support exercise in T1D, with PWD preferring to obtain information through a structured education program and HPs through eLearning. Conclusions Australian HPs and PWD appreciate the importance of exercise in T1D management and express a clear desire for improved educational resources. Our findings provide a basis for developing a comprehensive package of resources for both adult PWD and HPs, to support exercise in PWD

Clinical prediction tool to identify adults with type 2 diabetes at risk for persistent adverse glycemia in hospital

Objectives Given the high incidence of hyperglycemia and hypoglycemia in hospital and the lack of prediction tools for this problem, we developed a clinical tool to assist early identification of individuals at risk for persistent adverse glycemia (AG) in hospital. Methods We analyzed a cohort of 594 consecutive adult inpatients with type 2 diabetes. We identified clinical factors available early in the admission course that were associated with persistent AG (defined as ≥2 days with capillary glucose 15 mmol/L during admission). A prediction model for persistent AG was constructed using logistic regression and internal validation was performed using a split-sample approach. Results Persistent AG occurred in 153 (26%) of inpatients, and was associated with admission dysglycemia (odds ratio [OR], 3.65), glycated hemoglobin ≥8.1% (OR, 5.08), glucose-lowering treatment regimen containing sulfonylurea (OR, 3.50) or insulin (OR, 4.22), glucocorticoid medication treatment (OR, 2.27), Charlson Comorbidity Index score and the number of observed days. An early-identification prediction tool, based on clinical factors reliably available at admission (admission dysglycemia, glycated hemoglobin, glucose-lowering regimen and glucocorticoid treatment), could accurately predict persistent AG (receiver-operating characteristic area under curve = 0.806), and, at the optimal cutoff, the sensitivity, specificity and positive predictive value were 84%, 66% and 53%, respectively. Conclusions A clinical prediction tool based on clinical risk factors available at admission to hospital identified patients at increased risk for persistent AG and could assist early targeted management by inpatient diabetes teams

Lipid lowering agents, cognitive decline, and dementia: the three-city study.: Lipid Lowering Agents and Cognitive Decline

International audienceThe aim of this prospective cohort study was to evaluate the effects of lipid lowering agent (LLA) intake on cognitive function in 6,830 community-dwelling elderly persons. Cognitive performance (global cognitive functioning, visual memory, verbal fluency, psychomotor speed, and executive function), clinical diagnosis of dementia, and fibrate and statin use, were evaluated at baseline, and 2, 4, and 7 year follow-up. Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics, mental and physical health including vascular risk factors, and genetic vulnerability (apolipoprotein E and cholesteryl ester transfer protein). For women but not men, fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only (HR = 1.29, 95% CI = 1.09-1.54, p = 0.004), and did not increase risk for incident dementia. This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate (HR = 1.39, 95% CI = 1.08-1.79, p = 0.01) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment. For both genders, no significant associations were found between statins (irrespective of their lipophilicity) and either cognitive decline or dementia incidence. This prospective study, adjusting for multiple confounders, found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia, but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory