P. Narendran

Hypoglycaemia is associated with increased length of stay and mortality in people with diabetes who are hospitalized.

Diabet. Med. 29, e445–e448 (2012)

Follicular helper T cell signature in type 1 diabetes

The strong genetic association between particular HLA alleles and type 1 diabetes (T1D) indicates a key role for CD4+ T cells in disease; however, the differentiation state of the responsible T cells is unclear. T cell differentiation originally was considered a dichotomy between Th1 and Th2 cells, with Th1 cells deemed culpable for autoimmune islet destruction. Now, multiple additional T cell differentiation fates are recognized with distinct roles. Here, we used a transgenic mouse model of diabetes to probe the gene expression profile of islet-specific T cells by microarray and identified a clear follicular helper T (Tfh) cell differentiation signature. Introduction of T cells with a Tfh cell phenotype from diabetic animals efficiently transferred diabetes to recipient animals. Furthermore, memory T cells from patients with T1D expressed elevated levels of Tfh cell markers, including CXCR5, ICOS, PDCD1, BCL6, and IL21. Defects in the IL-2 pathway are associated with T1D, and IL-2 inhibits Tfh cell differentiation in mice. Consistent with these previous observations, we found that IL-2 inhibited human Tfh cell differentiation and identified a relationship between IL-2 sensitivity in T cells from patients with T1D and acquisition of a Tfh cell phenotype. Together, these findings identify a Tfh cell signature in autoimmune diabetes and suggest that this population could be used as a biomarker and potentially targeted for T1D interventions.

Addressing insulin resistance in type 1 diabetes

Type 1 diabetes is recognised to include an element of insulin resistance. Insulin resistance is an independent risk factor for the development of macro‐ and microvascular complications of Type 1 diabetes and may also contribute to the development of the disease. This understanding comes at a time when the incidence of Type 1 diabetes appears to be rising and the public health burden from its vascular complications is high. A variety of safe and efficacious manoeuvres are available to redress insulin resistance in Type 2 diabetes. So far however, clinical trials addressing insulin resistance in Type 1 diabetes have been small with only short periods of follow‐up. Regardless, these trials have yielded promising results. This review examines the evidence for insulin resistance in the pathophysiology of Type 1 diabetes and its complications, the problems associated with its measurement, and summarizes the trials aimed at reducing insulin resistance in Type 1 diabetes. This includes a meta‐analysis of controlled trials of adjuvant metformin in Type 1 diabetes.

Expression and function of the autoimmune regulator (Aire) gene in non-thymic tissue.

Educational immune tolerance to self‐antigens is induced primarily in the thymus where tissue‐restricted antigens (TRAs) are presented to T lymphocytes by cells of the thymic stroma – a process known as central tolerance. The expression of these TRAs is controlled in part by a transcription factor encoded by the autoimmune regulatory (Aire) gene. Patients with a mutation of this gene develop a condition known as autoimmune–polyendocrinopathy–candidiasis–ectodermal–dystrophy (APECED), characterized by autoimmune destruction of endocrine organs, fungal infection and dental abnormalities. There is now evidence for TRA expression and for mechanisms of functional tolerance outside the thymus. This has led to a number of studies examining Aire expression and function at these extra‐thymic sites. These investigations have been conducted across different animal models using different techniques and have often shown discrepant results. Here we review the studies of extra thymic Aire and discuss the evidence for its expression and function in both human and murine systems.

Effects of physical activity on the development and progression of microvascular complications in type 1 diabetes: retrospective analysis of the DCCT study

BackgroundTo examine the effects of physical activity on the development and progression of microvascular complications in patients with type 1 diabetes.MethodsA retrospective analysis of data from the Diabetes Control and Complications trial was undertaken. Physical activity data was collected at baseline for each of 1441 recruits, converted to metabolic equivalent of task values, and categorised according to the American College of Sports Medicine recommendations. The rates of development/progression of diabetic retinopathy, nephropathy and neuropathy were compared in those who achieved over twice recommended, up to twice recommended, and less than recommended metabolic equivalent of task levels of activity. The DCCT study had a mean duration of follow up of 6.5xa0years ending in 1993.ResultsA total of 271 subjects had a sustained three-step progression in diabetic retinopathy. The rates of development or progression of retinopathy showed no significant association with physical activity level. The number of outcomes for nephropathy and neuropathy were small and there was no significant association with physical activity level.ConclusionsWe found no evidence that physical activity improves microvascular outcomes in type 1 diabetes. However we demonstrate no evidence of harm. We suggest that physical activity continues to play an important role in the management of type 1 diabetes.

All-Cause Mortality in Patients With Diabetes Under Treatment With Dapagliflozin: A Population-Based, Open-Cohort Study in The Health Improvement Network Database

ContextnEmpagliflozin was found to decrease mortality in patients with type 2 diabetes mellitus (T2DM) and a prior cardiovascular disease (CVD) event.nnnObjectivesnTo establish whether these benefits can be replicated in a real-world setting, should be expected with the use of dapagliflozin, and apply to T2DM patients at low risk of CVD.nnnDesignnGeneral practice, population-based, retrospective cohort study (January 2013 to September 2015).nnnSettingnThe Health Improvement Network database.nnnParticipantsnA total of 22,124 T2DM patients (4444 exposed to dapagliflozin; 17,680 unexposed T2DM patients) matched for age, sex, body mass index, T2DM duration, and smoking.nnnMain Outcome MeasuresnThe primary outcome was all-cause mortality (high and low risk for CVD) in the total study population, expressed as the adjusted incidence rate ratio (aIRR) with 95% confidence intervals (CIs). As a secondary analysis in the low-risk population, all-cause mortality and incident CVD were considered.nnnResultsnPatients with T2DM exposed to dapagliflozin were significantly less likely to die of any cause (aIRR: 0.50; 95% CI: 0.33 to 0.75; P = 0.001). Similarly, in low-risk patients, death from any cause was significantly lower in the cohort exposed to dapagliflozin (aIRR: 0.44; 95% CI: 0.25 to 0.78; P = 0.002). The difference in the risk of incident CVD did not reach statistical significance between groups in low-risk patients (aIRR: 0.89; 95% CI: 0.61 to 1.31; P = 0.546).nnnConclusionsnPatients with T2DM who were exposed to dapagliflozin had a lower risk of death from any cause irrespective of baseline CVD status.

Inhibition of Islet Immunoreactivity by Adiponectin Is Attenuated in Human Type 1 Diabetes

CONTEXTnAdiponectin is an adipocyte-derived cytokine with insulin-sensitizing and antiinflammatory properties. These dual actions have not previously been examined in the context of human disease.nnnOBJECTIVESnOur objective was to examine the adiponectin axis in type 1 diabetes (T1D). T1D is an autoimmune inflammatory disease resulting from pancreatic β-cell destruction, in which insulin resistance associates with progression to disease.nnnDESIGN, PATIENTS, AND INTERVENTIONSnWe measured circulating adiponectin and adiponectin receptor expression on blood-immune cells from 108 matched healthy, T1D, and type 2 diabetic subjects. We tested adiponectin effect on T cell proliferation to islet antigens and antigen-presenting function of monocyte-derived dendritic cells (mDCs). Lastly, we assessed the effect of a 3-week lifestyle intervention program on immune cell adiponectin receptor expression in 18 healthy subjects.nnnRESULTSnCirculating concentrations of adiponectin were not affected by T1D. However, expression of adiponectin receptors on blood monocytes was markedly reduced and inversely associated with insulin resistance. Reduced adiponectin receptor expression resulted in increased T cell proliferation to islet-antigen presented by autologous mDCs. We demonstrated a critical role for adiponectin in down-regulating the costimulatory molecule CD86 on mDCs, and this function was impaired in T1D. We proceeded to show that lifestyle intervention increased adiponectin receptor but reduced CD86 expression on monocytes.nnnCONCLUSIONSnThese data indicate that T cells are released from the antiinflammatory effects of adiponectin in T1D and suggest a mechanism linking insulin resistance and islet immunity. Furthermore, we suggest that interventions that reduce insulin resistance could modulate the inflammatory process in T1D.

The time has come to test the beta cell preserving effects of exercise in patients with new onset type 1 diabetes

Type 1 diabetes is characterised by immune-mediated destruction of insulin-producing beta cells. Significant beta cell function is usually present at the time of diagnosis with type 1 diabetes, and preservation of this function has important clinical benefits. The last 30xa0years have seen a number of largely unsuccessful trials for beta cell preservation, some of which have been of therapies that have potential for significant harm. There is a need to explore new, more tolerable approaches to preserving beta cell function that can be implemented on a large clinical scale. Here we review the evidence for physical exercise as a therapy for the preservation of beta cell function in patients with newly diagnosed type 1 diabetes. We highlight possible mechanisms by which exercise could preserve beta cell function and then present evidence from other models of diabetes that demonstrate that exercise preserves beta cell function. We conclude by proposing that there is now a need for studies to explore whether exercise can preserve beta cell in patients newly diagnosed with type 1 diabetes.

Activated T cell subsets in human type 1 diabetes: evidence for expansion of the DR+ CD30+ subpopulation in new-onset disease

An important limitation in T cell studies of human autoimmune (type 1) diabetes is lack of direct access to cells infiltrating the pancreas. We hypothesized that cells recently released from the pancreas into the blood might express a characteristic combination of markers of activation. We therefore examined the recently activated circulating T cell population [CD3+, human leucocyte antigen D‐related (HLA‐DR+)] using cytokine production and 10 additional subset markers [CD69, CD25, CD122, CD30, CD44v6, CD57, CD71, CCR3 (CD193), CCR5 (CD195) or CXCR3 (CD183)], comparing newly diagnosed adult (ND) (age 18–40 years) patients (nu2003=u200319) to patients with diabetes foru2003>u200310u2003years [long‐standing (LS), nu2003=u200319] and HLA‐matched controls (C, nu2003=u200316). CD3+u2003DR+ cells were enriched by two‐step immunomagnetic separation. No differences in basal or stimulated production of interleukin (IL)‐4, IL‐10, IL‐13 or interferon (IFN)‐γ by CD3+u2003DR+ enriched cells were observed between the different groups of subjects. However, among the CD3+u2003DR+ population, significant expansions appeared to be present in the very small CD30+, CD69+u2003and CD122+u2003subpopulations. A confirmatory study was then performed using new subjects (NDu2003=u200326, LSu2003=u200315), three‐colour flow cytometry, unseparated cells and three additional subset markers (CD38, CD134, CD4/CD25). This confirmed the expansion of the CD3+u2003DR+u2003CD30+u2003subpopulation in ND subjects. We conclude that a relative expansion in the T cell subpopulation with the activated phenotype CD3+u2003DR+u2003CD30+u2003is seen in the peripheral blood of subjects with newly diagnosed type 1 diabetes. This subpopulation represents less than 0·7% of circulating T cells and may provide a rich source of disease‐specific T cells that can be isolated from blood.

Exercise to preserve beta cell function in recent-onset type 1 diabetes mellitus (EXTOD) - a study protocol for a pilot randomized controlled trial

BackgroundExercise has a beta cell preserving effect in patients with type 2 diabetes. This benefit of exercise has not been examined in type 1 diabetes. Significant beta cell function is present at the time of diagnosis of type 1 diabetes and therefore studies of beta cell preservation are ideally conducted immediately after diagnosis.Many of the variables required to design and power such a study are currently unknown. The aim of EXTOD is to obtain the information required to design a formal study of exercise and beta cell preservation in newly diagnosed patients with type 1 diabetes.MethodsBarriers to exercise will initially be assessed in a qualitative study of newly diagnosed patients. Then, sixty newly diagnosed adult type 1 diabetes patients will be randomized to either conventional treatment or exercise, stratified on beta cell function and fitness. The exercise group will be encouraged to increase their level of activity to a minimum of 150 minutes of moderate to vigorous intensity exercise per week, aiming for 240 minutes per week of exercise for 12 months. Beta cell function will be measured by meal-stimulated C peptide. Primary outcomes are recruitment, adherence to exercise, loss to follow-up, and exercise levels in the non-intervention arm (contamination). The secondary outcome of the study is rate of loss of beta cell function.DiscussionThe outcomes of the EXTOD study will help define the barriers, uptake and benefits of exercise in adults newly diagnosed with type 1 diabetes. This information will enable design of a formal study to assess the effect of exercise on beta cell preservation in newly diagnosed patients with type 1 diabetes.Trial registrationCurrent controlled trials ISRCTN91388505