Parth Narendran

What are the health benefits of physical activity in type 1 diabetes mellitus? A literature review

Physical activity improves well-being and reduces the risk of heart disease, cancer and type 2 diabetes mellitus in the general population. In individuals with established type 2 diabetes, physical activity improves glucose and lipid levels, reduces weight and improves insulin resistance. In type 1 diabetes mellitus, however, the benefits of physical activity are less clear. There is poor evidence for a beneficial effect of physical activity on glycaemic control and microvascular complications, and significant risk of harm through hypoglycaemia. Here we review the literature relating to physical activity and health in type 1 diabetes. We examine its effect on a number of outcomes, including glycaemic control, lipids, blood pressure, diabetic complications, well-being and overall mortality. We conclude that whilst there is sufficient evidence to recommend physical activity in the management of type 1 diabetes, it is still unclear as to what form, duration and intensity should be recommended and whether there is benefit for many of the outcomes examined.

Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4

During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.

Lymphotoxin Signals from Positively Selected Thymocytes Regulate the Terminal Differentiation of Medullary Thymic Epithelial Cells

The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire+ mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall’s corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire+ mTEC development, use of an inducible ZAP70 transgenic mouse line—in which positive selection can be temporally controlled—demonstrates that the emergence of involucrin+ mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire+ mTECs depends upon RANK signaling, continued mTEC development to the involucrin+ stage maps to activation of the LTα–LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells

To protect the organism against autoimmunity, self-reactive effector/memory T cells (TE/M) are controlled by cell-intrinsic and -extrinsic regulatory mechanisms. However, how some TE/M cells escape regulation and cause autoimmune disease is currently not understood. Here we show that blocking IL-7 receptor-α (IL-7Rα) with monoclonal antibodies in nonobese diabetic (NOD) mice prevented autoimmune diabetes and, importantly, reversed disease in new-onset diabetic mice. Surprisingly, IL-7–deprived diabetogenic TE/M cells remained present in the treated animals but showed increased expression of the inhibitory receptor Programmed Death 1 (PD-1) and reduced IFN-γ production. Conversely, IL-7 suppressed PD-1 expression on activated T cells in vitro. Adoptive transfer experiments revealed that TE/M cells from anti–IL-7Rα–treated mice had lost their pathogenic potential, indicating that absence of IL-7 signals induces cell-intrinsic tolerance. In addition to this mechanism, IL-7Rα blockade altered the balance of regulatory T cells and TE/M cells, hence promoting cell-extrinsic regulation and further increasing the threshold for diabetogenic T-cell activation. Our data demonstrate that IL-7 contributes to the pathogenesis of autoimmune diabetes by enabling TE/M cells to remain in a functionally competent state and suggest IL-7Rα blockade as a therapy for established T-cell–dependent autoimmune diseases.

Does exercise improve glycaemic control in type 1 diabetes? A systematic review and meta-analysis.

Objective Whilst regular exercise is advocated for people with type 1 diabetes, the benefits of this therapy are poorly delineated. Our objective was to review the evidence for a glycaemic benefit of exercise in type 1 diabetes. Research Design and Methods Electronic database searches were carried out in MEDLINE, Embase, Cochrane’s Controlled Trials Register and SPORTDiscus. In addition, we searched for as yet unpublished but completed trials. Glycaemic benefit was defined as an improvement in glycosylated haemoglobin (HbA1c). Both randomised and non-randomised controlled trials were included. Results Thirteen studies were identified in the systematic review. Meta-analysis of twelve of these (including 452 patients) demonstrated an HbA1c reduction but this was not statistically significant (standardised mean difference (SMD) −0.25; 95% CI, −0.59 to 0.09). Conclusions This meta-analysis does not reveal evidence for a glycaemic benefit of exercise as measured by HbA1c. Reasons for this finding could include increased calorie intake, insulin dose reductions around the time of exercise or lack of power. We also suggest that HbA1c may not be a sensitive indicator of glycaemic control, and that improvement in glycaemic variability may not be reflected in this measure. Exercise does however have other proven benefits in type 1 diabetes, and remains an important part of its management.

Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease

During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögrens syndrome, PEPITEM reduced T cell recruitment into inflamed tissues.

The Distribution of Adiponectin Receptors on Human Peripheral Blood Mononuclear Cells

Adiponectin, an adipocytokine with anti‐inflammatory and insulin‐sensitizing properties, may provide a mechanism by which insulin resistance accelerates autoimmunity in type 1 diabetes (T1D). Its actions are mediated by two receptors, adiponectin receptors 1 (ADIPOR1) and 2 (ADIPOR2). In this study, we measured their distribution on human peripheral mononuclear cells by flow cytometry. ADIPOR1 is present approximately on 1% of T cells, 93% of monocytes, 47% of B cells, and 21% of NK cells (P < 0.01 for difference between subsets). The distribution of ADIPOR2 was found to be similar (r= 0.992, P < 0.01), and staining could be blocked in an antigen‐specific manner. We were also able to confirm our finding at an RNA level by PCR using sequence‐specific primers. Our data are consistent with an immunoregulatory role for adiponectin in T1D.

Increased Left Ventricular Torsion in Uncomplicated Type 1 Diabetic Patients: The role of coronary microvascular function

OBJECTIVE We used speckle tracking echocardiography to study the early changes in left ventricular (LV) torsion in young patients with uncomplicated type 1 diabetes and stress magnetic resonance imaging (MRI) to assess its interrelationships with coronary microangiopathy. RESEARCH DESIGN AND METHODS We recruited 33 asymptomatic subjects with type 1 diabetes and 32 age-matched healthy control subjects. All subjects underwent echocardiograms. Stress MRIs were performed in 30 subjects (8 healthy control subjects) to compute myocardial perfusion reserve index (MPRI). RESULTS A significant increase in LV torsion (2 ± 0.7 vs. 1.4 ± 0.7°/cm, P < 0.05) was identified in longer-term and retinopathy-positive type 1 diabetic subjects (1.9 ± 0.7 vs. 1.4 ± 0.7°/cm, P < 0.05) as compared with the healthy control subjects. The MPRI was independently associated with increased LV torsion. CONCLUSIONS We demonstrate that LV torsion is increased in young patients with uncomplicated type 1 diabetes and that coronary microvascular disease may play a key pathophysiological role in the development of increased LV torsion.

Attitudes and Barriers to Exercise in Adults with Type 1 Diabetes (T1DM) and How Best to Address Them: A Qualitative Study

Background Regular physical activity has recognised health benefits for people with T1DM. However a significant proportion of them do not undertake the recommended levels of activity. Whilst questionnaire-based studies have examined barriers to exercise in people with T1DM, a formal qualitative analysis of these barriers has not been undertaken. Our aims were to explore attitudes, barriers and facilitators to exercise in patients with T1DM. Methodology A purposeful sample of long standing T1DM patients were invited to participate in this qualitative study. Twenty-six adults were interviewed using a semi-structured interview schedule to determine their level of exercise and barriers to initiation and maintenance of an exercise programme. Principal findings Six main barriers to exercise were identified: lack of time and work related factors; access to facilities; lack of motivation; embarrassment and body image; weather; and diabetes specific barriers (low levels of knowledge about managing diabetes and its complications around exercise). Four motivators to exercise were identified: physical benefits from exercise; improvements in body image; enjoyment and the social interaction of exercising at gym or in groups. Three facilitators to exercise were identified: free or reduced admission to gyms and pools, help with time management, and advice and encouragement around managing diabetes for exercise. Significance Many of the barriers to exercise in people with T1DM are shared with the non-diabetic population. The primary difference is the requirement for education about the effect of exercise on diabetes control and its complications. There was a preference for support to be given on a one to one basis rather than in a group environment. This suggests that with the addition of the above educational requirements, one to one techniques that have been successful in increasing activity in patients with other chronic disease and the general public should be successful in increasing activity in patients with T1DM.

Hypoglycemia in non-diabetic in-patients: clinical or criminal?

Background and Aim We wished to establish the frequency of unexpected hypoglycemia observed in non diabetic patients outside the intensive care unit and to determine if they have a plausible clinical explanation. Methods We analysed data for 2010 from three distinct sources to identify non diabetic hypoglycaemic patients: bedside and laboratory blood glucose measurements; medication records for those treatments (high-strength glucose solution and glucagon) commonly given to reverse hypoglycemia; and diagnostic codes for hypoglycemia. We excluded from the denominator admissions of patients with a diagnosis of diabetes or prescribed diabetic medication. Case notes of patients identified were reviewed. We used capture-recapture methods to establish the likely frequency of hypoglycemia in non-diabetic in-patients outside intensive care unit at different cut-off points for hypoglycemia. We also recorded co-morbidities that might have given rise to hypoglycemia. Results Among the 37,898 admissions, the triggers identified 71 hypoglycaemic episodes at a cut-off of 3.3 mmol/l. Estimated frequency at 3.3 mmol/l was 50(CI 33–93), at 3.0 mmol/l, 36(CI 24–64), at 2.7 mmol/l, 13(CI 11–19), at 2.5 mmol/l, 11(CI 9–15) and at 2.2 mmol/l, 8(CI 7–11) per 10,000 admissions. Admissions of patients aged above 65 years were approximately 50% more likely to have an episode of hypoglycemia. Most were associated with important co-morbidities. Conclusion Significant non-diabetic hypoglycemia in hospital in–patients (at or below 2.7 mmol/l) outside critical care is rare. It is sufficiently rare for occurrences to merit case-note review and diagnostic blood tests, unless an obvious explanation is found.