Jake Powrie

Self-monitoring in Type 2 diabetes mellitus: a meta-analysis

SUMMARY

Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated β-Cell Death

OBJECTIVE CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells. RESEARCH DESIGN AND METHODS Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat β-cells, and the rat insulinoma cell line INS-1E were examined. RESULTS A total of 27 patients (54%) showed IL-17 reactivity to one or more β-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1β/interferon (IFN)-γ–induced and tumor necrosis factor (TNF)-α/IFN-γ–induced apoptosis in human islets, rat β-cells, and INS-1E cells, in association with significant upregulation of β-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-κB. CONCLUSIONS Circulating IL-17+ β-cell–specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to β-cell death involving IL-17 and STAT1 and NF-κB, rendering this cytokine a novel disease biomarker and potential therapeutic target.

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ–positive, multiautoantibody-positive) and partially regulated (interleukin-10–positive, pauci-autoantibody–positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed “hyper-immune CD20Hi” and “pauci-immune CD20Lo.” Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

The influence of the route of oestrogen administration on serum levels of cortisol‐binding globulin and total cortisol

Objectives  Oral oestrogen preparations increase total cortisol concentration by increasing circulating cortisol‐binding globulin (CBG) levels. Transdermal oestrogen treatments are being used increasingly in clinical practice. These topical preparations may have less of an effect on CBG and hence on total serum cortisol levels by reducing hepatic oestrogen exposure. The purpose of this study was to compare the effects of oral and topical oestrogen treatments on CBG, total serum cortisol and salivary cortisol levels.

Circulating, Preproinsulin Signal Peptide–Specific CD8 T Cells Restricted by the Susceptibility Molecule HLA-A24 Are Expanded at Onset of Type 1 Diabetes and Kill β-Cells

Type 1 diabetes results from T cell–mediated β-cell destruction. The HLA-A*24 class I gene confers significant risk of disease and early onset. We tested the hypothesis that HLA-A24 molecules on islet cells present preproinsulin (PPI) peptide epitopes to CD8 cytotoxic T cells (CTLs). Surrogate β-cell lines secreting proinsulin and expressing HLA-A24 were generated and their peptide ligandome examined by mass spectrometry to discover naturally processed and HLA-A24–presented PPI epitopes. A novel PPI epitope was identified and used to generate HLA-A24 tetramers and examine the frequency of PPI-specific T cells in new-onset HLA-A*24+ patients and control subjects. We identified a novel naturally processed and HLA-A24–presented PPI signal peptide epitope (PPI3–11; LWMRLLPLL). HLA-A24 tetramer analysis reveals a significant expansion of PPI3–11-specific CD8 T cells in the blood of HLA-A*24+ recent-onset patients compared with HLA-matched control subjects. Moreover, a patient-derived PPI3–11-specific CD8 T-cell clone shows a proinflammatory phenotype and kills surrogate β-cells and human HLA-A*24+ islet cells in vitro. These results indicate that the type 1 diabetes susceptibility molecule HLA-A24 presents a naturally processed PPI signal peptide epitope. PPI-specific, HLA-A24–restricted CD8 T cells are expanded in patients with recent-onset disease. Human islet cells process and present PPI3–11, rendering themselves targets for CTL-mediated killing.

Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature

Lymphocytic adenohypophysitis can cause pituitary expansion and hypopituitarism closely mimicking the features of a pituitary adenoma. Discrimination between these two conditions is of importance since, despite the similarity of their presentation, there are significant differences in pathophysiology. In contrast to pituitary adenoma, lymphocytic adenohypophysitis occurs almost exclusively in young women in relation to pregnancy, there is a preference for destruction of ACTH and TSH secreting cells and computed tomographic scanning shows uniform contrast enhancement in a proportion of cases. There is, as yet, no proven specific non‐surgical treatment. There are anecdotal reports of a beneficial effect of steroids but there is also evidence that spontaneous resolution may occur. We have reviewed the literature and report two new cases of lymphocytic adenohypophysitis both of whom exhibited early striking diffuse homogeneous contrast enhancement on magnetic resonance imaging scanning which we suggest may be a diagnostic feature of this condition.

β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure

Autoreactive CD8 T cells play a central role in the destruction of pancreatic islet β-cells that leads to type 1 diabetes, yet the key features of this immune-mediated process remain poorly defined. In this study, we combined high-definition polychromatic flow cytometry with ultrasensitive peptide–human leukocyte antigen class I tetramer staining to quantify and characterize β-cell–specific CD8 T cell populations in patients with recent-onset type 1 diabetes and healthy control subjects. Remarkably, we found that β-cell–specific CD8 T cell frequencies in peripheral blood were similar between subject groups. In contrast to healthy control subjects, however, patients with newly diagnosed type 1 diabetes displayed hallmarks of antigen-driven expansion uniquely within the β-cell–specific CD8 T cell compartment. Molecular analysis of selected β-cell–specific CD8 T cell populations further revealed highly skewed oligoclonal T cell receptor repertoires comprising exclusively private clonotypes. Collectively, these data identify novel and distinctive features of disease-relevant CD8 T cells that inform the immunopathogenesis of type 1 diabetes.

18Flurodeoxyglucose positron emission tomography in the localization of ectopic ACTH‐secreting neuroendocrine tumours

Objective  Neuroendocrine tumours (NET) are a rare cause of Cushings syndrome. These tumours can be very small and therefore difficult to identify. Current localization techniques include CT, MRI and radioisotope scanning, but in a proportion of cases the NET remains occult. Positron emission tomography (PET) scanning, is a relatively new imaging modality that is increasingly used to detect and monitor lesions with high metabolic activity. We report on the use of PET scanning in the evaluation of the ectopic ACTH syndrome.

Growth hormone replacement therapy for growth hormone-deficient adults

SummaryRecent research has confirmed previous clinical suspicion that adults with pituitary disease and growth hormone (GH) deficiency have impaired physical and psychological performance even in the presence of adequate adrenal, thyroid and gonadal hormone replacement therapy. This GH deficiency syndrome is characterised particularly by impaired psychological well-being, abnormal body composition with increased abdominal adiposity, reduced strength and exercise capacity, reduced basal metabolic rate, reduced bone density and an elevation in total and low density lipoprotein cholesterol. This latter finding may be important in the context of the observed increase in cardiovascular mortality rates of GH-deficient adults. GH replacement therapy administered as a once-daily subcutaneous injection can restore a near normal quality of life to many of these patients, although there is as yet no evidence that this treatment reduces mortality. Adverse effects of GH therapy are few and have probably been overstated due to excessive doses used in the initial studies. These can be minimised by starting at a low initial dose and increasing gradually while monitoring clinical response and serum insulin-like growth factor-1 values. All adults with GH deficiency should now be considered for GH replacement therapy.

Cardiac valve disease and low-dose dopamine agonist therapy: an artefact of reporting bias?

Introduction  Chronic low‐dose cabergoline treatment for microprolactinoma may cause cardiac valve pathology, but the evidence is contradictory. We investigated whether the expectation of the echocardiographer could influence the report.