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Previous studies demonstrated the utility of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) as a positron emission tomography (PET) radiotracer for the vesicular monoamine transporter type 2 (VMAT2) to quantify beta cell mass in healthy control (HC) and type 1 diabetes mellitus (T1DM) groups. Quantification of specific binding requires measurement of non-displaceable uptake. Our goal was to identify a reference tissue (renal cortex or spleen) to quantify pancreatic non-specific binding of [18F]FP-(+)-DTBZ with the inactive enantiomer, [18F]FP-(−)-DTBZ. This was the first human study of [18F]FP-(−)-DTBZ. Six HCs and four T1DM patients were scanned on separate days after injection of [18F]FP-(+)-DTBZ or [18F]FP-(−)-DTBZ. Distribution volumes (VT) and standardized uptake values (SUVs) were compared between groups. Three methods for calculation of non-displaceable uptake (VND) or reference SUV were applied: (1) use of [18F]FP-(+)-DTBZ reference VT as VND, assuming VND is uniform across organs; (2) use of [18F]FP-(−)-DTBZ pancreatic VT as VND, assuming that VND is uniform between enantiomers in the pancreas; and (3) use of a scaled [18F]FP-(+)-DTBZ reference VT as VND, assuming that a ratio of non-displaceable uptake between organs is uniform between enantiomers. Group differences in VT (or SUV), binding potential (BPND), or SUV ratio (SUVR) were estimated using these three methods. [18F]FP-(−)-DTBZ VT values were different among organs, and VT(+) and VT(−) were also different in the renal cortex and spleen. Method 3 with the spleen to estimate VND (or reference SUV) gave the highest non-displaceable uptake and the largest HC vs. T1DM group differences. Significant group differences were also observed in VT (or SUV) with method 1 using spleen. SUV was affected by differences in the input function between groups and between enantiomers. Non-displaceable uptake was different among organs and between enantiomers. Use of scaled spleen VT values for VND is a suitable method for quantification of VMAT2 in the pancreas.

The increased availability of isolated human islets for diabetes research and the implementation of islet distribution programs in several countries worldwide have been driving forces behind the rapidly expanding number of scientific reports on studies using human islets. In Diabetologia , Hart and Powers (1) not only review the progress made in human islet research, made possible through their greater availability, but also identify the challenges associated with their use. These include the wide functional heterogeneity observed between islet preparations and the highly variable (and often inadequate) reporting of human islet characteristics in the scientific literature. Many factors contribute to the functional heterogeneity observed between human islet preparations. These include differences in donor characteristics (age, sex, ethnic background, health status prior to death, and cause of death); differences in pancreas procurement (isolation center, islet handling, estimated purity, and viability); warm and cold ischemia times; and tissue culture (1). All of these factors influence, to varying degrees, the morphology and function of the islets as investigated in the laboratory (2–5). For example, out of the 13 islet preparations from donors without diabetes for which islet cell composition is provided in the Human Pancreas Analysis Program PancDB database of the Human Islet Research Network …

GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). We estimate that there is a 98% probability that 20 μg GAD with alum administered twice yields a positive biological effect. The effect is probably a 15–20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between −0.250 and −0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of −0.294 pmol/ml at 1 year for untreated newly diagnosed patients. The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

The inaugural issue of this journal, published in November 2005, included articles on thyroid cancer, type 2 diabetes mellitus, the metabolic syndrome, pituitary adenomas and obesity. 10 years later, we are still publishing articles on these topics (and many others). Although a great deal of progress has been made in our understanding of the pathogenesis, diagnosis and treatment of diseases of the endocrine system over the past 10 years, many challenges still remain. For this Viewpoint, we have asked five of our Advisory Board Members to comment on the progress and challenges from the past 10 years. They were also asked to offer their thoughts on where money should be spent going forward, and their predictions for what advances might be achieved in the next 10 years.

Type 1 diabetes is a common, severe chronic autoimmune disease that is characterized by the progressive and insidious loss of self-tolerance to the insulin-producing pancreatic islet β-cells. This loss of self-tolerance leads to the destruction of β-cells and the development of overt hyperglycaemia at diagnosis. The incidence and prevalence of type 1 diabetes is rapidly increasing worldwide, and this has led to intensive efforts to develop immunotherapies to induce remission of the disease and improve clinical outcomes. Immunotherapy aims to restore self-tolerance, resulting in the downregulation of autoimmune responses to pancreatic self-antigens and arrested ongoing β-cell destruction. When combined with replacement of the lost insulin-producing cells, this may lead to the restoration of euglycaemia. In this review, we discuss the current knowledge of the immunopathogenesis of type 1 diabetes and how this information has been translated into clinical trials. We also discuss next-generation combination immunotherapies that may be administered as adjuvant therapy at time of diagnosis.

Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.

Immune-mediated insulin resistance should be considered in patients with increasing hyperglycemia despite high-dose insulin treatment. This article illustrates the differential diagnosis of insulin resistance and describes the features and management of the type B insulin resistance syndrome. Background A 55-year-old woman with vitiligo, hypothyroidism, interstitial lung disease and diabetes mellitus developed severe insulin resistance during a hospital admission for respiratory failure. Before hospitalization, her HbA1c level was 8.1% on ∼100 U/day of insulin. Her interstitial lung disease had been treated with glucocorticoids, but after their withdrawal her insulin requirements had increased dramatically. She remained hyperglycemic (blood glucose levels 16.7–27.8 mmol/l), despite intravenous insulin at doses as high as 30,000 U/day. Investigations The patient's serum creatinine level was 301 µmol/l and her liver function tests were normal. A mildly elevated white cell count was present. The patient was diagnosed with pneumonia due to Pseudomonas aeruginosa. When the patient's plasma glucose level was 22.5 mmol/l, her plasma C-peptide level was 0.9 nmol/l and her serum insulin level was 294 pmol/l. At that time the patient was on 2,600 U/day of intravenous insulin aspart. Anti-insulin and anti-islet-cell antibodies were not detected, but anti-insulin-receptor antibodies were found. Diagnosis Type B insulin resistance syndrome. Management The patient's insulin resistance responded to glucocorticoids and plasmapheresis. After the patient was treated with prednisone (60 mg/day), her insulin requirements decreased within 1 week to pre-admission doses. When steroids were subsequently discontinued, glycemic control deteriorated once again. Plasmapheresis was initiated, inducing a striking acute decline in insulin needs. On a maintenance dose of 10 mg prednisone/day, glucose control improved (HbA1c 5.8%) with an average of 60 U of isophane insulin twice daily.

Chronic immunological processes that underlie persistent viral infections and autoimmune disorders such as multiple sclerosis can be relapsing-remitting in nature. The progressive loss of beta-cell mass during the development of autoimmune type 1 diabetes (T1D) can also be non-linear, but the exact nature and kinetics of the immunological processes that govern T1D are not known. Here, we propose that the immunological process that is at the root of T1D is relapsing-remitting in nature and discuss the unresolved controversies and therapeutic implications of this hypothesis.

Vascular inflammation contributes critically to the initiation and progression of atherosclerosis. These processes are accelerated in hyperglycemia and play key roles in the increased incidence and severity of myocardial infarction and stroke observed in diabetes. Evidence suggests that the ligands of the receptor for advanced glycation endproducts (RAGE), a multiligand member of the immunoglobulin superfamily, interact with this receptor to play important roles in both early development and progression of atherosclerosis and vascular inflammation. Studies in animal models of vascular injury underscored the potent impact of RAGE blockade; administration of ligand-binding decoys of RAGE or antibodies to the receptor reduced the consequences of diabetes, hyperlipidemia, and physical injury to the vessel wall. This review focuses on the ligand repertoire of RAGE, the impact of ligand-RAGE interaction, and the potent effect of RAGE blockade in rodent models of vascular injury.

Studies in animal models of type 1 diabetes had suggested that the disease was due to an immune-mediated destruction of insulin-producing cells. As this understanding was developed, clinical trials that were directed against T cells were begun, because these lymphocytes were thought to be the primary mediators of disease. Initial studies used broad-spectrum agents and showed general efficacy in either preventing the loss of insulin secretion or reducing the need for exogenous insulin. Although encouraging, the enthusiasm for this approach waned due to the lack of long-term effects and toxicities. These studies were followed by trials with more specific agents, but the issue of toxicity remained. Newer agents, such as anti-CD3 antibody, are also targeted against T cells but the toxicity and efficacy of modified anti-CD3 antibody, for example, appears to be improved over previously tested agents. In addition, our understanding of the immunologic effects of anti-T-cell agents has evolved. Data now suggest that efficacy and duration of the effects of anti-T-cell drugs can be enhanced when the agents provoke immune modulation rather than depletion of effector cells.

Anti-CD3 monoclonal antibodies (MAbs) were developed as a way of inducing immune suppression of T cells. More recent studies have indicated that anti-CD3 MAbs can affect immune responses by inducing immune regulation. We recently reported that a single course of treatment with a non-FcR binding anti-CD3 MAb, hOKT3γ1 (Ala-Ala), can lead to preservation of insulin production in patients with new-onset Type 1 diabetes for even beyond 1 yr after treatment. The sustained insulin production was accompanied by improvement in glucose control and reduced use of insulin. Our studies of the mechanism of the non-FcR binding anti-CD3 MAb indicate that the MAb delivers an activation signal to T cells resulting in disproportionate production of interleukin-10 (IL-10) relative to interferon-γ(IFN-γ) in vitro compared with FcR binding anti-CD3 MAb, and detectable levels of IL-10, IL-5, but rarely IFN-γ or IL-2 in the serum after treament. In addition, the drug induces a population of CD4+IL-10+ CCR4+ cells in vivo. Preclinical data suggest that anti-CD3 MAb induces a population of regulatory T cells that can prevent or lead to reversal of Type 1 diabetes. The induction of cells with a regulatory phenotype may account for the ability of anti-CD3 MAb to induce immune regulation.

Anti-CD3 monoclonal antibodies (MAbs) were developed as a way of inducing immune suppression of T cells. More recent studies have indicated that anti-CD3 MAbs can affect immune responses by inducing immune regulation. We recently reported that a single course of treatment with a non-FcR binding anti-CD3 MAb, hOKT3gamma1(Ala-Ala), can lead to preservation of insulin production in patients with new-onset Type 1 diabetes for even beyond 1 yr after treatment. The sustained insulin production was accompanied by improvement in glucose control and reduced use of insulin. Our studies of the mechanism of the non-FcR binding anti-CD3 MAb indicate that the MAb delivers an activation signal to T cells resulting in disproportionate production of interleukin-10 (IL-10) relative to interferon-gamma(IFN-gamma) in vitro compared with FcR binding anti-CD3 MAb, and detectable levels of IL-10, IL-5, but rarely IFN-gamma or IL-2 in the serum after treatment. In addition, the drug induces a population of CD4+IL-10+ CCR4+ cells in vivo. Preclinical data suggest that anti-CD3 MAb induces a population of regulatory T cells that can prevent or lead to reversal of Type 1 diabetes. The induction of cells with a regulatory phenotype may account for the ability of anti-CD3 MAb to induce immune regulation.

Preliminary results of the randomized, double-blinded TRIGR trial suggest that dietary manipulation can affect progression of autoimmunity in those at risk of type 1 diabetes mellitus. These findings highlight the interplay of genetic and environmental factors that regulate tolerance and might be targeted by preventative interventions.

The autoimmune process that results in Type 1 (insulin-dependent) diabetes mellitus may be viewed as a failure to develop or maintain tolerance to self-antigens expressed in the islets of Langerhans. During T-cell development in the thymus, cells that are reactive with self antigens encountered there may undergo clonal deletion or, as more recently described, clonal anergy which effectively removes these cells from the pool of mature antigen reactive T cells. For antigens not found in the thymus, tolerance to self antigens is more complex and may depend on site of antigen expression, ambient concentrations of lymphokines, and availability of antigen-presenting cells that can deliver co-stimulatory signals. Transgenic mice in which the majority of T cells express T-cell receptors against "self" antigens or in which expression of antigens is targeted to peripheral tissues have proven useful for studies of tolerance in both T- and B-cell compartments. In general, T-cell reactivity against foreign antigen expressed on Beta cells does not occur because of the failure to activate T cells reactive with the antigen, termed clonal ignorance. This may be broken with, for example, viral infection or cytokines. In one transgenic model, dendritic cells that surround the islets of Langerhans have been shown to be responsible for presentation of islet antigens to the immune system. B-cell tolerance can also involve mechanisms of clonal deletion or clonal anergy similar to that occurring with T cells. In addition, a mechanism for changing the affinity of the B-cell antigen receptor termed "receptor editing" has been described, which may play an important role in diversifying the B-cell repertoire while removing self-reactive cells. Tolerance to antigens may also be inducible. For example, monoclonal antibodies against T-cell epitopes may induce antigen-specific tolerance that is transferable to other animals, and MHC blocking peptides which can inhibit T-cell responses that are restricted by disease associated MHC molecules. In conclusion, although several possible triggers and mechanisms of autoimmune diabetes can be envisioned, none can be excluded by existing data. However, advances in understanding mechanisms of tolerance to islet and other self antigens suggest potentially useful therapeutic approaches to arresting the autoimmune response.

Nature Nanotechnology 9, 639–647 (2014); published online 3 August 2014; corrected after print 14 August 2014. In the version of this Article previously published, the name of the co-author Kevan C. Herold was spelt incorrectly. This has now been corrected in the online versions of the Article.

Continuous glucose monitoring systems provide dynamic measurements of interstitial glucose levels, enabling patients with diabetes mellitus to act preemptively to reduce glycemic variability. The authors of this Viewpoint discuss the advantages of continuous glucose-monitoring systems over self-monitoring of blood glucose, as well factors that limit its availability and success.

Lessons from New York City—how diabetes might be affecting overall rates of coronary heart disease

The receptor for advanced glycation endproducts (RAGE) has complex roles in the immune/inflammatory response. RAGE is expressed on monocytes/macrophages, T and B lymphocytes, and dendritic cells. Previous studies illustrated that homozygous RAGE-/- mice subjected to overwhelming bacterial sepsis displayed normal clearance of pathogenic bacteria and significantly increased survival. In this issue of Critical Care, Lutterloh and colleagues confirm these findings and provide evidence that blocking antibodies to RAGE afford similar protection in mice, even when administration of anti-RAGE is delayed by 24 hours. Furthermore, these authors illustrate that deletion of RAGE is remarkably protective in mice infected with the intracellular pathogen Listeria monocytogenes. In this Commentary, we consider these findings and propose possible mechanisms by which RAGE exacts a heavy toll on the host in response to polymicrobial sepsis and L. monocytogenes.