Postprandial macrophage-derived IL-1ß stimulates insulin, and both synergistically promote glucose disposal and inflammation.

The deleterious effect of chronic activation of the IL-1ß system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1ß in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1ß, in a glucose-dependent manner. Subsequently, IL-1ß contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1ß signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1ß and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1ß mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1ß and insulin in the regulation of both metabolism and immunity.

Proteomic analysis of serum in a population-based cohort did not reveal a biomarker for Modic changes.

Introduction: Modic changes (MC) are bone marrow lesions of vertebral bones, which can be detected with magnetic resonance imaging (MRI) adjacent to degenerated intervertebral discs. Defined by their appearance on T1 and T2 weighted images, there are three interconvertible types: MC1, MC2, and MC3. The inter-observer variability of the MRI diagnosis is high, therefore a diagnostic serum biomarker complementing the MRI to facilitate diagnosis and follow-up would be of great value. Methods: We used a highly sensitive and reproducible proteomics approach: DIA/SWATH-MS to find serum biomarkers in a subset of the Northern Finland Birth Cohort 1966. Separately, we measured a panel of factors involved in inflammation and angiogenesis to confirm some potential biomarkers published before with an ELISA-based method called V-Plex. Results: We found neither an association between the serum concentrations of the proteins detected with DIA/SWATH-MS with the presence of MC, nor a correlation with the size of the MC lesions. We did not find any association between the factors measured with the V-Plex and the presence of MC or their size. Conclusion: Altogether, our study suggests that a robust and generally usable biomarker to facilitate the diagnosis of MC cannot readily be found in serum.

The cephalic phase of insulin release is modulated by IL-1ß.

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic ß cells. Recently, IL-1ß was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1ß involves neuronal transmission. Furthermore, we found that cephalic phase insulin release was mediated by IL-1ß originating from microglia. Moreover, IL-1ß activated the vagus nerve to induce insulin secretion and regulated the activity of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice, this was due to dysregulated IL-1ß signaling. Our findings attribute a regulatory role to IL-1ß in the integration of nutrient-derived sensory information, subsequent neuronally mediated insulin secretion, and the dysregulation of autonomic cephalic phase responses in obesity.

IL-1beta promotes the age-associated decline of beta cell function.

Aging is the prime risk factor for the development of type 2 diabetes. We investigated the role of the interleukin-1 (IL-1) system on insulin secretion in aged mice. During aging, expression of the protective IL-1 receptor antagonist decreased in islets, whereas IL-1beta gene expression increased specifically in the CD45 + islet immune cell fraction. One-year-old mice with a whole-body knockout of IL-1beta had higher insulin secretion in vivo and in isolated islets, along with enhanced proliferation marker Ki67 and elevated size and number of islets. Myeloid cell-specific IL-1beta knockout preserved glucose-stimulated insulin secretion during aging, whereas it declined in control mice. Isolated islets from aged myeloIL-1beta ko mice secreted more insulin along with increased expression of Ins2, Kir6.2, and of the cell-cycle gene E2f1. IL-1beta treatment of isolated islets reduced E2f1, Ins2, and Kir6.2 expression in beta cells. We conclude that IL-1beta contributes the age-associated decline of beta cell function.

Characteristics and opinions of MD-PhD students and graduates from different European countries: a study from the European MD-PhD Association.

BACKGROUND: MD-PhD programmes throughout the world provide a platform for medical trainees to commit to a physician-scientist career, qualifying with both a medical degree (MD or equivalent) and Doctor of Philosophy (PhD). However, there are limited studies assessing the characteristics of MD-PhD programmes in Europe and the outcomes of MD-PhD students and graduates. PURPOSE: This study aims at a first country-wise exploration of characteristics, opinions, and academic outcomes of MD-PhD students and graduates in Europe. METHODS: Two questionnaires were developed to assess the demographics, MD-PhD programme characteristics, opinions, future career paths and academic outcomes of European MD-PhD students and graduates. An online survey of 278 MD-PhD students and 121 MD-PhD graduates from nine and six European countries, respectively, was completed between April 2016 and December 2017. The country-wise categorical responses were then compared through chi-square analysis followed by multiple logistic regression. RESULTS: Responses from 266 MD-PhD students and 117 MD-PhD graduates were considered valid. Significant country-wise differences (p <0.05) were observed for age group, resident status, clinical time allocation, duration of studies, sources of funding, publications, average impact factor of the journals in which the research was published, satisfaction with the duration of MD-PhD studies and future career choices of MD-PhD students. Responses related to self-perception about clinical and research competence and challenges faced during MD-PhD training did not show a significant country-wise difference. CONCLUSION: The MD-PhD workforce in Europe is highly diverse in their demographics, programme characteristics and career paths but does not differ in opinions related to the challenges faced. The results of this study may be helpful for implementation and improvement of MD-PhD programmes.

Inhibition of IL-1beta improves Glycaemia in a Mouse Model for Gestational Diabetes.

Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1ß (IL-1ß) expression in the uterus and the placenta along with elevated circulating IL-1ß concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1ß antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1ß antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1ß is a causal driver of impaired glucose tolerance in GDM.

What Constitutes Good Health Care for Patients with Breathlessness? Perspectives of Patients, Caregivers, and Health Care Professionals.

Background/Objective: Breathlessness is a highly prevalent and distressing symptom in patients with cancer and advanced chronic diseases. Symptom management is often overlooked. We explored the experiences of patients, caregivers, and health care providers (HCPs) and their expectations for future service developments. Design: This is a multiperspective qualitative study drawing on semistructured interviews. Setting/Subjects: Participants were recruited from palliative, respiratory, and cardiology departments of the Munich University Hospital and from a chronic obstructive pulmonary disease (COPD) patient group. Measurements: Interviews were analyzed using qualitative content analysis. Subcategories used the directional views of participants (positive, negative, and indifferent). The coding tree identified three categories: (1) attributes of symptom management, (2) practice pattern gaps, and (3) components of good practice. Results: Ten patients (5 female, 65.2 median age; COPD n = 3, cancer n = 3, chronic heart failure n = 2, and lung fibrosis n = 2), 3 caregivers (2 female, 53.6 median age), and 10 HCPs were interviewed. Patients and caregivers felt stressed and frustrated due to a lack of awareness regarding the symptom burden and little support from HCPs. HCPs pointed to a lack of therapeutic concepts and unclear assumptions of responsibilities. Specialist breathlessness services are perceived as addressing important gaps in professional practice from the viewpoint of all stakeholders. Accessibility and collaboration with other local health care services are important features of such specialist services. Conclusions: Chronic refractory breathlessness in advanced disease is managed insufficiently for most patients, caregivers, and HCPs. Increased knowledge about effective interventions and availability of skills-based training for patients, caregivers, and HCPs would help in breathlessness management.

ß Cell-Specific Deletion of the IL-1 Receptor Antagonist Impairs ß Cell Proliferation and Insulin Secretion.

Interleukin-1 receptor antagonist (IL-1Ra) is elevated in the circulation during obesity and type 2 diabetes (T2D) but is decreased in islets from patients with T2D. The protective role of local IL-1Ra was investigated in pancreatic islet ß cell (ßIL-1Ra)-specific versus myeloid-cell (myeloIL-1Ra)-specific IL-1Ra knockout (KO) mice. Deletion of IL-1Ra in ß cells, but not in myeloid cells, resulted in diminished islet IL-1Ra expression. Myeloid cells were not the main source of circulating IL-1Ra in obesity. ßIL-1Ra KO mice had impaired insulin secretion, reduced ß cell proliferation, and decreased expression of islet proliferation genes, along with impaired glucose tolerance. The key cell-cycle regulator E2F1 partly reversed IL-1ß-mediated inhibition of potassium channel Kir6.2 expression and rescued impaired insulin secretion in IL-1Ra knockout islets. Our findings provide evidence for the importance of ß cell-derived IL-1Ra for the local defense of ß cells to maintain normal function and proliferation.

Fetuin-A aggravates lipotoxicity in podocytes via interleukin-1 signaling.

Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1ß antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1-ß antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF-α), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1ß signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1ß therapy for prevention and treatment of DN.

The Role of Inflammation in ß-cell Dedifferentiation.

Chronic inflammation impairs insulin secretion and sensitivity. ß-cell dedifferentiation has recently been proposed as a mechanism underlying ß-cell failure in T2D. Yet the effect of inflammation on ß-cell identity in T2D has not been studied. Therefore, we investigated whether pro-inflammatory cytokines induce ß-cell dedifferentiation and whether anti-inflammatory treatments improve insulin secretion via ß-cell redifferentiation. We observed that IL-1ß, IL-6 and TNFα promote ß-cell dedifferentiation in cultured human and mouse islets, with IL-1ß being the most potent one of them. In particular, ß-cell identity maintaining transcription factor Foxo1 was downregulated upon IL-1ß exposure. In vivo, anti-IL-1ß, anti-TNFα or NF-kB inhibiting sodium salicylate treatment improved insulin secretion of isolated islets. However, only TNFα antagonism partially prevented the loss of ß-cell identity gene expression. Finally, the combination of IL-1ß and TNFα antagonism improved insulin secretion of ex vivo isolated islets in a synergistic manner. Thus, while inflammation triggered ß-cell dedifferentiation and dysfunction in vitro, this mechanism seems to be only partly responsible for the observed in vivo improvements in insulin secretion.

Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for ß Cell Adaptation and Glucose Homeostasis.

Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for ß cell function remains unclear. We studied effects of locally derived insulin secretagogues on ß cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes.

[Evaluation of the German Type D Scale (DS14) and prevalence of the Type D personality pattern in cardiological and psychosomatic patients and healthy subjects]. / Evaluation der deutschen Typ-D-Skala (DS14) und Prävalenz der Typ-D-Persönlichkeit bei kardiologischen und psychosomatischen Patienten sowie Gesunden.

The Type D personality pattern, consisting of negative affectivity and social inhibition, has been shown by Denollet et al. to predict adverse prognosis in patients with coronary heart disease. For measuring the Type D characteristics, Denollet has devised the 14 item Type D scale (DS14). In the present study, this instrument was translated into German. The validity, reliability and adequacy of the German DS14 were then tested in 2421 persons, including cardiological and psychosomatic patients as well as healthy factory workers. The results document sound psychometric properties of the scale. Cronbach's alpha was 0.87 for the negative affectivity subscale and 0.86 for social inhibition. The two-factor structure of the original instrument could be clearly replicated. The prevalence rates of the Type D pattern were lowest in cardiological patients (25 %) and highest in psychosomatic patients (62 %). The prevalence in this German sample of cardiology patients was also lower than the one observed in healthy factory workers (32.5 %) and in CHD samples reported in the literature. These group differences could not be accounted for by differences in age and sex distribution. In conclusion, the DS14 is a valid and reliable instrument that can be used for an economic evaluation of the Type D characteristics in patients and healthy persons. The possible meaningfulness of the low Type D prevalence in cardiac patients and the prognostic relevance of this pattern require further study.