Mortality in patients with incident rheumatoid arthritis and depression: a Danish cohort study of 11 071 patients and 55 355 comparators.

OBJECTIVES: In patients with RA, the association between mortality and depression has been investigated only in patients with prevalent RA. In this study, we estimated the mortality risk associated with depression, defined as the first filling of a prescription for antidepressants, in patients with incident RA and background population comparators. METHODS: From 2008 to 2018, we identified patients with incident RA in the nationwide Danish rheumatologic database, DANBIO. For each patient, we randomly selected five comparators. Participants were not treated with antidepressants or diagnosed with depression 3 years prior to the index date. From other registers we collected data on socioeconomic status, mortality and cause of death using unique personal identifiers. Using Cox models, we calculated hazard rate ratios (HRR) with 95% CI. RESULTS: In depressed patients with RA vs patients without depression, adjusted HRR for all-cause mortality was 5.34 (95% CI 3.02, 9.45) during 0-2 years and 3.15 (95% CI 2.62, 3.79) during the total follow-up period, and highest in patients <55 years with HRR 8.13 (95% CI 3.89, 17.02). In comparators with depression vs comparators without depression, the association with mortality was similar to that in patients with RA. There were no unnatural causes of death among depressed patients with RA. The most frequent natural causes of death were cancer, cardiovascular disease, stroke and pneumonia. CONCLUSION: In patients with RA, depression was a predictor of death but with a strength similar to that in matched comparators.

Antibiotics in inflammatory arthritis and background population one year before and after diagnosis: a nationwide drug utilisation study.

OBJECTIVES: To describe antibiotic use in patients with inflammatory arthritis (IA) and in the background population (BP) within one year before and after IA diagnosis. METHODS: Using data from Danish nationwide registries, we identified all adults with a first-time diagnosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis/spondyloarthritis (AS/SpA) from 2010 through 2018. For each IA patient, we randomly sampled ten persons from the BP, matched on sex and birthdate. We calculated the prevalence (n [%]) of any antibiotic dispensing and the total antibiotic dispensing in the year before and after diagnosis. RESULTS: We identified 28 504 new-onset IA patients (RA, n = 16 130; PsA, n = 5,988; AS/SpA, n = 6,386) and 285 040 BP individuals. The one-year prevalence of any antibiotic dispensing was 42.1% in IA patients before diagnosis vs 30.7% in the BP. The total antibiotic dispensing was higher the one-year before both RA, PsA, and As/SpA compared with BP (prevalence rate ratios [PRR], 1.48 [1.46; 1.51]; 1.67 [1.62; 1.72]; 1.52 [1.47; 1.56], respectively), and increased with 22% in IA patients three months before diagnosis compared with the preceding three-month period. Although the prevalence of any antibiotic dispensing in IA patients decreased in the year following the diagnosis (IA; 40.6%), the total one-year antibiotic dispensing remained constant in RA (PRR 0.99 [0.97; 1.01]), decreased in PsA (0.91 [0.87; 0.94]), and increased in AS/SpA (1.08 [1.04; 1.12]) patients after diagnosis compared with before. CONCLUSION: Antibiotics are more frequently dispensed to individuals developing IA compared with the BP. Antibiotic utilisation patterns change after IA diagnosis with marked differences among IA subgroups.

Theory and experiment of transient two-wave mixing in Yb-doped single-frequency fiber amplifiers induced by frequency modulation.

This paper presents a theoretical and experimental characterization of an instability phenomenon observed in single-frequency fiber amplifiers when the frequency of the seed laser is modulated. The instability manifests itself as fluctuating elastic back-reflections that occur only when the frequency is decreasing with time. The theory is a generalization of a coupled-mode model developed for a single-frequency fiber amplifier back-seeded with a constant frequency shift relative to the main signal. It can explain most observed features of the experiments in a qualitative and semi-quantitative way. Open questions and directions for further developments are also discussed.

Adverse events reporting during the COVID-19 pandemic in a Danish region: a retrospective analysis.

The 2020 onset of the COVID-19 pandemic globally strained healthcare. Healthcare systems worldwide had to rapidly reorganize, impacting service delivery, patient care, and care-seeking behaviors. This left little time to assess the pandemic's effects on patient safety. This paper investigates COVID-19's influence on patient safety in a Danish region, using data from the national reporting system for adverse events during the initial COVID-19 surge in early 2020. This retrospective analysis investigated how the early phase of the COVID-19 pandemic (January-September 2020) affected the incidence of adverse events in a Danish Region, comparing it to the same period in 2019. Data were sourced from the Danish Patient Safety Database and regional systems. Adverse events were reported numerically. Descriptive statistics were employed to describe the percentage difference in adverse events and hospital activity, as well as the rate of adverse events per 1000 activities. Additionally, COVID-19-specific adverse events from April 2020 to March 2021 were identified and analyzed, categorizing them into seven risk areas across various healthcare sectors. During Denmark's initial COVID-19 surge in early 2020, the North Denmark Region's hospitals reported a significant decrease in adverse events, with a 42.5% drop in March 2020 compared to March 2019. From January to September 2020, the number of adverse events dropped 8.5% compared to the same period in 2019. In the same period, hospital activity declined by 10.2%. The ratio of reported adverse events per 1000 hospital activities thus decreased in early 2020 but showed only a minor difference overall for January-September compared to 2019. Between April 2020 and March 2021, out of 5703 total adverse events, 324 (5.7%) were COVID-19 related. COVID-19-related events were categorized into seven distinct risk areas, reflecting diverse impacts across healthcare sectors including hospitals, general practices, pre-hospital care, and specialized services. The initial decline in reporting of adverse events likely resulted from rapid healthcare changes and under-prioritization of the reporting system during the acute phase. However, a near return to pre-pandemic reporting levels suggests a resilient reporting system despite the crisis. The study's strength lies in the comprehensive data from Danish reporting systems, though it acknowledges potential underreporting and doesn't measure the pandemic's overall impact on patient safety.

Getting ahead in the social sciences: How parenthood and publishing contribute to gender gaps in academic career advancement.

How do parenthood and publishing contribute to gender gaps in academic career advancement? While extensive research examines the causes of gender disparities in science, technology, engineering, and mathematics (STEM) careers, we know much less about the factors that constrain women's advancement in the social sciences. Combining detailed career- and administrative register data on 976 Danish social scientists in Business and Management, Economics, Political Science, Psychology, and Sociology (5703 person-years) that obtained a PhD degree between 2000 and 2015, we estimate gender differences in attainment of senior research positions and parse out how publication outputs, parenthood and parental leave contribute to these differences. Our approach is advantageous over previous longitudinal studies in that we track the careers and publication outputs of graduates from the outset of their PhD education and match this data with time-sensitive information on each individual's publication activities and family situation. In discrete time-event history models, we observe a ∼24 per cent female disadvantage in advancement likelihoods within the first 7 years after PhD graduation, with gender differences increasing over the observation period. A decomposition indicates that variations in publishing, parenthood and parental leave account for ∼ 40 per cent of the gender gap in career advancement, suggesting that other factors, including recruitment disparities, asymmetries in social capital and experiences of unequal treatment at work, may also constrain women's careers.

Subspace tracking for phase noise source separation in frequency combs.

It is widely acknowledged that the phase noise of an optical frequency comb primarily stems from the common mode (carrier-envelope) and the repetition rate phase noise. However, owing to technical noise sources or other intricate intra-cavity factors, residual phase noise components, distinct from the common mode and the repetition rate phase noise, may also exist. We introduce a measurement technique that combines subspace tracking and multi-heterodyne coherent detection for the separation of different phase noise sources. This method allows us to break down the overall phase noise sources associated with a specific comb-line into distinct phase noise components associated with the common mode, the repetition rate and the residual phase noise terms. The measurement method allow us, for the first time, to identify and measure residual phase noise sources of a frequency modulated mode-locked laser.

Buoyancy and hydrostatic balance in a West Indian Ocean coelacanth Latimeria chalumnae.

BACKGROUND: Buoyancy and balance are important parameters for slow-moving, low-metabolic, aquatic organisms. The extant coelacanths have among the lowest metabolic rates of any living vertebrate and can afford little energy to keep station. Previous observations on living coelacanths support the hypothesis that the coelacanth is neutrally buoyant and in close-to-perfect hydrostatic balance. However, precise measurements of buoyancy and balance at different depths have never been made.  RESULTS: Here we show, using non-invasive imaging, that buoyancy of the coelacanth closely matches its depth distribution. We found that the lipid-filled fatty organ is well suited to support neutral buoyancy, and due to a close-to-perfect hydrostatic balance, simple maneuvers of fins can cause a considerable shift in torque around the pitch axis allowing the coelacanth to assume different body orientations with little physical effort. CONCLUSIONS: Our results demonstrate a close match between tissue composition, depth range and behavior, and our collection-based approach could be used to predict depth range of less well-studied coelacanth life stages as well as of deep sea fishes in general.

Aromatic Polyphenol π-π Interactions with Superoxide Radicals Contribute to Radical Scavenging and Can Make Polyphenols Mimic Superoxide Dismutase Activity.

Polyphenols are valuable natural antioxidants present in our diet that likely mitigate aging effects, neurodegenerative conditions, and other diseases. However, because of their poor absorption in the gut and consequent low concentration in biological fluids (µM range), reservations about polyphenol antioxidant efficiency have been raised. In this review, it is shown that after scavenging superoxide radicals, coumarin, chalcone, and flavonoid polyphenols can reform themselves, becoming ready for additional cycles of scavenging, similar to the catalytic cycle in superoxide dismutase (SOD) action. The π-π interaction between one polyphenol ring and superoxide is associated with oxidation of the latter due to transfer of its unpaired electron to a polyphenolic aromatic ring, and consequent formation of a molecule of O2 (one product of SOD action). Mechanistically, it is very difficult to establish if this π-π interaction proceeds before or after the most common mode of scavenging superoxide, e.g., abstraction of an aromatic polyphenol H(hydroxyl), which then is used to form H2O2 (the other molecule produced by SOD action). At the end of this cycle of superoxide scavenging, 4-methyl-7,8-di-hydroxy-coumarin and the flavonoid galangin reform themselves. An alternative mechanistic pathway by galangin forms the η-(H2O2)-galangin-η-O2 complex that includes additional H2O2 and O2 molecules. Another mode of action is seen with the chalcone butein, in which the polyphenol system incorporates a molecule of O2, e.g., a η-O2-butein complex is formed, ready for additional scavenging. Of the several families of polyphenols analyzed in this review, only butein was able to circumvent an initial π-π interaction, directing the superoxide towards H(hydroxyl) in position 4, e.g., acting as a typical polyphenol scavenger of superoxide. This fact did not impede an additional superoxide to later react with the aromatic ring in π-π fashion. It is concluded that by mimicking SOD enzyme action, the low concentration of polyphenols in biological fluids is not a limiting factor for effective scavenging of superoxide.

Conversion of the MDHAQ to the HAQ score: a simple algorithm developed and validated in a cohort of 13 391 real-world patients.

OBJECTIVES: To develop and validate in real-world patients a conversion algorithm from the Multidimensionel Health Assessment Questionnaire physical function scale (MDHAQ) to the Stanford Health Assessment Questionnaire disability index physical function scale (HAQ) score. METHODS: From the DANBIO registry, 13 391 patients with RA (n = 8983), PsA (n = 2649) and axial spondyloarthritis (axSpA, n = 1759) with longitudinal data on HAQ and MDHAQ were included, stratified by diagnosis, and randomized 1:1 into development and validation cohorts. Conversion algorithms were developed by linear regression and applied in validation cohorts. From MDHAQ, the HAQ was calculated (cHAQ) and validated against the observed HAQ for criterion, correlational and construct validity. RESULTS: For RA, we developed the conversion algorithm cHAQ = 0.15+MDHAQ*1.08, and validated it in the RA validation cohort. Criterion validity: HAQ and cHAQ had comparable discriminative power to distinguish between high and low patient global scores (standardized mean difference: HAQ:-1.29, cHAQ:-1.35). Kappa value between HAQ and cHAQ functional states indicated good agreement (0.83). Correlational validity: baseline HAQ and cHAQ, respectively, correlated well with patient global scores (r = 0.65/0.67). Bland-Altman plots showed good agreement across all functional states. Construct validity: HAQ and cHAQ discriminated equally well between patients reporting symptom state as acceptable vs not, and across responses to an external anchor. Aiming for a common algorithm, the RA conversion algorithm was validated for PsA and axSpA with similar results. CONCLUSION: This study suggests that in observational datasets with only the MDHAQ available, a simple algorithm allows valid conversion to HAQ on the group level in RA, PsA and axSpA.

Observation of two-wave mixing in a single-frequency fiber amplifier induced by frequency modulation.

We report on the observation of unstable two-wave mixing in a Yb-doped optical fiber amplifier induced by frequency modulation of a single-frequency laser. What is believed to be a reflection of the main signal experiences a gain much higher than that provided by the optical pumping and potentially limits power scaling under frequency modulation. We propose an explanation for the effect based on the dynamic population and refractive index gratings formed by the interference between the main signal and its slightly frequency-detuned reflection.

Flexible inclusion of dialogue about psychosocial aspects of life with type 1 diabetes in routine consultations: A study of a questionnaire-based dialogue tool to promote person-centred support.

AIMS: To explore (1) experiences among people with type 1 diabetes and diabetologists of using a questionnaire-based dialogue tool in routine consultations to identify and address psychosocial challenges and (2) experiences of person-centredness in this group compared with a group who did not use the tool. METHODS: In all, 42 people with type 1 diabetes (mean age 54 years, mean diabetes duration 31 years and 60% women) were interviewed and completed an evaluation questionnaire following a routine consultation with the use of a dialogue tool including PAID-5, WHO-5 and open-ended questions. A comparison group of 42 people with type 1 diabetes attending routine consultations without the use of dialogue tools completed evaluation questionnaires. All consultations were audio recorded. Diabetologists were interviewed after completing all test consultations. Interviews were analysed using thematic text condensation. Evaluation questionnaires were analysed using descriptive statistics, chi square tests and Student's two-sided t-tests. RESULTS: Most participants found questions in the dialogue tool relevant to discuss with the diabetologist, and two-thirds were satisfied with the time spent on that. Experiences of people with type 1 diabetes and diabetologists were related to three pathways: (1) the tool supported valuable conversations with the diabetologist, (2) conversations with the diabetologist were unchanged and (3) the tool derailed conversations. All participants reported high levels of person centredness; however, significantly more in the comparison group reported that the diabetologist made them feel at ease (80 vs. 55%) and discussed and planned specific changes with them (93 vs. 67%). CONCLUSION: A questionnaire-based dialogue tool in consultations can support the discussion of psychosocial issues of people with type 1 diabetes. However, flexible and tailored use of the dialogue tool is crucial as consultations may otherwise be derailed.

Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment.

The inflammatory protease caspase-1 is associated with the release of cytokines. An excessive number of cytokines (a "cytokine storm") is a dangerous consequence of COVID-19 infection and has been indicated as being among the causes of death by COVID-19. The anti-inflammatory drug colchicine (which is reported in the literature to be a caspase-1 inhibitor) and the corticosteroid drugs, dexamethasone and methylprednisolone, are among the most effective active compounds for COVID-19 treatment. The SERM raloxifene has also been used as a repurposed drug in COVID-19 therapy. In this study, inhibition of caspase-1 by these four compounds was analyzed using computational methods. Our aim was to see if the inhibition of caspase-1, an important biomolecule in the inflammatory response that triggers cytokine release, could shed light on how these drugs help to alleviate excessive cytokine production. We also measured the antioxidant activities of dexamethasone and colchicine when scavenging the superoxide radical using cyclic voltammetry methods. The experimental findings are associated with caspase-1 active site affinity towards these compounds. In evaluating our computational and experimental results, we here formulate a mechanism for caspase-1 inhibition by these drugs, which involves the active site amino acid Cys285 residue and is mediated by a transfer of protons, involving His237 and Ser339. It is proposed that the molecular moiety targeted by all of these drugs is a carbonyl group which establishes a S(Cys285)-C(carbonyl) covalent bond.

Comparative effectiveness of two adalimumab biosimilars in 1318 real-world patients with inflammatory rheumatic disease mandated to switch from originator adalimumab: nationwide observational study emulating a randomised clinical trial.

OBJECTIVES: In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). METHODS: Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months' remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). RESULTS: Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months' remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. CONCLUSION: This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.

Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial.

OBJECTIVES: Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA). METHODS: In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26. RESULTS: Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)). CONCLUSIONS: In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA. TRIAL REGISTRATION NUMBER: NCT03058900.

Impact of the COVID-19 pandemic on treat-to-target strategies and physical consultations in >7000 patients with inflammatory arthritis.

OBJECTIVES: To explore the impact of the COVID-19 pandemic on treat-to-target strategies (disease activity, remission rates) and access to physical consultations in patients with inflammatory rheumatic disease, as well as to explore characteristics of patients with/without physical consultations in the clinic and the impact of early vs established disease. METHODS: Patients with RA, PsA or axial SpA (axSpA) prospectively followed in the nationwide DANBIO registry answered online questionnaires and reported patient-reported outcomes (PROs) in June and November 2020. Patient characteristics, disease activity and physical consultations in the clinic before and during the pandemic were identified in DANBIO [all patients and subgroups with early disease (disease duration ≤2 years)]. In individual patients, changes in PROs before and during the pandemic were calculated. Characteristics of patients with/without physical consultations were described (age, gender, education level, comorbidities, disease duration, treatment). RESULTS: We included 7836 patients (22% of eligible patients), 12% of which had early disease. PROs were stable before and during the pandemic, with median changes approximating zero, as well as in patients with early disease. Remission rates were stable. The relative decrease in the number of patients with physical consultations was 21-72%, which was highest in axSpA. Characteristics of patients with/without physical consultations were similar. Self-reported satisfaction with treatment options and access was >70%; the preferred contact form was physical consultation (66%). CONCLUSION: In this nationwide study performed during the first 8 months of the pandemic, patient satisfaction was high and the PROs and remission rates remained stable despite the remarkable reduction in physical consultations, as well as in patients with early disease. Characteristics of patients with/without physical consultations appeared similar.

Glossary on atmospheric electricity and its effects on biology.

There is an increasing interest to study the interactions between atmospheric electrical parameters and living organisms at multiple scales. So far, relatively few studies have been published that focus on possible biological effects of atmospheric electric and magnetic fields. To foster future work in this area of multidisciplinary research, here we present a glossary of relevant terms. Its main purpose is to facilitate the process of learning and communication among the different scientific disciplines working on this topic. While some definitions come from existing sources, other concepts have been re-defined to better reflect the existing and emerging scientific needs of this multidisciplinary and transdisciplinary area of research.

Evaluation of the Free Radical Scavenging Activities of Ellagic Acid and Ellagic Acid Peracetate by EPR Spectrometry.

The purpose of this study was to examine the free radical scavenging and antioxidant activities of ellagic acid (EA) and ellagic acid peracetate (EAPA) by measuring their reactions with the radicals, 2,2-diphenyl-1-picrylhydrazyl and galvinoxyl using EPR spectroscopy. We have also evaluated the influence of EA and EAPA on the ROS production in L-6 myoblasts and rat liver microsomal lipid peroxidation catalyzed by NADPH. The results obtained clearly indicated that EA has tremendous ability to scavenge free radicals, even at concentration of 1 µM. Interestingly even in the absence of esterase, EAPA, the acetylated product of EA, was also found to be a good scavenger but at a relatively slower rate. Kinetic studies revealed that both EA and EAPA have ability to scavenge free radicals at the concentrations of 1 µM over extended periods of time. In cellular systems, EA and EAPA were found to have similar potentials for the inhibition of ROS production in L-6 myoblasts and NADPH-dependent catalyzed microsomal lipid peroxidation.

GLP-1-induced renal vasodilation in rodents depends exclusively on the known GLP-1 receptor and is lost in prehypertensive rats.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.

Alanine, arginine, cysteine, and proline, but not glutamine, are substrates for, and acute mediators of, the liver-α-cell axis in female mice.

The aim of this study was to identify the amino acids that stimulate glucagon secretion in mice and whose metabolism depends on glucagon receptor signaling. Pancreata of female C57BL/6JRj mice were perfused with 19 individual amino acids and pyruvate (at 10 mM), and secretion of glucagon was assessed using a specific glucagon radioimmunoassay. Separately, a glucagon receptor antagonist (GRA; 25-2648, 100 mg/kg) or vehicle was administered to female C57BL/6JRj mice 3 h before an intraperitoneal injection of four different isomolar amino acid mixtures (in total 7 µmol/g body wt) as follows: mixture 1 contained alanine, arginine, cysteine, and proline; mixture 2 contained aspartate, glutamate, histidine, and lysine; mixture 3 contained citrulline, methionine, serine, and threonine; and mixture 4 contained glutamine, leucine, isoleucine, and valine. Blood glucose, plasma glucagon, amino acid, and insulin concentrations were measured using well-characterized methodologies. Alanine (P = 0.03), arginine (P < 0.0001), cysteine (P = 0.01), glycine (P = 0.02), lysine (P = 0.02), and proline (P = 0.03), but not glutamine (P = 0.9), stimulated glucagon secretion from the perfused mouse pancreas. However, when the four isomolar amino acid mixtures were administered in vivo, the four mixtures elicited similar glucagon responses (P > 0.5). Plasma concentrations of total amino acids in vivo were higher after administration of GRA when mixture 1 (P = 0.004) or mixture 3 (P = 0.04) were injected. Our data suggest that alanine, arginine, cysteine, and proline, but not glutamine, are involved in the acute regulation of the liver-α-cell axis in female mice, as they all increased glucagon secretion and their disappearance rate was altered by GRA.

Glucagon receptor signaling is not required for N-carbamoyl glutamate- and l-citrulline-induced ureagenesis in mice.

Glucagon regulates the hepatic amino acid metabolism and increases ureagenesis. Ureagenesis is activated by N-acetylglutamate (NAG), formed via activation of N-acetylglutamate synthase (NAGS). With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we investigated whether glucagon receptor-mediated activation of ureagenesis is required in a situation where NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle in vivo. Female C57BL/6JRj mice treated with a glucagon receptor antagonist (GRA), glucagon receptor knockout (Gcgr-/-) mice, and wild-type (Gcgr+/+) littermates received an intraperitoneal injection of N-carbamoyl glutamate (Car; a stable variant of NAG), l-citrulline (Cit), Car and Cit (Car + Cit), or PBS. In separate experiments, Gcgr-/- and Gcgr+/+ mice were administered N-carbamoyl glutamate and l-citrulline (wCar + wCit) in the drinking water for 8 wk. Car, Cit, and Car + Cit significantly (P < 0.05) increased plasma urea concentrations, independently of pharmacological and genetic disruption of glucagon receptor signaling (P = 0.9). Car increased blood glucose concentrations equally in GRA- and vehicle-treated mice (P = 0.9), whereas the increase upon Car + Cit was impaired in GRA-treated mice (P = 0.008). Blood glucose concentrations remained unchanged in Gcgr-/- mice upon Car (P = 0.2) and Car + Cit (P = 0.9). Eight weeks administration of wCar + wCit did not change blood glucose (P > 0.2), plasma amino acid (P > 0.4), and urea concentrations (P > 0.3) or the area of glucagon-positive cells (P > 0.3) in Gcgr-/- and Gcgr+/+ mice. Our data suggest that glucagon-mediated activation of ureagenesis is not required when NAGS activity and/or NAG levels are sufficient to activate the first step of the urea cycle.NEW & NOTEWORTHY Hepatic ureagenesis is essential in amino acid metabolism and is importantly regulated by glucagon, but the exact mechanism is unclear. With the aim to identify the steps whereby glucagon both acutely and chronically regulates ureagenesis, we here show, contrary to our hypothesis, that glucagon receptor-mediated activation of ureagenesis is not required when N-acetylglutamate synthase activity and/or N-acetylglutamate levels are sufficient to activate the first step of the urea cycle in vivo.