Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis

Chemerin acting via its distinct G protein-coupled receptor CMKLR1 (ChemR23), is a novel adipokine, circulating levels of which are raised in inflammatory states. Chemerin shows strong correlation with various facets of the metabolic syndrome; these states are associated with an increased incidence of cardiovascular disease (CVD) and dysregulated angiogenesis. We therefore, investigated the regulation of ChemR23 by pro-inflammatory cytokines and assessed the angiogenic potential of chemerin in human endothelial cells (EC). We have demonstrated the novel presence of ChemR23 in human ECs and its significant up-regulation (P < 0.001) by pro-inflammatory cytokines, TNF-α, IL-1β and IL-6. More importantly, chemerin was potently angiogenic, as assessed by conducting functional in-vitro angiogenic assays; chemerin also dose-dependently induced gelatinolytic (MMP-2 & MMP-9) activity of ECs (P < 0.001). Furthermore, chemerin dose-dependently activated PI3K/Akt and MAPKs pathways (P < 0.01), key angiogenic and cell survival cascades. Our data provide the first evidence of chemerin-induced endothelial angiogenesis and MMP production and activity

Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study

Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible. Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study). Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk

Corticotropin-releasing factor receptors couple to multiple g-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning

Corticotropin-releasing factor (CRF) exerts a key neuroregulatory control on stress responses in various regions of the mammalian brain, including the hippocampus. Using hippocampal slices, extracts, and whole animals, we investigated the effects of human/rat CRF (h/rCRF) on hippocampal neuronal excitability and hippocampus-dependent learning in two mouse inbred strains, BALB/c and C57BL/6N. Intracellular recordings from slices revealed that application of h/rCRF increased the neuronal activity in both mouse inbred strains. Inhibition of protein kinase C (PKC) by bisindolylmaleimide I (BIS-I) prevented the h/rCRF effect only in hippocampal slices from BALB/c mice but not in slices from C57BL/6N mice. Inhibition of cAMP-dependent protein kinase (PKA) by H-89 abolished the h/rCRF effect in slices from C57BL/6N mice, with no effect in slices from BALB/c mice. Accordingly, h/rCRF elevated PKA activity in hippocampal slices from C57BL/6N mice but increased only PKC activity in the hippocampus of BALB/c mice. These differences in h/rCRF signal transduction were also observed in hippocampal membrane suspensions from both mouse strains. In BALB/c mice, hippocampal CRF receptors coupled to Gq/11 during stimulation by h/rCRF, whereas they coupled to Gs, Gq/11, and Gi in C57BL/6N mice. As expected on the basis of the slice experiments, h/rCRF improved context-dependent fear conditioning of BALB/c mice in behavioral experiments, and BIS-I prevented this effect. However, although h/rCRF increased neuronal spiking in slices from C57BL/6N mice, it did not enhance conditioned fear. These results indicate that the CRF system activates different intracellular signaling pathways in mouse hippocampus and may have distinct effects on associative learning depending on the mouse strain investigated

Atherosclerotic and Cardio-Metabolic Diseases::From Molecular Basis to Therapeutic Advances

Cardiovascular diseases (CVDs) still remain the major cause of death worldwide; however, CVD-related mortality has been reduced due to lifestyle modification interventions, as well as novel pharmacological therapies and advances in cardiovascular surgery [...

Familial Hypercholesterolemia::New Horizons for Diagnosis and Effective Management

Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). The reported prevalence rates for both heterozygous FH (HeFH) and homozygous FH (HoFH) vary significantly, and this can be attributed, at least in part, to the variable diagnostic criteria used across different populations. Due to lack of consistent data, new global registries and unified guidelines are being formed, which are expected to advance current knowledge and improve the care of FH patients. This review presents a comprehensive overview of the pathophysiology, epidemiology, manifestations, and pharmacological treatment of FH, whilst summarizing the up-to-date relevant recommendations and guidelines. Ongoing research in FH seems promising and novel therapies are expected to be introduced in clinical practice in order to compliment or even substitute current treatment options, aiming for better lipid-lowering effects, fewer side effects, and improved clinical outcomes

Retinol-binding protein 4 (RBP-4) levels do not change after oral glucose tolerance test and after dexamethasone, but correlate with some indices of insulin resistance in humans

Introduction: Secretory products from adipocytes may contribute to deterioration in glycaemic control and increased insulin resistance (IR). Retinol-binding protein 4 (RBP-4) may increase IR in mice, with elevated levels in insulin-resistant mice and humans with obesity and type 2 diabetes. However, the mechanisms regulating RBP-4 synthesis remain not fully understood. It is not clear whether short-term glucose-induced hyperglycaemia and hyperinsulinaemia as well as glucocorticosteroid-induced increase in IR might be reflected in alterations in serum RBP-4 levels in humans. In order to investigate this, we measured serum RBP-4, glucose and insulin concentrations during 75.0 gram oral glucose tolerance test (OGTT) - Study 1, as well as before and after oral administration of dexamethasone - Study 2. Material and methods: Both studies included 35 subjects (8 males), age (mean &#177; SD) 39.1 &#177; 15.6 years, BMI 35.8 &#177; 8.7 kg/m2. Twenty-four of those subjects (5 males), age 38.7 &#177; 15.1 years, BMI 34.4 &#177; 8.3 kg/m2, had 75 gram oral glucose tolerance test (OGTT) - Study 1. Blood samples were taken before (0 minutes), and at 60 and 120 minutes of OGTT. 17 subjects (3 males, 4 subjects with type 2 diabetes), age 43.1 &#177; 18.1 years, BMI 36.7 &#177; 9.0 kg/m2 underwent screening for Cushing&#8217;s disease/syndrome (Study 2). Dexamethasone was administered in a dose of 0.5 mg every 6 hours for 48 hours. Fasting serum concentrations of RBP-4, glucose and insulin were assessed before (D0) and after 48 hours of dexamethasone administration (D2). IR was assessed by HOMA in all non-diabetic subjects and in subjects participating in study 1 also by Insulin Resistance Index (IRI), which takes into account glucose and insulin levels during OGTT. Results: Glucose administration resulted in significant increases in insulin and glucose (p < 0.0001). There was, however, no change in RBP-4 concentrations (124.1 &#177; 32 mg/ml at 0 minutes, 123 &#177; 35 mg/ml at 60 minutes and 126.5 &#177; 37.5 mg/ml at 120 minutes of OGTT, p = ns). All subjects in Study 2 achieved suppression of cortisol below 50 nmo/l. Dexamethasone administration resulted in an increase in fasting insulin (from 11.6 &#177; 6.8 to 17.1 &#177; 7.2 &#956;U/ml; p = 0.003), and an increase in HOMA (from 2.73 &#177; 1.74 to 4.02 &#177; 2.27; p = 0.015), although without a significant change in RBP-4 levels (119 &#177; 26.8 vs. 117.5 &#177; 24.8 mg/ml, p = ns). RBP-4 correlated with fasting insulin (r = 0.40, p = 0.025), fasting glucose (r = 0.41, p = 0.02) and HOMA (r = 0.43, p = 0.015), but not with IRI (r = 0.19, p = 0.31). There was, however, only a moderate correlation between HOMA and IRI (r = 0.49 [r2 = 0.24]; p = 0.006, Spearman rank correlation), while the best correlation was obtained between the product of glucose and insulin levels at 60 min of OGTT and IRI in a non-linear model (r = 0.94 [r2 = 0.88]; pWstęp: Niektóre substancje syntetyzowane przez adipocyty mogą zwiększać insulinooporność oraz nasilać zaburzenia tolerancji glukozy. Białko wiążące retinol 4 (RBP-4) nasila insulinooporność u myszy, zaś podwyższone stężenia RBP-4 obserwuje się u myszy z insulinoopornością oraz u osób z otyłością i cukrzycą typu 2. Mechanizmy regulujące syntezę RBP-4 nie są do końca poznane. Między innymi nie howiadomo czy krótkotrwała hiperglikemia i hiperinsulinemia po podaniu glukozy, jak również zwiększona insulinooporność wyidukowana glukokortykosteroidami mogą w istotny sposób zmienić stężenie RBP-4 w surowicy u ludzi. W związku z tym autorzy artykułu ocenili stężenie RBP-4, glukozy i insuliny w teście doustnego obciążenia glukozą (75 g) (OGTT) - badanie 1, oraz przed i po doustnym podaniu deksametazonu - badanie 2. Materiał i metody: W obu badaniach uczestniczyło 35 osób (8 mężczyzn) w wieku 39,1 &#177; 15,6 lat, BMI 35,8 &#177; 8,7 kg/m2 (średnia &#177; SD). Spośród nich u 24 osób (5 mężczyzn) w wieku 38,7 &#177; 15,1 lat, BMI 34,4 &#177; 8,3 kg/m2 wykonano OGTT (badanie 1). Krew pobierano przed (0 minuta) oraz w 60. i 120. minucie OGTT. Badanie 2 objęło 17 osób (3 mężczyzn, 4 osoby z cukrzycą typu 2) poddanych badaniu przesiewowemu pod kątem choroby/zespołu Cushinga w wieku 43,1 &#177; 18,1 lat, BMI 36,7 &#177; 9,0 kg/m2. Deksametazon podawano co 6 godzin w dawce 0,5 mg przez 48 godzin. Stężenia RBP-4, glukozy i insuliny w surowicy oznaczono na czczo przed (D0) i po 48 godzinach podawania deksametazonu (D2). U osób niechorujących na cukrzycę IR oceniano metodą HOMA, zaś w badaniu 1 również według Insulin Resistance Index (IRI) obliczanego na podstawie zmian stężeń insuliny i glukozy podczas OGTT. Wyniki: Podczas OGTT w badaniu 1 wzrosły stężenia insuliny i glukozy (p < 0,001), przy braku istotnych zmian stężeń RBP-4 (124,1 &#177; 32 mg/ml w 0 min, 123 &#177; 35 mg/ml w 60. min i 126,5 &#177; 37,5 mg/ml w 120. min OGTT, p = ns). W badaniu 2 u wszystkich osób uzyskano supresję stężenia kortyzolu do wartości poniżej 50 nmo/l. Skutkiem podania deksametazonu był wzrost stężeń insuliny na czczo (z 11,6 &#177; 6,8 do 17,1 &#177; 7,2 &#956;U/ml; p = 0,003) oraz wzrost współczynnika HOMA (z 2,73 &#177; 1,74 do 4,02 &#177; 2,27; p = 0,015). Nie zaobserwowano jednak istotnych zmian stężeń RBP-4 (119 &#177; 26,8 mg/ml vs. 117,5 &#177; 24,8 mg/ml, p = ns). Stężenia RBP-4 korelowały z insulinemią na czczo (r = 0,40, p = 0,025), glukozą na czczo (r = 0,41, p = 0,02) oraz z HOMA (r = 0,43, p = 0,015), lecz już nie z IRI (r = 0,19, p = 0,31). Stwierdzono obecność korelacji pomiedzy indeksami insulinooporności HOMA i IRI (r = 0.49 [r2 = 0,24], p = 0,006, współczynnik korelacji rang Spearmana), lecz znacznie silniejszą korelację obserwowano dopiero miedzy IRI a iloczynem stężeń insuliny i glukozy w 60. minucie OGTT (r = 0,94 [r2 = 0,88];

Risk factors for readmission of inpatients with Diabetes : a systematic review

Aim We have limited understanding of which risk factors contribute to increased readmission rates amongst people discharged from hospital with diabetes. We aim to complete the first review of its kind, to identify, in a systematic way, known risk factors for hospital readmission amongst people with diabetes, in order to better understand this costly complication. Method The review was prospectively registered in the PROSPERO database. Risk factors were identified through systematic review of literature in PubMed, EMBASE & SCOPUS databases, performed independently by two authors prior to data extraction, with quality assessment and semi-quantitative synthesis according to PRISMA guidelines. Results Eighty-three studies were selected for inclusion, predominantly from the United States, and utilising retrospective analysis of local or regional data sets. 76 distinct statistically significant risk factors were identified across 48 studies. The most commonly identified risk factors were; co-morbidity burden, age, race and insurance type. Few studies conducted power calculations; unstandardized effect sizes were calculated for the majority of statistically significant risk factors. Conclusion This review is important in assessing the current state of the literature and in supporting development of interventions to reduce readmission risk. Furthermore, it provides an important foundation for development of rigorous, pre-specified risk prediction models

Diabetes and the direct secondary use of electronic health records : using routinely collected and stored data to drive research and understanding

Introduction Electronic health records provide an unparalleled opportunity for the use of patient data that is routinely collected and stored, in order to drive research and develop an epidemiological understanding of disease. Diabetes, in particular, stands to benefit, being a data-rich, chronic-disease state. This article aims to provide an understanding of the extent to which the healthcare sector is using routinely collected and stored data to inform research and epidemiological understanding of diabetes mellitus. Methods Narrative literature review of articles, published in both the medical- and engineering-based informatics literature. Results There has been a significant increase in the number of papers published, which utilise electronic health records as a direct data source for diabetes research. These articles consider a diverse range of research questions. Internationally, the secondary use of electronic health records, as a research tool, is most prominent in the USA. The barriers most commonly described in research studies include missing values and misclassification, alongside challenges of establishing the generalisability of results. Discussion Electronic health record research is an important and expanding area of healthcare research. Much of the research output remains in the form of conference abstracts and proceedings, rather than journal articles. There is enormous opportunity within the United Kingdom to develop these research methodologies, due to national patient identifiers. Such a healthcare context may enable UK researchers to overcome many of the barriers encountered elsewhere and thus to truly unlock the potential of electronic health records

Application of standardised effect sizes to hospital discharge outcomes for people with diabetes

Background: Patients with diabetes are at an increased risk of readmission and mortality when discharged from hospital. Existing research identifies statistically significant risk factors that are thought to underpin these outcomes. Increasingly, these risk factors are being used to create risk prediction models, and target risk modifying interventions. These risk factors are typically reported in the literature accompanied by unstandardized effect sizes, which makes comparisons difficult. We demonstrate an assessment of variation between standardised effect sizes for such risk factors across care outcomes and patient cohorts. Such an approach will support development of more rigorous risk stratification tools and better targeting of intervention measures. Methods: Data was extracted from the electronic health record of a major tertiary referral centre, over a 3-year period, for all patients discharged from hospital with a concurrent diagnosis of diabetes mellitus. Risk factors selected for extraction were pre-specified according to a systematic review of the research literature. Standardised effect sizes were calculated for all statistically significant risk factors, and compared across patient cohorts and both readmission & mortality outcome measures. Results: Data was extracted for 46,357 distinct admissions patients, creating a large dataset of approximately 10,281,400 data points. The calculation of standardized effect size measures allowed direct comparison. Effect sizes were noted to be larger for mortality compared to readmission, as well as for being larger for surgical and type 1 diabetes cohorts of patients. Conclusions: The calculation of standardised effect sizes is an important step in evaluating risk factors for healthcare events. This will improve our understanding of risk and support the development of more effective risk stratification tools to support patients to make better informed decisions at discharge from hospital