Non-transferrin-bound iron is associated with biomarkers of oxidative stress, inflammation and endothelial dysfunction in type 2 diabetes.

AIMS: To investigate the association between circulating non-transferrin-bound iron [NTBI], and markers of oxidative stress, endothelial function and inflammation in subjects with type 2 diabetes and non-diabetic subjects with varying degrees of obesity. METHODS: Plasma NTBI was measured by HPLC, together with total iron, iron-binding capacity, transferrin saturation and soluble transferrin receptor, together with total and reduced ascorbate, malondialdehyde [MDA], E-selectin and high-sensitivity c-reactive protein [hs-CRP] in groups of 28 subjects with type 2 diabetes, 28 non-obese controls and 17 obese non-diabetic subjects. RESULTS: Levels of NTBI were higher than controls in the diabetes group, but the total serum iron levels were lower. MDA levels were higher than controls in both the diabetes and obese groups, and this was associated with higher levels of oxidised ascorbate. hs-CRP levels were higher in both the diabetes and obese groups, and E-selectin was significantly higher in the diabetes group. There were strong positive correlations between HbA1c levels and NTBI [P<0.01], HbA1c and E-selectin [P<0.001] and NTBI and E-selectin [P<0.02] in the diabetes group. CONCLUSION: These results support the hypothesis that iron-mediated oxidative stress may be a mechanism linking poor glycaemic control with vascular dysfunction in type 2 diabetes

Regulation of the fibrosis and angiogenesis promoter SPARC/osteonectin in human adipose tissue by weight change, leptin, insulin, and glucose

This is the final version of the article. Available from the publisher via the DOI in this record.OBJECTIVE: Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS: Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. RESULTS: SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. CONCLUSIONS: Our data suggest that SPARC expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.This work was supported by Diabetes UK, Swedish Research Council (11285), University Hospital of Linkoping Research Funds; Diabetes Research Centre of Linkoping University; and the Gamla Tjaenarinnor Foundation. No potential conflicts of interest relevant to this article were reported. Parts of this study were presented in abstract form at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5–9 June 2009

Does treating obesity stabilize chronic kidney disease?

BACKGROUND: Obesity is a growing health issue in the Western world. Obesity, as part of the metabolic syndrome adds to the morbidity and mortality. The incidence of diabetes and hypertension, two primary etiological factors for chronic renal failure, is significantly higher with obesity. We report a case with morbid obesity whose renal function was stabilized with aggressive management of his obesity. CASE REPORT: A 43-year old morbidly obese Caucasian male was referred for evaluation of his chronic renal failure. He had been hypertensive with well controlled blood pressure with a body mass index of 46 and a baseline serum creatinine of 4.3 mg/dl (estimated glomerular filtration rate of 16 ml/min). He had failed all conservative attempts at weight reduction and hence was referred for a gastric by-pass surgery. Following the bariatric surgery he had approximately 90 lbs. weight loss over 8-months and his serum creatinine stabilized to 4.0 mg/dl. CONCLUSION: Obesity appears to be an independent risk factor for renal failure. Targeting obesity is beneficial not only for better control of hypertension and diabetes, but also possibly helps stabilization of chronic kidney failure

Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-α). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation.</p> <p>Methods</p> <p>We measured serum leptin, IGF-I, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-α, IL-1β, IL-6 and IL-8 were measured by ELISA.</p> <p>Results</p> <p>Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001). A positive correlation was observed between leptin and TNF-α on Day 1 (r = 0.620, p < 0.001). Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively).</p> <p>Conclusion</p> <p>Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later.</p

A Functional Variant of the Dimethylarginine Dimethylaminohydrolase-2 Gene Is Associated with Insulin Sensitivity

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P =3610 25). Methodology/Principal Findings: initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67633 vs.79644; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.6860.14 vs. 0.5760.14 mmol/l; P = 0.04). In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.364.1 vs. 11.064.2 mg6Kg 21 free fat mass6min 21; P = 0.009)

The uncoupling protein 1 gene, UCP1, is expressed in mammalian islet cells and associated with acute insulin response to glucose in African American families from the IRAS Family Study

BACKGROUND: Variants of uncoupling protein genes UCP1 and UCP2 have been associated with a range of traits. We wished to evaluate contributions of known UCP1 and UCP2 variants to metabolic traits in the Insulin Resistance and Atherosclerosis (IRAS) Family Study. METHODS: We genotyped five promoter or coding single nucleotide polymorphisms (SNPs) in 239 African American (AA) participants and 583 Hispanic participants from San Antonio (SA) and San Luis Valley. Generalized estimating equations using a sandwich estimator of the variance and exchangeable correlation to account for familial correlation were computed for the test of genotypic association, and dominant, additive and recessive models. Tests were adjusted for age, gender and BMI (glucose homeostasis and lipid traits), or age and gender (obesity traits), and empirical P-values estimated using a gene dropping approach. RESULTS: UCP1 A-3826G was associated with AIR(g )in AA (P = 0.006) and approached significance in Hispanic families (P = 0.054); and with HDL-C levels in SA families (P = 0.0004). Although UCP1 expression is reported to be restricted to adipose tissue, RT-PCR indicated that UCP1 is expressed in human pancreas and MIN-6 cells, and immunohistochemistry demonstrated co-localization of UCP1 protein with insulin in human islets. UCP2 A55V was associated with waist circumference (P = 0.045) in AA, and BMI in SA (P = 0.018); and UCP2 G-866A with waist-to-hip ratio in AA (P = 0.016). CONCLUSION: This study suggests a functional variant of UCP1 contributes to the variance of AIR(g )in an AA population; the plausibility of this unexpected association is supported by the novel finding that UCP1 is expressed in islets

Relativistic Dynamics and Extreme Mass Ratio Inspirals

It is now well-established that a dark, compact object (DCO), very likely a massive black hole (MBH) of around four million solar masses is lurking at the centre of the Milky Way. While a consensus is emerging about the origin and growth of supermassive black holes (with masses larger than a billion solar masses), MBHs with smaller masses, such as the one in our galactic centre, remain understudied and enigmatic. The key to understanding these holes - how some of them grow by orders of magnitude in mass - lies in understanding the dynamics of the stars in the galactic neighbourhood. Stars interact with the central MBH primarily through their gradual inspiral due to the emission of gravitational radiation. Also stars produce gases which will subsequently be accreted by the MBH through collisions and disruptions brought about by the strong central tidal field. Such processes can contribute significantly to the mass of the MBH and progress in understanding them requires theoretical work in preparation for future gravitational radiation millihertz missions and X-ray observatories. In particular, a unique probe of these regions is the gravitational radiation that is emitted by some compact stars very close to the black holes and which could be surveyed by a millihertz gravitational wave interferometer scrutinizing the range of masses fundamental to understanding the origin and growth of supermassive black holes. By extracting the information carried by the gravitational radiation, we can determine the mass and spin of the central MBH with unprecedented precision and we can determine how the holes "eat" stars that happen to be near them.Comment: Update from the first version, 151 pages, accepted for publication @ Living Reviews in Relativit

Right Iliac Fossa Pain Treatment (RIFT) Study: protocol for an international, multicentre, prospective observational study

Introduction Patients presenting with right iliac fossa (RIF) pain are a common challenge for acute general surgical services. Given the range of potential pathologies, RIF pain creates diagnostic uncertainty and there is subsequent variation in investigation and management. Appendicitis is a diagnosis which must be considered in all patients with RIF pain; however, over a fifth of patients undergoing appendicectomy, in the UK, have been proven to have a histologically normal appendix (negative appendicectomy). The primary aim of this study is to determine the contemporary negative appendicectomy rate. The study’s secondary aims are to determine the rate of laparoscopy for appendicitis and to validate the Appendicitis Inflammatory Response (AIR) and Alvarado prediction scores. Methods and analysis This multicentre, international prospective observational study will include all patients referred to surgical specialists with either RIF pain or suspected appendicitis. Consecutive patients presenting within 2-week long data collection periods will be included. Centres will be invited to participate in up to four data collection periods between February and August 2017. Data will be captured using a secure online data management system. A centre survey will profile local policy and service delivery for management of RIF pain. Ethics and dissemination Research ethics are not required for this study in the UK, as determined using the National Research Ethics Service decision tool. This study will be registered as a clinical audit in participating UK centres. National leads in countries outside the UK will oversee appropriate registration and study approval, which may include completing full ethical review. The study will be disseminated by trainee-led research collaboratives and through social media. Peer-reviewed publications will be published under corporate authorship including ‘RIFT Study Group’ and ‘West Midlands Research Collaborative’