FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease.

Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non-diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism

The imperialist claws of MetaCapitalism

The information and industrial revolutions are so different and yet similar. Both enjoyed the emergence of accounting measurement and management techniques which privileged the efficient allocation of resources as the principal imperative to a firm\u27s participation in a free market economy. MetaCapitalism is one such corporate change strategy which promised untold wealth and unprecedented growth, and under that guise a predatory Darwinistic corporate strategy was implemented. Fundamentally, it promotes extreme outsourcing and downsizing of human capital, de-capitalisation of all non-core capital assets and the diminished role of the State in the global free market economy. Yet the most disturbing aspect is its complete and total disregard for even the slightest social or public policy implications. Essentially then, its most salient danger is an unmistakable endorsement of a fundamentalist brand of value free, reckless capitalism that is ultimately detrimental not only to the long-term business interest, but human as well. One of the main findings of evaluating the Fortune 100 companies\u27 performance in implementing MetaCapitalism was the resulting monopolies. Lenin described monopolies as essential to imperialism which is the highest stage of capitalism. The parallels between the resulting monopolies under MetaCapitalism, and what Lenin described as the final stage of Capitalism are poignant. I would like to draw upon those parallels in the hope that earlier work might enlighten our understanding and inform our critique of MetaCapiatlism

The relationship of neutrophil elastase and proteinase 3 with risk factors, and chronic complications in type 2 diabetes: A Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) sub-study

Introduction: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. Methods: Plasma NE and PR3 levels were quantified at baseline (n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels (n = 200) were determined at four follow-up visits. Results: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. Conclusions: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate

Metabolomics Reveals Reduction of Metabolic Oxidation in Women with Polycystic Ovary Syndrome after Pioglitazone-Flutamide-Metformin Polytherapy

Polycystic ovary syndrome (PCOS) is a variable disorder characterized by a broad spectrum of anomalies, including hyperandrogenemia, insulin resistance, dyslipidemia, body adiposity, low-grade inflammation and increased cardiovascular disease risks. Recently, a new polytherapy consisting of low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen resulted in the regulation of endocrine clinical markers in young and non-obese PCOS women. However, the metabolic processes involved in this phenotypic amelioration remain unidentified. In this work, we used NMR and MS-based untargeted metabolomics to study serum samples of young non-obese PCOS women prior to and at the end of a 30 months polytherapy receiving low-dose flutamide, metformin and pioglitazone in combination with an estro-progestagen. Our results reveal that the treatment decreased the levels of oxidized LDL particles in serum, as well as downstream metabolic oxidation products of LDL particles such as 9- and 13-HODE, azelaic acid and glutaric acid. In contrast, the radiuses of small dense LDL and large HDL particles were substantially increased after the treatment. Clinical and endocrine-metabolic markers were also monitored, showing that the level of HDL cholesterol was increased after the treatment, whereas the level of androgens and the carotid intima-media thickness were reduced. Significantly, the abundance of azelaic acid and the carotid intima-media thickness resulted in a high degree of correlation. Altogether, our results reveal that this new polytherapy markedly reverts the oxidant status of untreated PCOS women, and potentially improves the pro-atherosclerosis condition in these patients

Skin fluorescence as a clinical tool for non-invasive assessment of advanced glycation and long-term complications of diabetes

Glycation is important in the development of complications of diabetes mellitus and may have a central role in the well-described glycaemic memory effect in developing these complications. Skin fluorescence has emerged over the last decade as a non-invasive method for assessing accumulation of advanced glycation endproducts. Skin fluorescence is independently related to micro- and macrovascular complications in both type 1 and type 2 diabetes mellitus and is associated with mortality in type 2 diabetes. The relation between skin fluorescence and cardiovascular disease also extends to other conditions with increased tissue AGE levels, such as renal failure. Besides cardiovascular complications, skin fluorescence has been associated, more recently, with other prevalent conditions in diabetes, such as brain atrophy and depression. Furthermore, skin fluorescence is related to past long-term glycaemic control and clinical markers of cardiovascular disease. This review will discuss the technique of skin fluorescence, its validation as a marker of tissue AGE accumulation, and its use as a clinical tool for the prediction of long-term complications in diabetes mellitus

HbA1c variability in adults with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy compared to multiple daily injection (MDI) treatment.

OBJECTIVE: To determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM). DESIGN: Retrospective audit. SETTING AND PARTICIPANTS: Clinic records from 506 adults with T1DM from two tertiary Australian hospitals. OUTCOME MEASURES: Long-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII. RESULTS: Adults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both p<0.001. Fifty-six adults (73% female, age 36±13 years, 16±13 years diabetes, HbA1c 7.8%±0.8% (62±9 mmol/mol)) transitioned from MDI to CSII. Mean HbA1c fell by 0.4%. GV from 1 year post-CSII commencement decreased significantly, HbA1c SD pre-CSII versus post-CSII 0.7%±0.5% (8±5 mmol/mol) vs 0.4%±0.4% (5±4 mmol/mol); p<0.001, and HbA1c CV 9.2%±5.5% (13±8 mmol/mol) vs 6.1%±3.9% (9±5 mmol/mol); p<0.001. CONCLUSIONS: In clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV

Cross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men.

Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35-80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross-sectional associations between age (β = 0.409, p<0.001), TT (β = 0.560, p<0.001), fT4 (β = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (β = -0.112, p<0.001), abdominal fat mass (β = -0.068, p = 0.032) and E2 (β = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (β = 0.406, p = <0.001), TT (β = 0.461, p = <0.001), and fT4 (β = 0.040, p = 0.034) and negative determinants were triglycerides (β = -0.065, p = 0.027) and abdominal fat mass (β = -0.078, p = 0.032). Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4