Acute effects of resistance training on cytokines and osteoprotegerin in women with metabolic syndrome

Chronic inflammation has been identified as an important component of metabolic syndrome (MetS). Inhibition of the inflammatory mediator signals is a promising strategy against insulin resistance, atherosclerosis and other problems associated with MetS. Regular exercise decreases the components associated with MetS, including inflammatory cytokines. However, the relationship between an acute resistance training (RT) session, cytokine levels and MetS is unclear. Therefore, the aim was to evaluate the effects of a single bout of acute RT on tumour necrosis factor (TNF‐α), interleukins (IL) IL‐1a, IL‐1β, IL‐12, IL‐6, IL‐10 and osteoprotegerin (OPG) in women with MetS. Twenty‐four women were divided into 2 groups: metabolic syndrome (MetS) and non‐metabolic syndrome (Non‐MetS). After the familiarization and testing for 1 repetition maximum (1RM), participants completed 3 sets of 10 repetitions in the following exercises: machine leg press, leg extension, leg curl, chest press, lat front pull‐down and machine shoulder press with 60% of 1RM followed by 15 repetitions of abdominal crunches. A rest interval of 1 min was allowed between sets and exercises. Plasma TNF‐α, IL‐1a, IL‐1β, IL‐12, IL‐6, IL‐10 and OPG were measured before, immediately post and 60 min after RT. MetS group showed significantly higher concentrations of IL‐1β (P = 0·024) and IL‐6 (P = 0·049) and a trend for higher TNF‐α values (P = 0·092) compared with Non‐MetS. There was no group × time interactions after the RT session on the measured cytokines and osteoprotegerin. In conclusion, acute RT session induced no additional increase in pro‐inflammatory cytokines nor a decrease in anti‐inflammatory cytokines and OPG in women with MetS.     

The echogenicity of the intima–media complex in the common carotid artery is related to insulin resistance measured by the hyperinsulinemic clamp in elderly men

The echogenicity of the intima–media complex (IM‐GSM) has recently been shown to be related to the echogenicity in carotid artery plaque and to predict cardiovascular (CV) mortality. The present study aims to evaluate the relationship between metabolic CV risk factors, with special emphasis on insulin resistance, and IM‐GSM in the carotid artery. Carotid artery ultrasound with grey‐scale median analysis of the intima–media complex, IM‐GSM, was performed in a population sample of 480 men aged 75 years. In these subjects, a euglycemic hyperinsulinemic clamp to investigate insulin resistance was performed together with measurements of conventional CV risk factors at the age of 70. The metabolic syndrome (MetS) was defined by the NCEP/ATPIII‐criteria. In univariate analysis, IM‐GSM in the common carotid artery was inversely correlated with the intima–media thickness (IMT), body mass index (BMI), waist/hip ratio, fasting glucose, serum triglycerides, low HDL cholesterol and insulin resistance at the clamp (r = ?0·24, P<0·001). In multiple regression analysis, only insulin resistance at the clamp and BMI were independently related to IM‐GSM. Subjects with the MetS (22%) showed a reduced IM‐GSM when compared to those without (64 ± 20 SD versus 68 ± 19, P<0·05). Because the echogenicity of the intima–media complex in the carotid artery is related to obesity and insulin resistance at clamp independently of IMT, this new vascular characteristic would serve as a marker of vascular alterations induced by insulin resistance and the MetS and has the advantage to be obtainable in almost all subjects.     

Metabolic syndrome aggravates the increased endothelial activation and low‐grade inflammation in subjects with familial low HDL

Background. Inhibition of cytokine‐induced expression of adhesion molecules is one of the atheroprotective mechanisms of high‐density lipoprotein (HDL).

Aim. We investigated whether increased endothelial activation and low‐grade inflammation are present in Finnish subjects with familial low HDL, and which factors contribute to the inflammatory parameters.

Method. High‐sensitivity C‐reactive protein (hsCRP), soluble intercellular adhesion molecule‐1 (sICAM‐1), vascular cell adhesion molecule‐1 (sVCAM‐1), and sE‐selectin were measured in 91 subjects with low HDL‐cholesterol from 41 low‐HDL families and in 112 normolipidemic controls with comparable age‐ and gender distribution. Presence of the features of the metabolic syndrome (MetS) was recorded.

Results. sVCAM‐1, sICAM‐1, sE‐selectin, and hsCRP were significantly higher in low‐HDL subjects than in the controls (sVCAM‐1: 560±147?ng/mL versus 496±95?ng/mL, P = 0.001; sICAM‐1: 247±60?ng/mL versus 215±47?ng/mL, P<0.001; sE‐selectin: 52±20?ng/mL versus 44±16?ng/mL, P = 0.022; and hsCRP: 1.73±2.05?mg/L versus 0.85±1.10?mg/L, P<0.001). Low‐HDL subjects had increased body mass index (BMI) and waist, and elevated insulin and triglyceride levels. Adhesion molecules and hsCRP increased according to the number of the features of the MetS.

Conclusions. The presence of the MetS in subjects with familial low HDL‐cholesterol aggravates the low‐grade inflammation and endothelial activation, and ultimately may add to the higher susceptibility for atherosclerotic disease in these individuals.     

Effects of 1-year orlistat treatment compared to placebo on insulin resistance parameters in patients with type 2 diabetes

What is known and Objective: The behavioural approach is usually slow and not always sufficient to achieve optimal targets in weight and metabolic control in obese diabetic patients, and a pharmacological treatment is often necessary. The aim of this study was to compare the effects of orlistat and placebo on body weight, glycaemic and lipid profile and insulin resistance in patients with type 2 diabetes. Methods: Two hundred and fifty‐four obese, diabetic patients were enrolled in this study and randomized to take orlistat 360 mg or placebo for 1 year. We evaluated at baseline and after 3, 6, 9 and 12 months body weight, waist circumference (WC), body mass index (BMI), glycated haemoglobin (HbA_1c), fasting plasma glucose (FPG), post‐prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA‐IR), lipid profile, retinol‐binding protein‐4 (RBP‐4), resistin, visfatin and high‐sensitivity C‐reactive protein (Hs‐CRP). Results and Discussion: We observed a significant reduction in body weight, WC, BMI, lipid profile, RBP‐4 and visfatin in the orlistat group but not in control group. Faster improvements in HbA_1c, PPG, FPI, HOMA‐IR, resistin and Hs‐CRP were recorded with orlistat than with placebo. A similar decrease in FPG was seen in the two groups. Significant predictors of change in insulin resistance (HOMA‐IR) were RBP‐4 and resistin concentration in the orlistat group (r = ?0·53, P < 0·05, and r = ?0·59, P < 0·01, respectively). What is new and Conclusion: To the best of our knowledge, this is the first study investigating the effect of orlistat on insulin resistance and markers of inflammation. Orlistat improved lipid profile and led to faster glycaemic control and insulin resistance parameters than the control, without any serious adverse event. Orlistat also improved RBP‐4 and visfatin, effects not observed with placebo.     

Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia

Background Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized‐low‐density lipoprotein cholesterol (ox‐LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox‐LDL lectin‐like receptor‐1 (LOX‐1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment. Materials and methods A prospective 4‐year study involving 1039 event‐free subjects (643 males, 396 females) treated with atorvastatin (10–40 mg day^?1) to reach the appropriate Adult Treatment Panel‐III LDL target of 3·36 mmol L^?1. Enrolled subjects were evaluated every 6 months or at a clinical event. LOX‐1 3′UTR/T‐C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic‐colorimetric method, ox‐LDL by enzyme linked immunosorbent assay, platelet activation by P‐selectin (P‐sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C‐reactive protein (CRP) by sensitive nephelometric technique. Results LOX‐1 3′UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4·90, 95% CI 3·19–6·98, P < 0·00001). Smoking influenced events in LDL‐targeted subjects (P < 0·0001). Ox‐LDL and P‐sel were better indicators than LDL or other variables according to 3′UTR/C genotype regardless of the magnitude of LDL reduction (OR 4·21, 95% CI 2·29–6·70 P < 0·0001). Conclusions LOX‐1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.     

Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study

Objective. To evaluate risk factors for progression from persistent microalbuminuria to diabetic nephropathy in the Irbesartan in Patients with Type 2 diabetes and Microalbuminuria (IRMA 2) study, including biomarkers of endothelial dysfunction, chronic low‐grade inflammation, growth factors and advanced glycation end products (AGE peptides). Methods. IRMA 2 was a 2‐year multicentre, randomized, double‐blind trial comparing irbesartan (150 and 300?mg once daily) versus placebo. The primary end‐point was time to onset of diabetic nephropathy. Samples from a subgroup from the placebo and the 300?mg irbesartan treatment group were used in this post‐hoc analysis (n = 269, 68?%). Nine biomarkers were analysed: high sensitivity C‐reactive protein (hs‐CRP), interleukin 6 (IL‐6), fibrinogen, von Willebrand Factor (vWf), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble intercellular cell adhesion molecule‐1 (sICAM‐1), sE‐selectin, transforming growth factor‐beta (TGF‐β) and AGE peptides. Mean standard deviation scores (Z‐scores) were used to combine biomarker information. Results. In a Cox enter model with combined Z‐scores for biomarkers of endothelial dysfunction (vWf, sVCAM‐1, sICAM‐1, sE‐selectin) and for biomarkers of inflammation (hs‐CRP, IL‐6, fibrinogen), endothelial dysfunction (hazard ratio for a 28?% increase ( = 1 SD) in Z‐score) 3.20 (1.56 to 6.56), p = 0.001) and UAER (HR for a 75?% increase ( = 1 SD) in UAER) 2.61 (1.30 to 5.23), p = 0.007) were found as independent predictors. Independently, IL‐6 and vWf predicted the end‐point. In addition, endothelial Z‐score was associated with progression of albuminuria (p = 0.038). Conclusion. Endothelial dysfunction and possibly inflammation are novel predictors of progression to diabetic nephropathy in patients with type 2 diabetes and microalbuminuria independently of traditional risk factors.

Trial registration: ClinicalTrials.gov identifier: NCT00317915.     

Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes

What is known and Objective: Telmisartan is an angiotensin receptor blocker (ARB) originally developed for the treatment of hypertension. It can also partially activate peroxisome proliferator‐activated receptor (PPAR)‐γ, which may improve insulin sensitivity. This effect may prove useful in hypertensive patients with insulin resistance or diabetes mellitus. Such activity is more marked than that observed with other ARBs. This systematic review and meta‐analysis evaluated the benefit of telmisartan on insulin sensitivity compared with that of other ARBs in hypertensive patients who had either insulin resistance or diabetic states. Methods: Clinical trials of telmisartan were identified through electronic searches (MEDLINE, CINAHL, Scopus, and The Cochrane Library) up to and including May 2011. Studies were included if they met the following inclusion criteria: (i) randomized controlled trials that compared telmisartan with other ARBs in hypertensive patients who had insulin resistance or type 2 diabetes mellitus; (ii) using telmisartan as an add‐on therapy or a monotherapy for treating hypertension; and (iii) reporting fasting plasma glucose (FPG) and fasting plasma insulin (FPI), or homeostasis model assessment of insulin resistance (HOMA‐IR), or adiponectin as an outcome measure. Treatment effect was estimated with the mean difference in the final value of FPG, FPI, HOMA‐IR and adiponectin between the telmisartan and the control groups. Results and Discussion: Eight trials involving a total of 763 patients met the inclusion criteria. Telmisartan was superior to other ARBs in reducing FPG level (mean difference, ?8·63 mg/dL; 95% CI ?12·29 mg/dL to ?4·98 mg/dL; P < 0·00001) and increasing adiponectin level (mean difference, 0·93 μg/dL; 95% CI 0·28 μg/dL to 1·59 μg/dL; P = 0·005). At 80 mg dose, telmisartan may reduce FPI level and HOMA‐IR. What is new and Conclusions: The available evidence suggests a beneficial effect of telmisartan in improving insulin sensitivity in hypertensive patients with insulin resistance or diabetes as demonstrated by the decrease in FPG and increase in adiponectin levels. The effect in decreasing FPG was greater with 80 mg dose than with the 40 mg dose. FPI and insulin resistance may be improved with 80 mg of telmisartan.     

Elevation of matrix metalloproteinases and interleukin-6 in the culprit coronary artery of myocardial infarction

Background Interleukin‐6 (IL‐6) and metalloproteinases (MMPs) are involved in the instability of vulnerable plaque associated with the induction of acute myocardial infarction (AMI). We examined the regional changes of cytokines, MMPs and adhesion molecules in patients with AMI to elucidate how these factors are involved in the onset of AMI. Materials and methods One hundred and twenty‐two patients with AMI were included. Blood was aspirated from the culprit coronary artery with a thrombectomy catheter, and was also sampled from peripheral veins during the coronary intervention. Control samples were obtained from the peripheral blood of age‐matched patients. Results The serum levels of IL‐6 (P < 0·05), tumour necrosis factor‐α (P < 0·005), MMP‐1 (P < 0·001), MMP‐13 (P < 0·001), soluble intercellular adhesion molecule‐1 (P < 0·005), and soluble vascular cellular adhesion molecule‐1 (P < 0·05) in peripheral blood were significantly higher in the AMI group than in the controls. Aspirated serum contained significantly higher levels of IL‐6 (P < 0·001), MMP‐1 (P < 0·001), and MMP‐13 (P < 0·05) compared to the peripheral blood of AMI. Serum IL‐6 levels were significantly higher in the aspirated than in the peripheral blood in the patients hospitalized within 6 h and 6–12 h, but were similar in the aspirated and peripheral blood of the patients hospitalized 12–24 h after the onset of AMI. There were no differences between the aspirated serum and peripheral blood in the levels of interleukin‐1β and MMP‐2. Conclusions The levels of MMP‐1, MMP‐13 and IL‐6 were higher in the culprit coronary artery than in the peripheral blood. These factors appear to be involved in the early stage of AMI.     

Improvement of glycaemic control by nateglinide decreases systolic blood pressure in drug-naive patients with type 2 diabetes

Background It has been speculated that oral hypoglycaemic agents that block K‐ATP channels could potentially increase blood pressure by blocking such channels in vascular myocytes. No information about this issue exists regarding nateglinide. Design A multicentre, double‐blind, placebo‐controlled, randomized trial was conducted in 109 drug‐naive 30‐ to 75‐year‐old patients with type 2 diabetes and < 5 years of diabetes diagnosis, who are not taking antihypertensive drugs. These patients were assigned to receive placebo or fixed doses of nateglinide (120 mg before each main meal: breakfast, lunch and dinner) and evaluated at weeks 0 and 12 for (i) body mass index and blood pressure; (ii) standard laboratory tests, including haemoglobin A1c (HbA1c) and fasting plasma glucose; and (iii) incremental area under the curve for glucose and C‐peptide after a standardized liquid breakfast challenge, homeostasis model assessment (HOMA)‐B% (as surrogate of β‐cell activity) and HOMA‐S% (as surrogate of insulin sensitivity). Results At the end of the follow‐up period, patients in the nateglinide group (n = 55), compared to patients in the placebo group (n = 54), showed lower values of HbA1c (6·7 ± 0·6 vs. 7·2 ± 0·7%, respectively; P < 0·001), fasting plasma glucose (7·9 ± 2·1 vs. 8·5 ± 2·0 mmol L^?1; P = 0·023) and systolic blood pressure (125·3 ± 15·4 vs. 129·3 ± 18·7 mmHg; P = 0·015), and higher values of HOMA‐B%[75·7 (51·8–99·4) vs. 57·7 (42·2–83·4); P = 0·033]. A positive correlation was found between changes in HbA1c and systolic blood pressure in the nateglinide group (r = 0·355, P = 0·011). Conclusions In drug‐naive patients with type 2 diabetes, the improvement in glycaemic control with nateglinide is associated with a decrease in systolic blood pressure.     

Visceral fat accumulation is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients

Background The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. The elevated visceral fat accumulation (VFA) has been reported to be closely related to the development of atherosclerosis. This preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with VFA and insulin resistance in type 2 diabetic patients not receiving insulin treatment. Material and methods Based on brain magnetic resonance imaging (MRI), 95 type 2 diabetic patients were divided into two groups: WML‐positive group (aged 59 ± 7 years, mean ± SD n = 37) and WML‐negative group (aged 58 ± 5, years, n = 58). The level of blood glucose was assessed by fasting plasma glucose (FPG), fasting immunoreactive insulin, homeostasis model assessment (HOMA) index, and haemoglobin A1c. The fat distribution was evaluated by measuring the visceral fat accumulation by abdominal computerized tomography at the umbilical level. Results The body mass index was higher in the WML‐positive group than in the WML‐negative group (P < 0·005). Plasma levels of triglycerides were higher while high‐density lipoprotein cholesterol was lower in the WML‐positive group than in the WML‐negative group (P < 0·05 and P < 0·01, respectively). FPG (P < 0·01), insulin concentrations (P < 0·0001), HOMA index (P < 0·0001) and VFA (<0·0001) levels were higher in the WML‐positive group than in the WML‐negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high VFA and insulin resistance (P < 0·001, P < 0·0001, respectively). Conclusions The results of this preliminary study indicate that the presence of WML was associated with the high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus. Further larger cohort studies are warranted to confirm these findings.     

Life course influences on insulin resistance: findings from the British Women's Heart and Health Study

OBJECTIVE: To assess the independent associations of a broad range of early life risk factors and adult obesity with adult insulin resistance. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of 1,394 women, aged 60-79 years, from 23 British towns. RESULTS: There was a strong (independent of confounding factors, other early life factors, and adult waist-to-hip ratio) inverse association between birth weight and insulin resistance in women in the highest third of BMI (>28.77 kg/m2): -0.12 (95% CI -0.19 to -0.04) log homeostasis model assessment (HOMA) score per 1 SD birth weight, but no association between birth weight and insulin resistance in women in the two lowest thirds of BMI (P for interaction = 0.04). Offspring birth weight, own leg length, and childhood manual social class did not interact with adult obesity and were all independently inversely associated with insulin resistance: -0.05 (-0.09 to -0.01) log HOMA score per 1 SD offspring birth weight, -0.09 (-0.12 to -0.06) log HOMA score per 1 SD leg length, and a -0.07 (-0.14 to 0.00) difference in log HOMA score between manual and nonmanual childhood social class. Childhood manual social class and shorter leg length were both independently associated with adverse lipid profiles. BMI and waist-to-hip ratio were independently positively associated with insulin resistance and with all other components of the insulin resistance syndrome. CONCLUSIONS: Insulin resistance is an important risk factor for type 2 diabetes and coronary heart disease. Our results suggest that genetic factors, intrauterine environment, early childhood, and adult environmental factors are all relevant in determining adult insulin resistance.     

Insulin resistance and risk of venous thromboembolism: results of a population‐based cohort study

Summary. Background: Obesity is an established risk factor for venous thromboembolism (VTE), but it is uncertain how this is mediated. Insulin resistance has a central role in the pathophysiology of the metabolic effects of obesity. Objective: We aimed to investigate whether insulin resistance is a risk factor for VTE. Methods: For this analysis we used the PREVEND prospective community‐based observational cohort study. Insulin resistance was measured as HOMA‐IR (homeostasis model assessment of insulin resistance) and fasting insulin. VTE was assessed using databases of the national registries of hospital discharge diagnoses, death certificates and the regional anticoagulation clinic. Results: Out of 7393 subjects, 114 developed VTE during a median follow‐up of 10.5 years. High HOMA‐IR was associated with increased risk of VTE after adjustment for traditional cardiovascular risk factors, CRP and markers of endothelial dysfunction (hazard ratio [HR], 1.38; 95% confidence interval [95% CI], 1.09–1.75; P = 0.007). When body mass index (BMI) was added to the model, BMI was a strong risk predictor for VTE (HR, 1.53; 95% CI, 1.24–1.88; P < 0.001) whereas HOMA‐IR no longer showed such an association (HR, 1.11; 95% CI, 0.85–1.43; P = 0.45). Results were similar for fasting insulin. Conclusion: Our population‐based cohort study shows an increased risk of VTE in subjects with increasing insulin resistance but not independently of BMI.     

Elevated VEGF-plasma levels in young patients with mild essential hypertension

Background Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Vascular endothelial cell growth factor (VEGF) is currently discussed as a possible mediator of inflammation. To investigate the hypothesis that VEGF plays a role as an inflammatory mediator in EH we performed the present pilot study of young patients in a very early stage of EH. Materials and methods 15 young patients with mild EH [33·8 ± 7·3 years, systolic blood pressure (SBP): 143·8 ± 10·5 mmHg, diastolic blood pressure (DBP): 88·2 ± 11·1 mmHg, mean arterial pressure (MAP) 106·6 ± 10·4 mmHg] and 15 healthy controls (31·7 ± 10·6 years) were examined. Blood was drawn from a peripheral vein and serum levels of VEGF, monocyte‐chemoattractant‐protein (MCP)‐1, high‐sensitivity C‐reactive protein (hsCRP), interleukin (IL)‐6, and tumour‐necrosis‐factor (TNF)‐α were measured via commercially available enzyme‐linked immunoassays. Results Hypertensives showed increased plasma levels of VEGF (P < 0·05) and MCP‐1 (P < 0·05). VEGF positively correlated with MAP (r = 0·46, P < 0·05) and MCP‐1 (r = 0·63, P < 0·01). Multivariate analysis demonstrated VEGF to be an independent predictor of MCP‐1 levels. Furthermore, hypertensives had higher levels of hsCRP (P < 0·01), IL‐6 (P < 0·001) and TNF‐α (P < 0·05). IL‐6 levels correlated with SBP (r = 0·59, P < 0·001), DBP (r = 0·67, P < 0·001) and MAP (r = 0·46, P < 0·001). A significant positive correlation was also found between hsCRP levels and SBP (r = 0·39, P < 0·05). Conclusions This pilot study demonstrates that in an early state of EH, inflammatory pathways have already been activated. Besides classical pro‐inflammatory cytokines, VEGF serum levels are significantly elevated. The positive correlation of VEGF with MCP‐1 is suggestive for the already described induction of MCP‐1 via VEGF.     

Impact of antiretroviral therapy on visfatin and retinol-binding protein 4 in HIV-infected subjects

Background To determine circulating levels of adipocytokines, especially the recently characterized visfatin, and the fat‐derived factor retinol‐binding protein‐4 (RBP‐4) in HIV‐infected subjects and their respective changes following treatment with highly active antiretroviral therapy (HAART). Materials and methods Fourteen HIV‐positive, HAART‐naïve subjects were compared with 10 HIV‐negative healthy controls and reassessed after a 1‐year treatment with HAART. Plasma visfatin and RBP‐4 were determined by ELISA, whereas leptin and adiponectin by RIA. Body composition was measured with dual X‐ray absorptiometry (DXA). Homeostasis model assessment (HOMA‐IR) was assessed using insulin and glucose levels. Results Visfatin and RBP‐4 levels in HIV‐positive subjects were comparable with those of HIV‐negative controls before treatment with HAART. Treatment with HAART for 12 months resulted in a 6·9‐fold and 7·1‐fold increase of visfatin and RBP‐4 levels (+54·0 ± 9·7 ng mL^?1, P < 0·0001 and +95·3 ± 31·7 ng mL^?1, P < 0·01), respectively. Leptin (?2·7 ± 1·6 ng mL^?1, P = 0·054) was unchanged and adiponectin (?2·8 ± 0·7 µg mL^?1, P < 0·01) decreased. Changes of visfatin concentrations correlated significantly with the increases of RBP‐4 (r = 0·78, P = 0·001), fat‐free mass (FFM, r = 0·75, P < 0·05) and change of HOMA‐IR (r = 0·64, P < 0·05). Parameters of glucose metabolism and body fat mass were unchanged during the observation period. Conclusions Treatment with HAART induced a pronounced increase of plasma visfatin and RBP‐4 as well as a decrease of adiponectin in HIV‐infected patients on HAART. Although body weight, fat mass and parameters of glucose metabolism remained stable, the changes in the adipocytokines might herald subsequent alterations of these parameters.     

Similar hypotensive effects of combined aerobic and resistance exercise with 1 set versus 3 sets in women with metabolic syndrome

The aim of the present study was to compare the response of systolic blood pressure (SBP), mean blood pressure (MBP) and diastolic blood pressure (DBP) following combined training with 1 set or with 3 sets of resistance exercise (RE). Sixteen women with metabolic syndrome (MetS) were randomly assigned to perform two combined exercise protocols and a control session (CON): 1‐set, 30 min of aerobic exercise (AE) at 65–70% of reserve heart rate and 1 set of 8–12 repetitions at 80% of 10‐RM in six resistance exercises; 3‐sets, same protocol but with 3 sets; and CON, 30 min of seated rest. The SBP, MBP and DBP were measured before and every 15 min during 90 min following the experimental sessions. The SBP displayed a decrease (P≤0·05) during the 90 min following the RE session with 1‐set and 3‐set, while MBP was decreased (P≤0·05) up to 75 min after 1‐set and up to 30 min after the 3‐set exercise session compared with pre‐intervention values. There was a decrease in DBP only for the greatest individual decrease following 1‐set (?6·1 mmHg) and 3‐set (?4·9 mmHg) combined exercise sessions, without differences between them. The rate‐pressure product and heart rate remained significantly higher (P≤0·05) 75 min and 90 min after the combined exercise session with 1‐ and 3‐sets compared with the CON, respectively. In conclusion, a low‐volume RE combined with AE resulted in similar decrease of SBP when compared with RE with 3‐sets in women with MetS, which could be beneficial in situations of limited time.     

Low-grade inflammation can partly explain the association between the metabolic syndrome and either coronary artery disease or severity of peripheral arterial disease: the CODAM study

Background Low‐grade inflammation has been hypothesized to underlie the coronary artery disease (CAD) risk associated with the metabolic syndrome, but the evidence is not conclusive. For peripheral arterial disease (PAD; as measured by the ankle‐arm index), this association has not been studied before. The aim was to study whether the association between the metabolic syndrome and CAD or the severity of PAD can be explained by low‐grade inflammation. Methods The Cohort study Diabetes and Atherosclerosis Maastricht population includes 574 subjects, with an increased risk of type 2 diabetes, of whom 560 were included in the analyses (343 males; age: 59·5 ± 7·0 years). The inflammation markers that were measured were C‐reactive protein, interleukin 6, soluble vascular cell adhesion molecule‐1, soluble intercellular adhesion molecule‐1 and serum amyloid A. All analyses were adjusted for age, sex and smoking. Results Logistic regression showed that the metabolic syndrome was significantly associated with CAD [odds ratio (OR) = 1·86, 95% CI: 1·21; 2·84, P = 0·004]. Further adjustment for inflammatory status, as captured in a combination of the inflammation markers (using an averaged Z‐score), resulted in significant associations of both the metabolic syndrome and inflammatory status with CAD [OR_{metabolic syndrome} (95% CI) = 1·58 (1·01; 2·46), P = 0·044; OR_inflammation (95% CI) = 1·59 (1·14; 2·21), P = 0·007]. Linear regression analysis showed similar results for the ankle‐arm index. Conclusions The association between the metabolic syndrome, on the one hand, and prevalence of CAD or the severity of PAD, on the other, can be partly but not completely, 26% and 29% respectively, explained by low‐grade inflammation.     

Tissue factor and IL8 production by P-selectin-dependent platelet–monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10

Summary. Background: P‐selectin and CD40L expressed by activated platelets induce tissue factor (TF) and inflammatory cytokines in monocytes, but little is known of the cellular signaling pathways involved. The anti‐inflammatory cytokine IL10 reduces atherosclerotic plaque formation. Objectives: To evaluate the importance of P‐selectin upon platelet–monocyte aggregate (PMA) formation in thrombin receptor activator peptide (TRAP) stimulated whole blood, the P‐selectin–P‐selectin glycoprotein ligand (PSGL)‐1‐induced cellular signaling pathway, and the effects of IL10 on these functions. Methods: TF, IL8, and monocyte chemotactic protein‐1 (MCP‐1) production, PMAs and phosphorylation of Lyn were analyzed in whole blood, purified monocytes, and vitamin D₃‐differentiated U‐937 cells stimulated with TRAP or P‐selectin with or without IL10. Anti‐P‐selectin or anti‐CD40L antibodies (Abs), Src‐kinases inhibitors, SU6656 or PP2, were added in some experiments. Results: TRAP and P‐selectin increased TF, IL8, and MCP‐1 mRNA in whole blood and purified monocytes. Anti‐P‐selectin Ab reduced TRAP‐induced PMA formation by 80 ± 2% (P = 0.001) and production of TF (P = 0.04) and IL8 (P = 0.01). IL10 and SU6656 had no effect on PMA formation, although both significantly reduced TF (P = 0.002 and P = 0.02) and IL8 (P = 0.009 and P = 0.001) mRNA upon TRAP and P‐selectin stimulation. Induced Lyn phosphorylation in monocytes was diminished by SU6656 (P = 0.02), anti‐P‐selectin Ab (P = 0.02), and IL10 (P = 0.03) upon TRAP or P‐selectin stimulation. These results were confirmed in the vitamin D₃‐differentiated U‐937 cells. Conclusions: The formation of PMAs in whole blood was P‐selectin‐dependent in the long term. P‐selectin–PSGL‐1‐induced TF and IL8 expression through Lyn phosphorylation, and part of the inhibitory effect of IL10 depends on reduced phosphorylation.     

Hyperproinsulinaemia in normoglycaemic lipodystrophic HIV-infected patients

Background We aimed to investigate whether the insulin precursors, intact (IP) and 32–33 split proinsulin (SP), which are elevated in states of insulin resistance and predict type 2 diabetes, would be elevated in human immunodeficiency virus (HIV)‐infected patients with lipodystrophy (LIPO). Materials and methods Forty‐three normoglycaemic HIV‐infected patients [18 LIPO and 18 without lipodystrophy (NONLIPO) receiving antiretroviral drugs, and seven patients naïve to antiretroviral drugs (NAÏVE)] were examined. Insulin precursors were measured during fasting, during an intravenous glucose tolerance test and during a hyperinsulinaemic–euglycaemic clamp, respectively. Insulin secretion rates (ISR) were determined by deconvolution of C‐peptide concentrations. Disposition index (DI) was calculated as insulin sensitivity (Si_RD) multiplied by the first‐phase insulin response to intravenous glucose. Results LIPO exhibited increased fasting IP and SP (P < 0·05), a higher proportion of elevated fasting IP (3·1 pmol L^?1, 66% vs. 33% and 28%, P < 0·05) and SP (7·2 pmol L^?1, 50%, 11% and 0%, P < 0·01), reduced Si_RD (> 50%, P < 0·001) and increased ISR (P < 0·001) compared with NONLIPO and NAÏVE. Fasting SP and IP correlated positively with ISR (P < 0·001) and inversely and hyperbolically with Si_RD (P < 0·001). Fasting SP/insulin ratio correlated inversely with Si_RD (P < 0·05). Incremental IP + SP/insulin ratio after an intravenous glucose bolus correlated inversely with DI (P < 0·01), but did not differ between study groups. Conclusions Proinsulin appeared to be increased in HIV‐lipodystrophy, but no more than caused by the increased ISR. Nevertheless, the inverse correlations between SP/insulin ratio versus Si_RD and incremental total proinsulin/insulin ratio versus DI may argue for a subtle β‐cell dysfunction in those patients with insulin resistance and low DI.     

Insulin resistance is associated with the metabolic syndrome and is not directly linked to coronary artery disease

BackgroundInsulin resistance (IR) is the key feature of the metabolic syndrome (MetS). Its association with directly visualized coronary atherosclerosis is unclear. We hypothesised that insulin resistance is associated with both angiographically determined coronary artery disease (CAD) and with the MetS.MethodsIn 986 consecutive patients undergoing coronary angiography for the evaluation CAD, IR was determined by the HOMA index; the MetS was defined according to NCEP-ATPIII criteria; and significant CAD was diagnosed when coronary stenoses ≥ 50% were present.ResultsHOMA IR scores were higher in MetS patients than in subjects without the MetS (4.9 ± 6.4 vs. 2.2 ± 2.0; p < 0.001). HOMA IR did not differ significantly between patients with significant CAD and those who did not have significant CAD. When both, the presence of MetS and of significant CAD were considered, HOMA IR was significantly higher in patients with the MetS both among those who had significant CAD (4.9 ± 6.8 vs. 2.2 ± 1.8; p < 0.001) and among those who did not have significant CAD (5.0 ± 5.8 vs. 2.1 ± 2.3; p < 0.001), it did not differ significantly between patients with significant CAD and subjects without significant CAD among patients with the MetS nor among those without MetS. Similar results were obtained with the IDF definition of the MetS.ConclusionIR is significantly associated with the MetS but not with angiographically determined CAD. IR may play a greater role in the eventual precipitation of thrombosis than in the gradual progression of atherosclerosis.     

Lipoprotein (a) and acute-phase response in patients with vestibular neuronitis

Background Vestibular neuronitis (VN) is a relatively common condition characterized by the acute onset of vertigo, nausea and vomiting, in the absence of auditory or central nervous system involvement. The exact aetiology (inflammatory, viral or vascular?) remains obscure. Lipoprotein (a) [Lp(a)] is an atherogenic particle. Its serum levels are mainly genetically determined and vary widely between individuals. Whether Lp(a) is consistently a positive acute‐phase reactant is controversial. Purpose We evaluated the alterations in lipidaemic parameters and serum biological markers (including acute‐phase reactants) in adult patients presenting acutely with VN. Subjects and methods A total of 34 consecutive VN patients (24 men and 11 women) and 37 apparently healthy controls (25 men and 12 women) were studied. Laboratory evaluation was performed during the acute episode and 6 months later (stable state). Results Serum Lp(a) concentrations were significantly lower at the time of presentation (median value 6·4 vs. 16·4 mg dL^?1 in the stable state, P < 0·001), whereas fibrinogen levels were significantly higher during the acute episode than in the stable state (median value 293·0 vs. 202·0 mg dL^?1, respectively, P < 0·0001). During the acute episode, plasma fibrinogen correlated with CRP levels (Spearman r = 0·84, P < 0·0001). By contrast, inverse correlations were noted between Lp(a) levels and CRP (Spearman r = ?0·47, P = 0·007) as well as between Lp(a) and fibrinogen levels (Spearman r = ?0·35, P = 0·05). Conclusion Vestibular neuronitis episodes are associated with evidence of an acute inflammatory response as reflected by significant elevations in plasma fibrinogen and CRP concentrations, whereas Lp(a) behaves as a negative acute‐phase reactant.