Homoeostasis Model Assessment Research Articles

Association of low baseline free thyroxin levels with progression of coronary artery calcification over 4 years in euthyroid subjects: the Kangbuk Samsung Health Study.

Overt and subclinical hypothyroidism are risk factors for atherosclerosis and cardiovascular diseases. It is unclear whether thyroid hormone levels within the normal range are also associated with atherosclerosis measured by coronary artery calcium (CAC). This study aimed to examine the relationship between normal variations in thyroid function and changes in CAC. We conducted a 4-year retrospective study of 2173 apparently healthy men and women with normal thyroid hormone levels. Their free thyroxin (FT4), free triiodothyronin (FT3) and thyroid-stimulating hormone (TSH) levels were measured by electrochemiluminescent immunoassay. The CAC score (CACS) of each subject was measured by multidetector computed tomography in both 2010 and 2014. Progression of CAC was defined as a CACS change over 4 years > 0. The mean CACS changes over 4 years by quartiles of baseline FT4 level (lowest to highest) were 12·9, 8·43, 7·82 and 7·81 (P = 0·028). CAC progression was not significantly associated with either the baseline FT3 or TSH levels. The odds ratios (OR) for CAC progression over 4 years (highest vs lowest quartile for baseline FT4) were 0·647 (95% confidence interval (CI) 0·472-0·886) after adjustment for confounding factor, which were attenuated with further adjustment for lipid profiles, homoeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein and hypertension [0·747 (95% CI 0·537-1·038)]. Quartiles of baseline FT3 or TSH level did not show any increased OR for CAC progression after adjustment for confounding factors. In this cohort of euthyroid men and women, a low baseline FT4 level was associated with a high risk of CACS progression over 4 years.

Effect of vitamins C and E on insulin resistance indiabetes: a meta-analysis study.

Data regarding the effect of vitamin C (VC) and vitamin E (VE) supplementation on insulin resistance in type 2 diabetes mellitus (T2DM) are controversial. We aimed to systematically review the current data on this topic. All randomized controlled trials (RCTs) conducted to assess the effect of VC and/or VE on insulin resistance in diabetes published in Google Scholar and PubMed web databases until January 2014 were included. Exclusion criteria were studies conducted in animal, type 1 DM, children or pregnant women. Main outcome measure was insulin resistance by homoeostasis model assessment (HOMA) index. According to degree of heterogeneity, fixed- or random-effect model was employed by stata software (11.0). We selected 14 RCTs involving 735 patients with T2DM. VE or mixture-mode supplementation did not have any significant effect on HOMA with a standardized mean difference (SMD): 0·017, 95% CI: -0·376 to 0·411 (P=0·932); and SMD: -0·035, 95% CI: -0·634 to 0·025 (P=0·070), respectively, by random-effect model. VC supplement alone did not improve insulin resistance with a SMD: -0·150, 95% CI: -0·494 to 0·194 (P=0·391), by fixed-effect model. Meta-regression test demonstrated that HOMA index may have not been influenced by the year of publication, dosage or duration of treatment. The sole intake of VC, VE or their combination with other antioxidants could not improve insulin resistance in diabetes.

Black elderberry extract attenuates inflammation and metabolic dysfunction in diet-induced obese mice.

Dietary anthocyanins have been shown to reduce inflammation in animal models and may ameliorate obesity-related complications. Black elderberry is one of the richest sources of anthocyanins. We investigated the metabolic effects of anthocyanin-rich black elderberry extract (BEE) in a diet-induced obese C57BL/6J mouse model. Mice were fed either a low-fat diet (n 8), high-fat lard-based diet (HFD; n 16), HFD+0·25 % (w/w) BEE (0·25 %-BEE; n 16) or HFD+1·25 % BEE (1·25 %-BEE; n 16) for 16 weeks. The 0·25 % BEE (0·034 % anthocyanin, w/w) and 1·25 % BEE (0·17 % anthocyanin, w/w) diets corresponded to estimated anthocyanin doses of 20-40 mg and 100-200 mg per kg of body weight, respectively. After 16 weeks, both BEE groups had significantly lower liver weights, serum TAG, homoeostasis model assessment and serum monocyte chemoattractant protein-1 compared with HFD. The 0·25 %-BEE also had lower serum insulin and TNFα compared with HFD. Hepatic fatty acid synthase mRNA was lower in both BEE groups, whereas PPARγ2 mRNA and liver cholesterol were lower in 1·25 %-BEE, suggesting decreased hepatic lipid synthesis. Higher adipose PPARγ mRNA, transforming growth factor β mRNA and adipose tissue histology suggested a pro-fibrogenic phenotype that was less inflammatory in 1·25 %-BEE. Skeletal muscle mRNA expression of the myokine IL-6 was higher in 0·25 %-BEE relative to HFD. These results suggest that BEE may have improved some metabolic disturbances present in this mouse model of obesity by lowering serum TAG, inflammatory markers and insulin resistance.

TM6SF2 rs58542926 is not associated with steatosis and fibrosis in largecohort of patients with genotype 1 chronic hepatitis C.

We tested the putative association of the rs58542926 variant of TM6SF2, a recently described genetic determinant of nonalcoholic fatty liver disease, with steatosis and fibrosis in genotype 1(G1) chronic hepatitis C(CHC) patients. A total of 694 consecutively biopsied Caucasian G1 CHC patients were genotyped for TM6SF2 rs58542926, IL28B rs12979860 and PNPLA3 rs738409. Steatosis was classified as absent (<5%), mild-moderate(5-29%) and severe(≥30%), Fibrosis was considered severe if=F3-F4. Carriers of TM6SF2 rs58542926 (6.3% of patients) exhibited lower serum levels of cholesterol (P = 0.04) and triglycerides (P = 0.01), but a similar distribution of steatosis severity (P = 0.63), compared to noncarriers. Prevalence and severity of steatosis were reduced in IL28B C allele carriers (P = 0.005) and elevated in PNPLA3 G allele carriers (P < 0.001). After adjustment for age, gender, body mass index and homoeostasis model assessment score, steatosis severity was independently associated with IL28B rs12979860 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.55-0.86, P = 0.001) and PNPLA3 rs738409 (OR 1.84, 95% CI 1.46-2.83, P < 0.001), but not TM6SF2 rs58542926 (OR 1.48, 95% CI 0.82-2.69, P = 0.19). Variants of TM6SF2 (30.9% vs. 25%, P = 0.40), IL28B and PNPLA3 were not directly associated with fibrosis severity, although variants of IL28B and PNPLA3 promoted steatosis (OR 1.36, 95% CI 1.06-1.75, P = 0.01) that in turn is associated with severe fibrosis. In G1 CHC patients, TM6SF2 rs58542926 does not affect the histological severity of liver damage. However, IL28B rs12979860 and PNPLA3 rs738409 modify steatosis.

Early Diet and Later Cancer Risk: Prospective Associations of Dietary Patterns During Critical Periods of Childhood with the GH-IGF Axis, Insulin Resistance and Body Fatness in Younger Adulthood

Early life, adiposity rebound, and puberty represent critical growth periods when food choices could have long-term relevance for cancer risk. We aimed to relate dietary patterns during these periods to the growth hormone-insulin-like-growth-factor (GH-IGF) axis, insulin resistance, and body fatness in adulthood. Data from the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study participants with outcome data at 18–37 years, and ≥2 dietary records during early life (1–2 yr; n = 128), adiposity rebound (4–6 years, n = 179), or puberty (girls 9–14, boys 10–15 yr; n = 213) were used. Dietary patterns at these ages were derived by 1) reduced rank regression (RRR) to explain variation in adult IGF-I, IGF-binding protein-3 (IGFBP-3), homoeostasis model assessment for insulin resistance (HOMA-IR) and fat-mass index; 2) principal component analysis (PCA). Regarding RRR, the patterns “cake/canned fruit/cheese & eggs” (early life), “sweets & dairy” (adiposity rebound) and “high-fat foods” (pubertal boys) were independently associated with higher adult HOMA-IR. Furthermore, the patterns “favorable carbohydrate sources” (early life), “snack & convenience foods” (adiposity rebound), and “traditional & convenience carbohydrates” (pubertal boys) were related to adult IGFBP-3 (P trend < 0.01). PCA identified “healthy” patterns for all periods, but none was associated with the outcomes (P trend > 0.1). In conclusion, dietary patterns during sensitive growth periods may be of long-term relevance for adult insulin resistance and IGFBP-3.

Association between thyroid hormones, thyroid antibodies and insulin resistance in euthyroid individuals: A population-based cohort

AimThe association between insulin resistance and thyroid function in euthyroid subjects has not yet been clarified. This study aimed to investigate the association between thyroid function within the normal reference range and insulin resistance in participants of the Tehran Thyroid Study (TTS). MethodsThis cross-sectional study was conducted within the framework of the TTS. Of 5786subjects aged≥20 years, 2758euthyroid subjects free of thyroid disorders, diabetes, chronic kidney disease and cardiovascular disease, and not taking steroids and lipid-lowering agents, were included. Serum concentrations of free thyroxine (FT4) and TSH were measured. The homoeostasis model assessment index for insulin resistance (HOMA-IR) was used to evaluate IR. ResultsOn linear regression analysis, a negative association was found between serum FT4 levels and HOMA-IR in the model with age, smoking and physical activity (B=−0.09, P<0.001) and in the WC-adjusted model with age, smoking and physical activity for men (B=−0.06, P<0.01). In addition, there was a positive association between serum TSH levels and HOMA-IR in both models [with age, smoking and physical activity (B=0.07, P=0.006), and age, smoking, physical activity and adjusted for WC (B=0.05, P=0.01)] that was not more significant on logistic regression analysis. In women, neither serum FT4 nor TSH levels were associated with HOMA-IR; the prevalence of IR decreased from 27.2 to 19.1 with increasing tertiles of FT4 only in men (P=0.01). No significant differences were observed in HOMA-IR and its components between thyroid peroxidase antibody (TPOAb)-negative and -positive groups. Also, it was found that metabolically healthy but obese (MHO) subjects had higher levels of TSH than individuals who were MONW (metabolically obese but normal weight; P<0.01). ConclusionLow FT4 was independently associated with IR in healthy euthyroid Iranian men.

Lower serum zinc levels are associated with unhealthy metabolic status in normal-weight adults: The 2010 Korea National Health and Nutrition Examination Survey

AimThis study investigated whether serum zinc concentration is associated with glucose tolerance, insulin resistance and metabolic health status in Korean adults. MethodsSubjects with available serum zinc levels were recruited from the fifth Korea National Health and Nutrition Examination Survey (KNHANESV) cohort. Those in the highest quartile on homoeostasis model assessment for insulin resistance (HOMA-IR) and with a body mass index (BMI) of 18.5–25kg/m2 were classified as metabolically obese and normal weight (MONW). ResultsA total of 1813 subjects with a mean age of 45.2±0.5 years and a mean BMI of 24.01±0.11kg/m2 were enrolled. Those in the lower serum zinc quartiles exhibited higher levels of fasting blood glucose and insulin resistance indices compared with those in the higher quartiles. However, these associations were positive only in normal-weight subjects. Those categorized as MONW exhibited significantly lower serum zinc levels than the metabolically healthy and normal weight (MHNW) subjects (131.6±3.0μg/dL vs 141.7±2.8μg/dL, respectively; P=0.0026), whereas serum zinc levels did not differ according to metabolic health in obese subjects. The odds ratio for being categorized as MONW was 4.12 (95% CI: 1.75, 9.72) among those in the lowest serum zinc quartile compared with those in the highest quartile even after adjusting for possible confounding factors. ConclusionLower serum zinc levels were associated with unhealthy metabolic status in normal-weight adults. Further prospective studies are required to define the role of zinc in metabolic health.

Uric acid levels in patients with schizophrenia on clozapine monotherapy

Background. We tested the hypothesis that uric acid levels are higher in subjects with schizophrenia treated with clozapine than in healthy control and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. Methods. Data for 24 subjects with schizophrenia treated with clozapine and 24 age- and sex-matched healthy volunteers was analyzed. Results. There was no difference of fasting uric acid concentrations between clozapine and control groups (4.5 ± 1.4 vs. 4.3 ± 1.3 mg/dl, P = 0.87). Regarding the whole group, uric acid levels were significantly higher in men (5.2 ± 1.2 vs. 3.6 ± 0.9, P < 0.001). Uric acid levels correlated with weight (R = 0.58, P = 0.003), body mass index (BMI; R = 0.49, P = 0.01), abdominal circumference (R = 0.45, P = 0.03), waist circumference (R = 0.47, P = 0.02), waist-to-hip ratio (R = 0.42, P = 0.04), insulin (R = 0.50, P = 0.01), homoeostasis model assessment of insulin resistance 2 (HOMA2-IR; R = 0.49, P = 0.01), basal metabolic rate (R = 0.56, P = 0.004), lean body mass (R = 0.55, P = 0.005) and body water (R = 0.55, P = 0.005). There were no significant differences of uric acid levels for smoking status, impaired fasting glucose, abdominal obesity, obesity/overweight and dyslipidemia. Uric acid levels did not correlate with age, duration of clozapine treatment, clozapine dose, leg circumference, systolic blood pressure, diastolic blood pressure, total body fat, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), homocysteine, corrected calcium, glucose and homoeostasis model assessment of insulin resistance 1 (HOMA1-IR). Conclusions. We did not find significant differences in blood uric acid levels between subjects with schizophrenia and controls. Association with weight, BMI, abdominal and waist circumferences, insulin levels and insulin resistance may support uric acid role as an important cardiovascular risk factor. Association with lean weight may explain why men have higher levels of uric acid than women.

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C.

The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002). In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects.

Evaluation of diabetes risk among Turkish nurses: The role of insulin resistance and life style on diabetes risk

Aims: The aim of this study was to investigate diabetes risk in healthy young nurses in a Training and Research Hospital in Turkey. Methods: The study was conducted in 338 nurses. Entire participants underwent laboratory examination including biochemical analysis and homoeostasis model assessment of insulin resistance. Risk of developing diabetes questionnaire (FINDRISK) was performed by interviewing with nurses. Pearson's simple linear regression analysis, Student's t-test, chi-square and Fisher's exact test were used for statistical analysis. Results: Insulin resistance (IR) and impaired fasting glucose were observed in 41.1% (n = 139) and 21.6% (n = 73), respectively. Only 42.6% of participants had normal body mass index whereas 34.6% were overweight and 22.8% were obese. The percentage of nurses under the age of 45 years was 83.4%, of this population, only 17.8% of them had a lower diabetes risk. Conclusions: Individuals with low diabetes risk may exhibit IR; however, IR is more frequent in indivi...

Effect of maternal age at childbirth on insulin resistance: the 2010 Korean National Health and Nutrition Examination Survey.

This study aimed to assess insulin resistance according to maternal age at childbirth. The data used in this study were obtained from the 2010 Korean National Health and Nutrition Examination Survey. This study included a total of 2233 nondiabetic female subjects ≥30 years of age that were subdivided into groups according to their obesity and abdominal obesity (AOB) statuses. The homoeostasis model assessment of insulin resistance (HOMA-IR) was used to quantify the insulin resistance according to age at first childbirth and last childbirth. Age at first childbirth showed a negative relationship with HOMA-IR in both the nonobese and non-AOB groups, while age at last childbirth showed a positive relationship with HOMA-IR in both the nonobese and non-AOB groups. A multivariate logistic regression analysis revealed that ages at first and last childbirth were significantly associated with the highest HOMA-IR quartile. The odds ratio was 0·9 (95% confidence interval: 0·82-0·98) for age at first childbirth, and 1·07 (95% confidence interval: 1·01-1·14) for age at last childbirth in the nonobese and non-AOB groups. In conclusion, this study suggests that insulin resistance is increased in females who experienced their first childbirth at a younger age or their last childbirth at a later age, particularly in nonobese individuals. Because these data suggest that childbearing age could be an independent risk factor for diabetes, a high-quality prospective study assessing the relationship between childbearing age and insulin resistance should be performed.

The role of metalloproteinases and their tissue inhibitors in adipose tissue remodelling and whole-body lipid distribution: a cross-sectional clinical study

BackgroundMetabolically unhealthy obesity is associated with insulin resistance. Dysfunctional adipose tissue remodelling might explain features of this disorder, such as chronic white adipose tissue inflammation, adipocyte hypertrophy, and ectopic lipid deposition. Metalloproteinases and their tissue inhibitors (TIMPs) have been implicated in human adipose tissue remodelling. In a cross-sectional study, we investigated the association of adipose metalloproteinase and TIMP expression with whole-body lipid distribution and insulin resistance. MethodsHealthy women undergoing elective surgery donated fasting blood samples (for calculation of homoeostasis model assessment of insulin resistance [HOMA2-IR], the primary outcome). At operation 2 cm3 biopsy samples of subcutaneous and visceral adipose tissue were obtained. 1 cm3 was fixed, paraffin-embedded, and stained for adipocyte size quantification, and RNA was extracted from the remaining tissue for quantitative RT-PCR analysis. The women also underwent whole-body MRI for analysis of fat distribution. Findings26 women were recruited (mean age 50·3 years, SD 13·1) into five body-mass index categories (18·5–24·9 kg/m2 [n=12, 46·1%], 25–29·9 [n=6, 23·1%], 30–34·9 [n=3, 11·5%], 35–39·9 [n=3, 11·5%], >40 [n=2, 7·8%]). Mean fasting glucose was 5·29 mmol/L (SD 0·66), mean fasting insulin 71·29 pmol/L (47·72), and mean HOMA2-IR 1·35 (0·91). HOMA2-IR correlated with body-mass index (r=0·73, p<0·0001), subcutaneous and visceral adipose tissue volumes (r=0·94 and r=0·87, respectively; both p<0·0001), and hepatic fat fraction (r=0·57, p=0·013). Visceral adipose tissue MMP14 expression correlated strongly with hepatic fat fraction (r=0·944, p<0·0001), HOMA2-IR (r=0·74, p=0·01), and visceral adipose tissue volume (r=0·74, p=0·036). Subcutaneous adipose tissue TIMP3 expression correlated with subcutaneous adipocyte area (r=0·72, p=0·029), but not with HOMA2-IR (r=–0·53, p=0·062). InterpretationThe results suggest that metalloproteinases and TIMPs regulate adipose tissue remodelling and distribution. MMP14 has been implicated in collagen turnover in pre-adipocyte differentiation, whereas TIMP3 may modulate the shedding of DLK1, a regulator of adipogenesis. In our concurrent in-vitro study, we have shown that human adipocytes express metalloproteinases and TIMPs, and that their expression varies with inflammatory stimulation. These proteins might therefore integrate inflammatory signals with dysregulated adipose remodelling in metabolically unhealthy obesity. FundingBritish Heart Foundation, Diabetes Research & Wellness Foundation Open Funding 2011.

Inter-relationships between proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III and plasma apolipoprotein B-48 transport in obese subjects: a stable isotope study in the postprandial state.

Postprandial lipaemia, due to elevated plasma apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular (CV) risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating triacylglycerol-rich lipoprotein (TRL)-apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects. Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after an intravenous 2H3-leucine administration using GC-MS. Kinetic parameters, including secretion and fractional catabolic rates (FCRs), were derived using a multi-compartmental model. Plasma PCSK9 and apoC-III concentrations were significantly and positively (P<0.05 in all) associated with the total area-under-curve (AUC) and incremental AUC for apoB-48 and inversely with TRL-apoB-48 FCR. Plasma PCSK9 and apoC-III concentrations were not correlated (P>0.05 in all) with basal secretion or the number of TRL-apoB-48 secreted over the postprandial period. In the stepwise regression analysis, plasma PCSK9 was the best predictor of the total and incremental AUCs for plasma apoB-48 and the FCR of TRL-apoB-48. The association between plasma PCSK9 and apoC-III and TRL-apoB-48 FCR remained significant (P<0.05 in all) after adjusting for age, homoeostasis model assessment (HOMA) score, hepatic lipase or lipoprotein lipase (LPL). In a multiple regression model, 31% of variance in TRL-apoB-48 FCR was accounted for by plasma PCSK9 and apoC-III concentrations (adjusted R2=0.306, P<0.05). However, their associations with TRL-apoB-48 FCR were not independent of each other. Our results suggest that the catabolism of TRL-apoB-48 in the postprandial state may be co-ordinated by PCSK9 and apoC-III in obese individuals.

Insulin resistance in patients on valproic acid: relation to adiponectin.

To investigate the presence of insulin resistance in obese children with idiopathic epilepsy on valproic acid (VPA) monotherapy in comparison to obese otherwise healthy subjects. Secondary outcome was to explore the relation between adiponectin and insulin resistance among those patients. Fifty obese children with generalized idiopathic epilepsy on VPA monotherapy and a control group of 49 obese clinically healthy age and sex-matched children with simple obesity were recruited in the study. Anthropometric assessment, fasting plasma insulin (FI), fasting glucose (FG) and fasting adiponectin levels were measured. Fasting glucose insulin ratio (FGIR) and homoeostasis model assessment for insulin resistance (HOMA-IR) were calculated for both patients and control subjects. Measurement of serum VPA trough level was also performed in patients. Patients had significantly higher fasting blood glucose, fasting insulin, lower FGIR and higher HOMA-IR values, compared to controls. Mean adiponectin level was significantly lower in patients compared to controls. The duration of treatment with valproic acid negatively correlated with adiponectin (r=-0.285, P=0.045), but did not correlate with fasting glucose, insulin, FGIR or HOMA-IR. Total daily VPA dose significantly correlated with fasting insulin (r=0.495, P<0.001), FGIR (r=-0.525, P<0.001) and HOMA-IR (r=0.404, P=0.004). This study ascertains the relationship between dose and duration of VPA therapy, insulin resistance and the adipocytokine axis. We are reporting the novel proposal that obese VPA-treated children are more insulin resistant and have lower adiponectin levels than obese and otherwise healthy children.

Short-term high-fat diet increases macrophage markers in skeletal muscle accompanied by impaired insulin signalling in healthy male subjects.

Macrophage markers in skeletal muscle of obese subjects are elevated and inversely relate to insulin sensitivity. The present study aimed to investigate whether short-term high-fat high-calorie (HFHC) diet already increases macrophage markers and affects glucose metabolism in skeletal muscle of healthy lean subjects. Muscle biopsies were obtained from 24 healthy lean young men before and after a 5-day HFHC-diet. mRNA expression levels of relevant genes in muscle and glucose, insulin, C-peptide and cholesteryl ester transfer protein (CETP) levels in plasma were measured. In addition, we assessed hepatic triacylglycerol ('triglyceride') (HTG) content by magnetic resonance spectroscopy and subcutaneous white adipose tissue (sWAT) biopsies were analysed histologically from a subset of subjects (n=8). A 5-day HFHC-diet markedly increased skeletal muscle mRNA expression of the general macrophage markers CD68 (3.7-fold, P<0.01) and CD14 (3.2-fold, P<0.01), as well as the M1 macrophage markers MARCO (11.2-fold, P<0.05), CD11c (1.8-fold, P<0.05) and MRC1 (1.7-fold, P<0.05). This was accompanied by down-regulation of SLC2A4 and GYS1 mRNA expression, and elevated plasma glucose (+4%, P<0.001) and insulin (+55%, P<0.001) levels together with homoeostasis model assessment of insulin resistance (HOMA-IR) (+48%, P<0.001), suggesting development of insulin resistance (IR). Furthermore, the HFHC-diet markedly increased HTG (+118%, P<0.001) and plasma CETP levels (+21%, P<0.001), a marker of liver macrophage content, whereas sWAT macrophage content remained unchanged. In conclusion, short-term HFHC-diet increases expression of macrophage markers in skeletal muscle of healthy men accompanied by reduced markers of insulin signalling and development of IR. Therefore, recruitment of macrophages into muscle may be an early event in development of IR in response to short-term HFHC-feeding.

Association of nutritional risk index with metabolic biomarkers, appetite-regulatory hormones and inflammatory biomarkers and outcome in patients with chronic heart failure.

We aimed to evaluate the association of the nutritional status by using the nutritional risk index (NRI) with metabolic and inflammatory biomarkers, and appetite-regulatory hormones in a cohort of stable patients with heart failure (HF), and to analyse its prognostic value. In this prospective observational cohort study, we included 137 stable chronic HF patients (median age, 60years; median body mass index, 27kg/m(2) ) with optimised medical treatment. Baseline NRI of <113 (n=45) was associated with a significant increase in the levels of ghrelin (p<0.001), peptide YY (p=0.007), pentraxin-3 (p=0.001), tumour necrosis factor-alpha (p=0.018), adiponectin (p<0.0001) and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP; p<0.0001) compared with those in patients with NRI of ≥113. The NRI was found to be correlated with the homoeostasis model assessment of insulin resistance index (r=0.444; p<0.0001) and inversely correlated with the NT-proBNP level (r=-0.410; p<0.0001). The overall mortality rate was 20%. A baseline NRI of <113 was associated with a higher risk of all-cause mortality (log rank=0.031). We propose that the NRI is a useful and easily applicable tool for the early identification of nutritional depletion in patients with chronic HF as it discriminates metabolic changes prior to the clinical manifestation of body wasting. Furthermore, poor nutritional status, represented as a low NRI, is associated with an increased incidence of death in such cases.

Male hypogonadism and metabolic syndrome.

The role of androgens in cardiovascular disease is still controversial in men. In this study, we investigated metabolic disorders in Tunisian hypogonadal men compared with healthy controls. Forty hypogonadal men and 80 control subjects were enrolled. Patients with a history of pre-existing panhypopituitarism, thyroid dysfunction or inflammatory disease were excluded. Glycaemia, glycated haemoglobin (HbA1c), high-sensitive C-reactive protein (hsCRP), lipid profile, insulin, testosterone and gonadotrophins were measured. Insulin resistance was assessed by homoeostasis model assessment of insulin resistance (Homa IR). Waist circumference, body mass index and blood pressure were significantly higher in patients compared with controls. Glycemia, HbA1c, fasting serum insulin and Homa IR were significantly increased among hypogonadal men. In univariate analysis, testosterone levels were inversely correlated with body mass index, waist circumference, blood pressure, glycaemia, HbA1C, insulin, Homa IR and hsCRP. In multivariate analysis including all significant variables, initial testosterone level was the only independent risk factor for developing dyslipidaemia. With logistic regression, male hypogonadism was an independent risk factor for MS (P<0.001). We conclude that low testosterone level plays a central role in the development of metabolic syndrome. Further prospective data are required to establish the causative link.

Identifying subgroups of obesity using the product of triglycerides and glucose: the Korea National Health and Nutrition Examination Survey, 2008-2010.

To determine whether the TyG index, a product of the levels of triglycerides and glucose, may be a valuable marker for identifying metabolically obese but normal weight (MONW) or metabolically healthy but obese (MHO) individuals. A total of 17 029 nondiabetic subjects (7185 men and 9844 women) were selected from the Korea National Health and Nutrition Examination Survey conducted in 2008-2010. Individuals with a normal body mass index (BMI) (≥18·5 and <23 kg/m(2) ) and the highest quartile of the homoeostasis model assessment of insulin resistance (HOMA-IR) were classified as MONW. Individuals with obesity (BMI ≥25 kg/m(2) ) and the lowest quartile of HOMA-IR were classified as MHO. The TyG index was calculated as ln[fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. The levels of the TyG index paralleled with various metabolic risk parameters. The index was significantly higher in the MONW group and lower in the MHO group when compared with the non-MONW group and the non-MHO group, respectively. The odds ratios (ORs) of being categorized into the MONW group were approximately fourfold higher in the highest vs lowest quartiles of the TyG index (3·999: 95% CI, 2·508-6·376 in men; 4·737: 95% CI, 3·418-6·565 in women) among normal weight subjects. Conversely, there was a stepwise decrease in the OR of being categorized into the MHO group across the TyG index quartiles among obese subjects. These data highlight the value of the TyG index in discriminating those subjects with higher risks of metabolic diseases.

Serum levels of desacyl ghrelin in patients with schizophrenia on clozapine monotherapy.

Desacyl ghrelin is a hormone that might be a functional inhibitor of ghrelin, a potent hunger-stimulating peptide. We determined fasting serum desacyl ghrelin levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition determined using bioelectric impedance analysis. There were no differences in desacyl ghrelin levels between patients taking clozapine and the control group (272.09 ± 137.96 vs 259.62 ± 140.91 pg/mL, z = 0.17, P = 0.87). In the clozapine group, there were no differences between men and women for ghrelin levels (246.66 ± 123.17 vs 295.39 ± 151.77 pg/mL, z = -0.98, P = 0.32). In the clozapine group, fasting serum levels of ghrelin negatively correlated with waist-to-hip ratio (WHR) (r = -0.45, P = 0.03) and ionized calcium (r = -0.45, P = 0.03). Levels of ghrelin were lower in patients with WHR above World Health Organization-defined cut-off points (246.84 ± 114.34 [Q1 = 152.18, Q2 = 220.92, Q3 = 327.85] vs 400.30 ± 123.36 [Q1 = 283.73, Q2 = 414.03, Q3 = 485.8] pg/mL, z = 2.52, P = 0.01). In the clozapine group, there were no correlation with age, height, weight, body mass index, abdominal circumference, waist circumference, hip circumference, WHR, blood pressure, total cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, uric acid, homocysteine, glucose, insulin, clozapine dose, duration of treatment with antipsychotics, duration of treatment with clozapine, total fat, target fat, basal metabolic rate, target weight, lean weight, body water, homoeostasis model assessment of insulin resistance (HOMA) 1-IR, HOMA2-IR and quantitative insulin sensitivity check index. Based on our results, we cannot conclude that treatment with clozapine affects levels of desacyl ghrelin. Also, in our study population we did not confirm previously described associations between desacyl ghrelin and various metabolic parameters.

Randomised clinical trial: The beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis.

Gut microbiota modifiers may have beneficial effects of non-alcoholic fatty liver disease (NAFLD) but randomised controlled trials (RCT) are lacking in children. To perform a double-blind RCT of VSL#3 vs. placebo in obese children with biopsy-proven NAFLD. Of 48 randomised children, 44 (22 VSL#3 and 22 placebo) completed the study. The main outcome was the change in fatty liver severity at 4 months as detected by ultrasonography. Secondary outcomes were the changes in triglycerides, insulin resistance as detected by the homoeostasis model assessment (HOMA), alanine transaminase (ALT), body mass index (BMI), glucagon-like peptide 1 (GLP-1) and activated GLP-1 (aGLP-1). Ordinal and linear models with cluster confidence intervals were used to evaluate the efficacy of VSL#3 vs. placebo at 4 months. At baseline, moderate and severe NAFLD were present in 64% and 36% of PLA children and in 55% and 45% of VSL#3 children. The probability that children supplemented with VSL#3 had none, light, moderate or severe FL at the end of the study was 21%, 70%, 9% and 0% respectively with corresponding values of 0%, 7%, 76% and 17% for the placebo group (P < 0.001). No between-group differences were detected in triglycerides, HOMA and ALT while BMI decreased and GLP-1 and aGLP1 increased in the VSL#3 group (P < 0.001 for all comparisons). A 4-month supplement of VSL#3 significantly improves NAFLD in children. The VSL#3-dependent GLP-1 increase could be responsible for these beneficial effects. Trial identifier: NCT01650025 (www.clinicaltrial.gov).