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1.  Circulating adiponectin levels are lower in Latino versus non-Latino white patients at risk for cardiovascular disease, independent of adiposity measures 
Background
Latinos in the United States have a higher prevalence of type 2 diabetes than non-Latino whites, even after controlling for adiposity. Decreased adiponectin is associated with insulin resistance and predicts T2DM, and therefore may mediate this ethnic difference. We compared total and high-molecular-weight (HMW) adiponectin in Latino versus white individuals, identified factors associated with adiponectin in each ethnic group, and measured the contribution of adiponectin to ethnic differences in insulin resistance.
Methods
We utilized cross-sectional data from subjects in the Latinos Using Cardio Health Actions to reduce Risk study. Participants were Latino (n = 119) and non-Latino white (n = 60) men and women with hypertension and at least one other risk factor for CVD (age 61 ± 10 yrs, 49% with T2DM), seen at an integrated community health and hospital system in Denver, Colorado. Total and HMW adiponectin was measured by RIA and ELISA respectively. Fasting glucose and insulin were used to calculate the homeostasis model insulin resistance index (HOMA-IR). Variables independently associated with adiponectin levels were identified by linear regression analyses. Adiponectin's contribution to ethnic differences in insulin resistance was assessed in multivariate linear regression models of Latino ethnicity, with logHOMA-IR as a dependent variable, adjusting for possible confounders including age, gender, adiposity, and renal function.
Results
Mean adiponectin levels were lower in Latino than white patients (beta estimates: -4.5 (-6.4, -2.5), p < 0.001 and -1.6 (-2.7, -0.5), p < 0.005 for total and HMW adiponectin), independent of age, gender, BMI/waist circumference, thiazolidinedione use, diabetes status, and renal function. An expected negative association between adiponectin and waist circumference was seen among women and non-Latino white men, but no relationship between these two variables was observed among Latino men. Ethnic differences in logHOMA-IR were no longer observed after controlling for adiponectin levels.
Conclusions
Among patients with CVD risk, total and HMW adiponectin is lower in Latinos, independent of adiposity and other known regulators of adiponectin. Ethnic differences in adiponectin regulation may exist and future research in this area is warranted. Adiponectin levels accounted for the observed variability in insulin resistance, suggesting a contribution of decreased adiponectin to insulin resistance in Latino populations.
doi:10.1186/1472-6823-11-13
PMCID: PMC3141565  PMID: 21736747
2.  Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population 
PLoS ONE  2013;8(6):e66808.
Background
Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear.
Objectives
We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada.
Methods
Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes.
Results
Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67).
Conclusion
The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.
doi:10.1371/journal.pone.0066808
PMCID: PMC3691277  PMID: 23826141
3.  The Impact of Full-Length, Trimeric and Globular Adiponectin on Lipolysis in Subcutaneous and Visceral Adipocytes of Obese and Non-Obese Women 
PLoS ONE  2013;8(6):e66783.
Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5'-AMP-activated protein kinase) in adiponectin-dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 µg/ml of: A) full-length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti-lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti-lipolytic activity in obese SCAAT and VAT, respectively.
doi:10.1371/journal.pone.0066783
PMCID: PMC3689658  PMID: 23805277
4.  Weight Change as a Predictor of Incidence and Remission of Insulin Resistance 
PLoS ONE  2013;8(5):e63690.
Objective
The objective of this study was to assess the longitudinal relationship of weight change on incidence and remission of insulin resistance (IR).
Methods
We performed a cohort study in apparently healthy Korean men, 30 to 59 years of age, who underwent a health checkup and were followed annually or biennially between 2002 and 2009. The computer model of homeostasis model assessment, HOMA2-IR, was obtained at each visit, and IR was defined as HOMA2-IR ≥75th percentile.
Results
For IR development, 1,755 of the 6,612 IR-free participants at baseline developed IR (rate 5.1 per 100 person-years) during 34,294.8 person-years of follow-up. The hazard ratios (95% confidence intervals) for incident IR with weight changes of <−0.9 kg, 0.6–2.1 kg and ≥2.2 kg from visit 1 to visit 2 (average 1.8 years) compared to weight change of −0.9–0.5 kg (reference) were 0.78 (0.68–0.90), 1.19 (1.04–1.35) and 1.26 (1.11–1.44), respectively. This association persisted in normal-weight individuals or those without any metabolic syndrome traits and remained significant after introducing weight categories and confounders as time-dependent exposures (P-trend <0.001). For IR remission, 903 of 1,696 IR participants had no IR (remission rate 10.3 per 100 person-years) during 8,777.4 person-years of follow-up. IR remission decreased with increasing quartiles of weight change (P-trend <0.001) and this association persisted in normal-weight individuals.
Conclusions
Weight gain was associated with increased IR development and decreased IR remission regardless of baseline BMI status. Preventing weight gain, even in healthy and normal-weight individuals, is an important strategy for reducing IR and its associated consequences.
doi:10.1371/journal.pone.0063690
PMCID: PMC3661661  PMID: 23717466
5.  The Association between Dietary Energy Density and Type 2 Diabetes in Europe: Results from the EPIC-InterAct Study 
PLoS ONE  2013;8(5):e59947.
Background
Observational studies implicate higher dietary energy density (DED) as a potential risk factor for weight gain and obesity. It has been hypothesized that DED may also be associated with risk of type 2 diabetes (T2D), but limited evidence exists. Therefore, we investigated the association between DED and risk of T2D in a large prospective study with heterogeneity of dietary intake.
Methodology/Principal Findings
A case-cohort study was nested within the European Prospective Investigation into Cancer (EPIC) study of 340,234 participants contributing 3.99 million person years of follow-up, identifying 12,403 incident diabetes cases and a random subcohort of 16,835 individuals from 8 European countries. DED was calculated as energy (kcal) from foods (except beverages) divided by the weight (gram) of foods estimated from dietary questionnaires. Prentice-weighted Cox proportional hazard regression models were fitted by country. Risk estimates were pooled by random effects meta-analysis and heterogeneity was evaluated. Estimated mean (sd) DED was 1.5 (0.3) kcal/g among cases and subcohort members, varying across countries (range 1.4–1.7 kcal/g). After adjustment for age, sex, smoking, physical activity, alcohol intake, energy intake from beverages and misreporting of dietary intake, no association was observed between DED and T2D (HR 1.02 (95% CI: 0.93–1.13), which was consistent across countries (I2 = 2.9%).
Conclusions/Significance
In this large European case-cohort study no association between DED of solid and semi-solid foods and risk of T2D was observed. However, despite the fact that there currently is no conclusive evidence for an association between DED and T2DM risk, choosing low energy dense foods should be promoted as they support current WHO recommendations to prevent chronic diseases.
doi:10.1371/journal.pone.0059947
PMCID: PMC3655954  PMID: 23696784
6.  Quality of Clinical Practice Guidelines for Glycemic Control in Type 2 Diabetes Mellitus 
PLoS ONE  2013;8(4):e58625.
Background
Several studies have reported that clinical practice guidelines (CPGs) in a variety of clinical areas are of modest or variable quality. The objective of this study was to evaluate the quality of an international cohort of CPGs that provide recommendations on pharmaceutical management of glycemic control in patients with type 2 diabetes mellitus (DM2).
Methods and Findings
We searched the National Guideline Clearinghouse (NGC) on February 15th and June 4th, 2012 for CPGs meeting inclusion criteria. Two independent assessors rated the quality of each CPG using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument. Twenty-four guidelines were evaluated, and most had high scores for clarity and presentation. However, scope and purpose, stakeholder involvement, rigor of development, and applicability domains varied considerably. The majority of guidelines scored low on editorial independence, and only seven CPGs were based on an underlying systematic review of the evidence.
Conclusions
The overall quality of CPGs for glycemic control in DM2 is moderate, but there is substantial variability among quality domains within and across guidelines. Guideline users need to be aware of this variability and carefully appraise and select the guidelines that they apply to patient care.
doi:10.1371/journal.pone.0058625
PMCID: PMC3618153  PMID: 23577058
7.  Association between Serum Leptin Concentrations and Insulin Resistance: A Population-Based Study from China 
PLoS ONE  2013;8(1):e54615.
Background
Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported.
Methods
A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance.
Results
In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001).
Conclusions
There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.
doi:10.1371/journal.pone.0054615
PMCID: PMC3551759  PMID: 23349940
8.  Major Cardiovascular Risk Factors in Latin America: A Comparison with the United States. The Latin American Consortium of Studies in Obesity (LASO) 
PLoS ONE  2013;8(1):e54056.
Background
Limited knowledge on the prevalence and distribution of risk factors impairs the planning and implementation of cardiovascular prevention programs in the Latin American and Caribbean (LAC) region.
Methods and Findings
Prevalence of hypertension, diabetes mellitus, abnormal lipoprotein levels, obesity, and smoking were estimated from individual-level patient data pooled from population-based surveys (1998–2007, n = 31,009) from eight LAC countries and from a national survey of the United States (US) population (1999–2004) Age and gender specific prevalence were estimated and age-gender adjusted comparisons between both populations were conducted. Prevalence of diabetes mellitus, hypertension, and low high-density lipoprotein (HDL)-cholesterol in LAC were 5% (95% confidence interval [95% CI]: 3.4, 7.9), 20.2% (95% CI: 12.5, 31), and 53.3% (95% CI: 47, 63.4), respectively. Compared to LAC region’s average, the prevalence of each risk factor tended to be lower in Peru and higher in Chile. LAC women had higher prevalence of obesity and low HDL-cholesterol than men. Obesity, hypercholesterolemia, and hypertriglyceridemia were more prevalent in the US population than in LAC population (31 vs. 16.1%, 16.8 vs. 8.9%, and 36.2 vs. 26.5%, respectively). However, the prevalence of low HDL-cholesterol was higher in LAC than in the US (53.3 vs. 33.7%).
Conclusions
Major cardiovascular risk factors are highly prevalent in LAC region, in particular low HDL-cholesterol. In addition, marked differences do exist in this prevalence profile between LAC and the US. The observed patterns of obesity-related risk factors and their current and future impact on the burden of cardiovascular diseases remain to be explained.
doi:10.1371/journal.pone.0054056
PMCID: PMC3547948  PMID: 23349785
9.  Intake of Gnetum Africanum and Dacryodes Edulis, Imbalance of Oxidant/Antioxidant Status and Prevalence of Diabetic Retinopathy in Central Africans 
PLoS ONE  2012;7(12):e49411.
Objective
To estimate the prevalence of DR and to correlate cardiometabolic, sociodemographic, and oxidant/antioxidant imbalance data to the prevalence of DR.
Design
This case-control study included type 2 DM (T2 DM) patients with DR (n = 66), T2 DM patients without DR (N = 84), and healthy controls (n = 45) without DR, in Kinshasa town. Diet, albuminemia, serum vitamins, and 8-isoprostane were examined.
Results
No intake of safou (OR = 2.7 95% CI 1.2–5.8; P = 0.014), low serum albumin <4.5 g/dL (OR-2.9 95% CI 1.4–5.9; P = 0.003), no intake of fumbwa (OR = 2.8 95% CI 1.2–6.5; P = 0.014), high 8-isoprostane (OR = 14.3 95% CI 4.5–46; P<0.0001), DM duration ≥5 years (OR = 3.8 95% CI 1.6–9.1; P = 0.003), and low serum vitamin C (OR = 4.5 95% CI 1.3–15.5; P = 0.016) were identified as the significant independent determinants of DR.
Conclusion
The important role of oxidant/antioxidant status imbalance and diet is demonstrated in DR.
doi:10.1371/journal.pone.0049411
PMCID: PMC3513305  PMID: 23226496
10.  Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes 
PLoS ONE  2012;7(11):e49345.
Fibroblast growth factor 21 (FGF21) is a promising drug candidate for the treatment of type 2 diabetes. However, the use of wild type native FGF21 is challenging due to several limitations. Among these are its short half-life, its susceptibility to in vivo proteolytic degradation and its propensity to in vitro aggregation. We here describe a rationale-based protein engineering approach to generate a potent long-acting FGF21 analog with improved resistance to proteolysis and aggregation. A recombinant Fc-FGF21 fusion protein was constructed by fusing the Fc domain of human IgG1 to the N-terminus of human mature FGF21 via a linker peptide. The Fc positioned at the N-terminus was determined to be superior to the C-terminus as the N-terminal Fc fusion retained the βKlotho binding affinity and the in vitro and in vivo potency similar to native FGF21. Two specific point mutations were introduced into FGF21. The leucine to arginine substitution at position 98 (L98R) suppressed FGF21 aggregation at high concentrations and elevated temperatures. The proline to glycine replacement at position 171 (P171G) eliminated a site-specific proteolytic cleavage of FGF21 identified in mice and cynomolgus monkeys. The derived Fc-FGF21(RG) molecule demonstrated a significantly improved circulating half-life while maintaining the in vitro activity similar to that of wild type protein. The half-life of Fc-FGF21(RG) was 11 h in mice and 30 h in monkeys as compared to 1-2 h for native FGF21 or Fc-FGF21 wild type. A single administration of Fc-FGF21(RG) in diabetic mice resulted in a sustained reduction in blood glucose levels and body weight gains up to 5-7 days, whereas the efficacy of FGF21 or Fc-FGF21 lasted only for 1 day. In summary, we engineered a potent and efficacious long-acting FGF21 analog with a favorable pharmaceutical property for potential clinical development.
doi:10.1371/journal.pone.0049345
PMCID: PMC3507880  PMID: 23209571
11.  Medical Students’ Attitudes towards Overweight and Obesity 
PLoS ONE  2012;7(11):e48113.
Objective
Studies from the USA have identified medical students as a major source of stigmatizing attitudes towards overweight and obese individuals. As data from Europe is scarce, medical students’ attitudes were investigated at the University of Leipzig in Leipzig, Germany.
Design
Cross-sectional survey containing an experimental manipulation consisting of a pair of vignettes depicting an obese and a normal weight 42-year-old woman, respectively. Vignettes were followed by the Fat Phobia Scale (FPS), a semantic differential assessing weight related attitudes. In case of the overweight vignette a panel of questions on causal attribution for the overweight preceded administration of the FPS.
Subjects
671 medical students were enrolled at the University of Leipzig from May to June 2011.
Results
The overweight vignette was rated significantly more negative than the normal weight vignette (mean FPS score 3.65±0.45 versus 2.54±0.38, p<0.001). A higher proportion of students had negative attitudes towards the overweight as compared to the normal weight individual (98.9% versus 53.7%, p<0.001). A “positive energy balance” was perceived as the most relevant cause for the overweight, followed by “negligent personality trait”, “societal and social environment” and “biomedical causes”. Attributing a “positive energy balance” or “negligent personality trait” as relevant cause for the overweight was positively associated with negative attitudes.
Conclusion
The results of this study confirm and complement findings from other countries, mainly the USA, and indicate that weight bias in the health care setting may be a global issue. Stigmatizing attitudes towards overweight and obesity are prevalent among a sample of medical students at the University of Leipzig. Negative attitudes arise on the basis of holding the individual accountable for the excess weight. They call for bringing the topic of overweight and obesity more into the focus of the medical curriculum and for enhancing medical students’ awareness of the complex aetiology of this health condition.
doi:10.1371/journal.pone.0048113
PMCID: PMC3489830  PMID: 23144850
12.  Acute Inhibition of PI3K-PDK1-Akt Pathway Potentiates Insulin Secretion through Upregulation of Newcomer Granule Fusions in Pancreatic β-Cells 
PLoS ONE  2012;7(10):e47381.
In glucose-induced insulin secretion from pancreatic β-cells, a population of insulin granules fuses with the plasma membrane without the typical docking process (newcomer granule fusions), however, its mechanism is unclear. In this study, we investigated the PI3K signaling pathways involved in the upregulation of newcomer granule fusions. Acute treatment with the class IA-selective PI3K inhibitors, PIK-75 and PI-103, enhanced the glucose-induced insulin secretion. Total internal reflection fluorescent microscopy revealed that the PI3K inhibitors increased the fusion events from newcomer granules. We developed a new system for transfection into pancreatic islets and demonstrated the usefulness of this system in order for evaluating the effect of transfected genes on the glucose-induced secretion in primary cultured pancreatic islets. Using this transfection system together with a series of constitutive active mutants, we showed that the PI3K-3-phosphoinositide dependent kinase-1 (PDK1)-Akt pathway mediated the potentiation of insulin secretion. The Akt inhibitor also enhanced the glucose-induced insulin secretion in parallel with the upregulation of newcomer granule fusions, probably via increased motility of intracellular insulin granules. These data suggest that the PI3K-PDK1-Akt pathway plays a significant role in newcomer granule fusions, probably through an alteration of the dynamics of the intracellular insulin granules.
doi:10.1371/journal.pone.0047381
PMCID: PMC3471824  PMID: 23077605
13.  Metabolomics Approach for Analyzing the Effects of Exercise in Subjects with Type 1 Diabetes Mellitus 
PLoS ONE  2012;7(7):e40600.
The beneficial effects of exercise in patients with type 1 diabetes (T1D) are not fully proven, given that it may occasionally induce acute metabolic disturbances. Indeed, the metabolic disturbances associated with sustained exercise may lead to worsening control unless great care is taken to adjust carbohydrate intake and insulin dosage. In this work, pre- and post-exercise metabolites were analyzed using a 1H-NMR and GC-MS untargeted metabolomics approach assayed in serum. We studied ten men with T1D and eleven controls matched for age, body mass index, body fat composition, and cardiorespiratory capacity, participated in the study. The participants performed 30 minutes of exercise on a cycle-ergometer at 80% VO2max. In response to exercise, both groups had increased concentrations of gluconeogenic precursors (alanine and lactate) and tricarboxylic acid cycle intermediates (citrate, malate, fumarate and succinate). The T1D group, however, showed attenuation in the response of these metabolites to exercise. Conversely to T1D, the control group also presented increases in α-ketoglutarate, alpha-ketoisocaproic acid, and lipolysis products (glycerol and oleic and linoleic acids), as well as a reduction in branched chain amino acids (valine and leucine) determinations. The T1D patients presented a blunted metabolic response to acute exercise as compared to controls. This attenuated response may interfere in the healthy performance or fitness of T1D patients, something that further studies should elucidate.
doi:10.1371/journal.pone.0040600
PMCID: PMC3394718  PMID: 22792382
14.  A Systematic Review Investigating Healthy Lifestyle Interventions Incorporating Goal Setting Strategies for Preventing Excess Gestational Weight Gain 
PLoS ONE  2012;7(7):e39503.
Background
Excess gestational weight gain (GWG) is an important risk factor for long term obesity in women. However, current interventions aimed at preventing excess GWG appear to have a limited effect. Several studies have highlighted the importance of linking theory with empirical evidence for producing effective interventions for behaviour change. Theorists have demonstrated that goals can be an important source of human motivation and goal setting has shown promise in promoting diet and physical activity behaviour change within non-pregnant individuals. The use of goal setting as a behaviour change strategy has been systematically evaluated within overweight and obese individuals, yet its use within pregnancy has not yet been systematically explored.
Aim of review
To explore the use of goal setting within healthy lifestyle interventions for the prevention of excess GWG.
Data collection and analysis
Searches were conducted in seven databases alongside hand searching of relevant journals and citation tracking. Studies were included if interventions used goal setting alongside modification of diet and/or physical activity with an aim to prevent excess GWG. The PRISMA guidelines were followed and a two-stage methodological approach was used. Stage one focused on systematically evaluating the methodological quality of included interventions. The second stage assessed intervention integrity and the implementation of key goal setting components.
Findings
From a total of 839 citations, 54 full-text articles were assessed for eligibility and 5 studies met the inclusion criteria. Among interventions reporting positive results a combination of individualised diet and physical activity goals, self-monitoring and performance feedback indicators were described as active components.
Conclusion
Interventions based on goal setting appear to be useful for helping women achieve optimal weight gain during pregnancy. However, overweight and obese women may require more theoretically-designed interventions. Further high quality, theoretically-designed interventions are required to determine the most effective and replicable components for optimal GWG.
doi:10.1371/journal.pone.0039503
PMCID: PMC3390339  PMID: 22792178
15.  Effect of Anti-Obesity Drug on Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2012;7(6):e39062.
Background
Anti-obesity drugs are widely used to prevent the complications of obesity, however, the effects of anti-obesity drugs on cardiovascular risk factors are unclear at the present time. We carried out a comprehensively systematic review and meta-analysis to assess the effects of anti-obesity drugs on cardiovascular risk factors.
Methodology and Principal Findings
We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles and proceedings of major meetings for relevant literatures. We included randomized placebo-controlled trials that reported the effects of anti-obesity drugs on cardiovascular risk factors compared to placebo. Overall, orlistat produced a reduction of 2.39 kg (95%CI-3.34 to −1.45) for weight, a reduction of 0.27 mmol/L (95%CI: −0.36 to −0.17) for total cholesterol, a reduction of 0.21 mmol/L (95%CI: −0.30 to −0.12) for LDL, a reduction of 0.12 mmol/L (95%CI: −0.20 to −0.04) for fasting glucose, 1.85 mmHg reduction (95%CI: −3.30 to −0.40) for SBP, and a reduction of 1.49 mmHg (95%CI: −2.39 to −0.58) for DBP. Sibutramine only showed effects on weight loss and triglycerides reduction with statistical significances. Rimonabant was associated with statistically significant effects on weight loss, SBP reduction and DBP reduction. No other significantly different effects were identified between anti-obesity therapy and placebo.
Conclusion/Significance
We identified that anti-obesity therapy was associated with a decrease of weight regardless of the type of the drug. Orlistat and rimonabant could lead to an improvement on cardiovascular risk factors. However, Sibutramine may have a direct effect on cardiovascular risk factors.
doi:10.1371/journal.pone.0039062
PMCID: PMC3380040  PMID: 22745703
16.  Hypoadiponectinemia in Extremely Low Gestational Age Newborns with Severe Hyperglycemia – A Matched-Paired Analysis 
PLoS ONE  2012;7(6):e38481.
Background
Hyperglycemia is commonly observed in extremely low gestational age newborns (ELGANs) and is associated with both increased morbidity and mortality. The objective of this study was to examine the relationship between neonatal hyperglycemia and adiponectin levels in ELGANs.
Methodology/Principal Findings
Ten preterm infants between 22+6/7 and 27+3/7 weeks’ gestation with neonatal hyperglycemia (defined as pre-feeding blood glucose levels above 200mg/dl on two consecutive measurements with a maximum parenteral glucose infusion of 4mg/kg*min−1) formed the case cohort of this study. To every single patient of this case cohort a patient with normal fasting ( = pre-feeding) blood glucose levels was matched in terms of gestational age and gender. Adiponectin ELISAs were performed both at onset of hyperglycemia and at term-equivalent age.
In the case cohort 9/10 patients had to be treated with insulin for 1–26 days (range 0.01–0.4 IU/kg*h−1). Compared to matched-paired controls, significant hypoadiponectinemia was observed at onset of hyperglycemia in these affected patients (6.9µg/ml versus 15.1µg/ml, p = 0.009). At term equivalent age, normoglycemia without any insulin treatment was found in both groups. Moreover, adiponectin levels at that time were no longer significantly different (12.3µg/ml versus 20.0µg/ml; p = 0.051) possibly indicating a mechanistic relevance of this adipokine in regulating insulin sensitivity in ELGANs.
Conclusions/Significance
Decreased circulating adiponectin levels are correlated with hyperglycemia in ELGANs and may contribute to the pathogenesis of impaired glucose homeostasis in these infants. These findings suggest that adiponectin might be a potential future drug target for the potentially save treatment of hyperglycemia in pre-term infants.
doi:10.1371/journal.pone.0038481
PMCID: PMC3367948  PMID: 22679509
17.  Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect 
PLoS ONE  2012;7(5):e37757.
Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis.
doi:10.1371/journal.pone.0037757
PMCID: PMC3359316  PMID: 22649556
18.  Body Adiposity Index Utilization in a Spanish Mediterranean Population: Comparison with the Body Mass Index 
PLoS ONE  2012;7(4):e35281.
Background
Body fat content and fat distribution or adiposity are indicators of health risk. Several techniques have been developed and used for assessing and/or determining body fat or adiposity. Recently, the Body Adiposity Index (BAI), which is based on the measurements of hip circumference and height, has been suggested as a new index of adiposity. The aim of the study was to compare BAI and BMI measurements in a Caucasian population from a European Mediterranean area and to assess the usefulness of the BAI in men and women separately.
Research Methodology/Principal Findings
A descriptive cross-sectional study was conducted in a Caucasian population. All participants in the study (1,726 women and 1,474 men, mean age 39.2 years, SD 10.8) were from Mallorca (Spain). Anthropometric data, including percentage of body fat mass obtained by Bioelectrical Impedance Analysis, were determined. Body Mass Index (BMI) and BAI were calculated. BAI and BMI showed a good correlation (r = 0.64, p<0.001). A strong correlation was also found between BAI and the % fat determined using BIA (r = 0.74, p<0.001), which is even stronger than the one between BMI and % fat (r = 0.54, p<0.001). However, the ROC curve analysis showed a higher accuracy for BMI than for the BAI regarding the discriminatory capacity.
Conclusion
The BAI could be a good tool to measure adiposity due, at least in part, to the advantages over other more complex mechanical or electrical systems. Probably, the most important advantage of BAI over BMI is that weight is not needed. However, in general it seems that the BAI does not overcome the limitations of BMI.
doi:10.1371/journal.pone.0035281
PMCID: PMC3322155  PMID: 22496915
19.  Monitoring Inequalities in the Health Workforce: The Case Study of Brazil 1991–2005 
PLoS ONE  2012;7(3):e33399.
Introduction
Both the quantity and the distribution of health workers in a country are fundamental for assuring equitable access to health services. Using the case of Brazil, we measure changes in inequalities in the distribution of the health workforce and account for the sources of inequalities at sub-national level to identify whether policies have been effective in decreasing inequalities and increasing the density of health workers in the poorest areas between 1991 and 2005.
Methods
With data from Datasus 2005 and the 1991 and 2000 Census we measure the Gini and the Theil T across the 4,267 Brazilian Minimum Comparable Areas (MCA) for 1991, 2000 and 2005 to investigate changes in inequalities in the densities of physicians; nurse professionals; nurse associates; and community health workers by states, poverty quintiles and urban-rural stratum to account for the sources of inequalities.
Results
We find that inequalities have increased over time and that physicians and nurse professionals are the categories of health workers, which are more unequally distributed across MCA. The poorest states experience the highest shortage of health workers (below the national average) and have the highest inequalities in the distribution of physicians plus nurse professionals (above the national average) in the three years. Most of the staff in poor areas are unskilled health workers. Most of the overall inequalities in the distribution of health workers across MCA are due to inequalities within states, poverty quintiles and rural-urban stratum.
Discussion
This study highlights some critical issues in terms of the geographical distribution of health workers, which are accessible to the poor and the new methods have given new insights to identify critical geographical areas in Brazil. Eliminating the gap in the health workforce would require policies and interventions to be conducted at the state level focused in poor and rural areas.
doi:10.1371/journal.pone.0033399
PMCID: PMC3314019  PMID: 22479392
20.  Maternal Obesity Enhances Collagen Accumulation and Cross-Linking in Skeletal Muscle of Ovine Offspring 
PLoS ONE  2012;7(2):e31691.
Maternal obesity (MO) has harmful effects on both fetal development and subsequent offspring health. We previously demonstrated that MO enhances collagen accumulation in fetal skeletal muscle, but its impact on mature offspring muscle collagen accumulation is unknown. Ewes were fed either a control diet (Con, fed 100% of NRC nutrient recommendations) or obesogenic diet (OB, fed 150% of NRC nutrient recommendations) from 60 days before conception to birth. All ewes received the Con diet during lactation. Male offspring were euthanized at 2.5 years (mean) and the left Longissimus dorsi (LD) muscle and semitendinosus (ST) muscle were sampled. Collagen concentration increased by 37.8±19.0% (P<0.05) in LD and 31.2±16.0% (P<0.05) in ST muscle of OB compared to Con offspring muscle. Mature collagen cross-linking (pyridinoline concentration) was increased for 22.3±7.4% and 36.3±9.9% (P<0.05) in LD and ST muscle of OB group respectively. Expression of lysyl oxidase, lysyl hydroxylase-2b (LH2b) and prolyl 4-hydroxylase (P4HA) was higher in OB LD and ST muscle. In addition, the expression of metalloproteinases (MMPs) was lower but tissue inhibitor of metalloproteinases (TIMPs) was higher in OB offspring muscle, indicating reduced collagen remodeling. MO enhanced collagen content and cross-linking in offspring muscle, which might be partially due to reduced collagen remodeling. Our observation that the collagen content and cross-linking are enhanced in MO offspring muscle is significant, because fibrosis is known to impair muscle functions and is a hallmark of muscle aging.
doi:10.1371/journal.pone.0031691
PMCID: PMC3279401  PMID: 22348119
21.  Early Hypothalamic FTO Overexpression in Response to Maternal Obesity – Potential Contribution to Postweaning Hyperphagia 
PLoS ONE  2011;6(9):e25261.
Background
Intrauterine and postnatal overnutrition program hyperphagia, adiposity and glucose intolerance in offspring. Single-nucleotide polymorphisms (SNPs) of the fat mass and obesity associated (FTO) gene have been linked to increased risk of obesity. FTO is highly expressed in hypothalamic regions critical for energy balance and hyperphagic phenotypes were linked with FTO SNPs. As nutrition during fetal development can influence the expression of genes involved in metabolic function, we investigated the impact of maternal obesity on FTO.
Methods
Female Sprague Dawley rats were exposed to chow or high fat diet (HFD) for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1 (PND1), some litters were adjusted to 3 pups (vs. 12 control) to induce postnatal overnutrition. At PND20, rats were weaned onto chow or HFD for 15 weeks. FTO mRNA expression in the hypothalamus and liver, as well as hepatic markers of lipid metabolism were measured.
Results
At weaning, hypothalamic FTO mRNA expression was increased significantly in offspring of obese mothers and FTO was correlated with both visceral and epididymal fat mass (P<0.05); body weight approached significance (P = 0.07). Hepatic FTO and Fatty Acid Synthase mRNA expression were decreased by maternal obesity. At 18 weeks, FTO mRNA expression did not differ between groups; however body weight was significantly correlated with hypothalamic FTO. Postnatal HFD feeding significantly reduced hepatic Carnitine Palmitoyltransferase-1a but did not affect the expression of other hepatic markers investigated. FTO was not affected by chronic HFD feeding.
Significance
Maternal obesity significantly impacted FTO expression in both hypothalamus and liver at weaning. Early overexpression of hypothalamic FTO correlated with increased adiposity and later food intake of siblings exposed to HFD suggesting upregulation of FTO may contribute to subsequent hyperphagia, in line with some human data. No effect of maternal obesity was observed on FTO in adulthood.
doi:10.1371/journal.pone.0025261
PMCID: PMC3182187  PMID: 21980407

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