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1.  Leukotriene Production Is Increased in Abdominal Obesity 
PLoS ONE  2014;9(12):e104593.
Obesity is a major risk factor for insulin resistance and type-2 diabetes. A chronic low grade inflammatory state has been described during obesity and associated with insulin resistance pathogenesis. Results from animal studies are in favor of a role of the leukotriene (LT) pathway in obesity induced-insulin resistance. However, there is a paucity of data regarding this association in human obesity. Therefore, the aim of this study was to investigate whether LT production was associated with insulin resistance and other metabolic parameters in a cohort of obese subjects. Forty-six (70% females) obese subjects (BMI≧30 kg/m2) without known diabetes and without inflammatory disease (CRP<10 mg/l) were included. Median age was 44 years (16–80) with a median BMI of 36.8 kg/m2 (30–51). Insulin resistance was evaluated by HOMA-IR index and glucose tolerance test. Urinary LTE4 (U-LTE4) concentration was measured by enzyme immune assay. Screening for obstructive sleep apnea was performed. There was a positive association of U-LTE4 with waist to hip ratio, systolic blood pressure and HOMA-IR in univariate analysis. Further, waist to hip ratio remained the only parameter significantly correlated with U-LTE4, in adjusted multivariate analysis. Taken together, these results confirm the previously established notion of chronic low grade inflammation in obesity and further suggests a role for the LT pathway in obesity-associated development of insulin resistance in humans.
doi:10.1371/journal.pone.0104593
PMCID: PMC4249847  PMID: 25437865
2.  Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients 
Diabetes Care  2013;36(6):1454-1461.
OBJECTIVE
To assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk.
RESEARCH DESIGN AND METHODS
Thirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR.
RESULTS
In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.
CONCLUSIONS
A natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.
doi:10.2337/dc12-1652
PMCID: PMC3661802  PMID: 23275372
3.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
4.  Long-Term Outcome and Disability of Diabetic Patients Hospitalized for Diabetic Foot Ulcers 
Diabetes Care  2008;31(7):1288-1292.
OBJECTIVE—The long-term outcome and functional status of subjects hospitalized for diabetic foot ulcers have been poorly studied and thus are the topics of this study.
RESEARCH DESIGN AND METHODS—Ninety-four consecutive diabetic subjects hospitalized for diabetic foot ulcers between January 1998 and December 2000 were prospectively followed for mean ± SD 79.5 ± 13.3 months. We calculated rates of primary healing, new ulcers, amputations, mortality, and disability and evaluated the global therapeutic success (GTS) of foot care management as defined by the association of primary healing without recurrence or disability at the end of follow-up.
RESULTS—Follow-up was successful in 89 of 94 subjects (63 men and 31 women; age 63.7 ± 10.8 years). Of these, 69 (77.5%) experienced primary healing without major amputation, 39 (43.8%) underwent amputation (24 minor and 15 major), and 46 died (51.7%), including 23 from cardiovascular events. Forty-two of 69 patients who experienced primary healing (60.9%) had ulcer recurrence. At the end of the follow-up period, 25 patients (28.1%) were dependent and 40 subjects (44.9%) had achieved GTS. Multivariate analysis showed the role of age as an independent predictor of GTS (P < 0.05) and of impaired renal function/albuminuria as independent predictors of healing failure, first amputation, and mortality (P < 0.01).
CONCLUSIONS—Despite a satisfactory initial healing rate, the global long-term outcome of patients hospitalized for diabetic foot ulcers was poor. Nephropathy appears to be an important predictor of long-term outcome. Further studies are needed to establish recognized criteria for therapeutic success going beyond just the evaluation of healing rate in the management of diabetic foot ulcers.
doi:10.2337/dc07-2145
PMCID: PMC2453665  PMID: 18390801

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