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Context:Excess adipose tissue is a source of inflammation. Polycystic ovary syndrome (PCOS) is a proinflammatory state and is often associated with excess abdominal adiposity (AA) alone and/or frank obesity.Objective:To determine the effect of glucose ingestion on cytokine release from mononuclear cells (MNC) in women with PCOS with and without excess AA and/or obesity.Design:A cross-sectional study.Setting:Academic medical center.Patients:Twenty-three women with PCOS (seven normal weight with normal AA, eight normal weight with excess AA, eight obese) and 24 ovulatory controls (eight normal weight with normal AA, eight normal weight with excess AA, eight obese).Intervention:Three-hour 75-g oral glucose tolerance test (OGTT).Main Outcome Measures:Body composition was measured by dual energy x-ray absorptiometry. Insulin sensitivity was derived from the OGTT (ISOGTT). TNFα, IL-6, and IL-1β release was measured in supernatants of cultured MNC isolated from blood samples drawn while fasting and 2 hours after glucose ingestion.Results:Insulin sensitivity was lower in obese subjects regardless of PCOS status and in normal-weight women with PCOS compared with normal-weight controls regardless of body composition status. In response to glucose ingestion, MNC-derived TNFα, IL-6, and IL-1β release decreased in both normal-weight control groups but failed to suppress in either normal-weight PCOS group and in obese women regardless of PCOS status. For the combined groups, the cytokine responses were negatively correlated with insulin sensitivity and positively correlated with abdominal fat and androgens.Conclusions:Women with PCOS fail to suppress MNC-derived cytokine release in response to glucose ingestion, and this response is independent of excess adiposity. Nevertheless, a similar response is also a feature of obesity per se. Circulating MNC and excess adipose tissue are separate and distinct sources of inflammation in this population.

Our objective was to determine whether peripheral blood mononuclear cells express amyloid precursor protein (APP) and other mediators involved in the pathogenesis of Alzheimer's disease and whether their expression is suppressed by insulin.Ten obese type 2 diabetic patients were infused with insulin (2 U/h with 100 ml 5% dextrose/h) for 4 h. Patients were also infused with 5% dextrose/h or normal physiological saline for 4 h, respectively, on two other days as controls. Blood samples were obtained at 0, 2, 4, and 6 h.Insulin infusion significantly suppressed the expression of APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3β in peripheral blood mononuclear cells. Dextrose and saline infusions did not alter these indices. Insulin infusion also caused significant parallel reductions in nuclear factor-κB binding activity and plasma concentrations of serum amyloid A and intercellular adhesion molecule-1.A low dose infusion of insulin suppresses APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3β, key proteins involved in the pathogenesis of Alzheimer's disease, in parallel with exerting its other antiinflammatory effects.

Background: High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3). Hypothesis: The intake of a nutritional supplement containing resveratrol and muscadine grape polyphenols reduces HFHC meal-induced oxidative and inflammatory stress and stimulates the activity of the antioxidant transcription factor, Nrf-2, and its downstream targets. Methods: Ten normal, healthy subjects were given a 930-kcal HFHC meal either with placebo or with the supplement. Indices of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein (LBP), and the expression of TLR-4, CD14, IL-1β, TNFα, SOCS-3, Keap-1, NQO-1, and GST-P1 were measured. Results: The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47phox, TLR-4, CD14, SOCS-3, IL-1β, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes. Conclusion: A supplement containing resveratrol and muscadine polyphenols reduces the magnitude of oxidative stress, increase in lipopolysaccharide and LBP and TLR-4, CD14, IL-1β and SOCS-3 expression after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state.

Background: Because obesity is associated with chronic oxidative and inflammatory stress, and high-fat, high-carbohydrate meals induce significant oxidative and inflammatory stress in normal subjects, we have now hypothesized that the intake of a high-fat, high-carbohydrate meal would result in a greater and more prolonged oxidative and inflammatory stress in the obese than in normal subjects. Methods: Ten normal-weight and eight obese subjects were given a high-fat, high-carbohydrate meal after an overnight fast. Blood samples were collected at baseline and hourly following the meal for 3 h. Results: Reactive oxygen species generation by mononuclear cells increased significantly by 2 h in both groups but continued to increase significantly at 3 h in the obese subjects, whereas in normal subjects it returned to baseline. Levels of p47phox increased significantly (by 81 ± 26%) at 3 h in obese individuals (P < 0.05), whereas there was no significant change in p47phox in normal subjects. Nuclear factor-κB DNA binding in mononuclear cells increased significantly (by 48 ± 58%, P < 0.036) at 2 h but not at 3 h in normal subjects, whereas in the obese, nuclear factor-κB increased significantly at both 2 and 3 h (by 36 ± 57 and 42 ± 63%, respectively, P < 0.004). Matrix metalloproteinase-9 concentrations were significantly higher in the obese at baseline (580 ± 103.9 vs. 373 ± 30.03 ng/ml, P < 0.05) and increased to significantly greater concentrations after the meal than in the lean subjects. Conclusions: High-fat, high-carbohydrate meals induced a significantly more prolonged and greater oxidative and inflammatory stress in the obese. This may contribute to the increased atherogenic risk in obesity.