Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss.

OBJECTIVE: To determine whether the expression of key asthma related genes, IL-4, LIGHT, LTBR, MMP-9, CCR-2, and ADAM-33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP-9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB). DESIGN AND METHODS: The expression of these genes in MNC and plasma concentrations of these indices was measured in healthy lean and in obese with and without T2DM and following RYGB in obese T2DM. RESULTS: The expression of IL-4, MMP-9, LIGHT and CCR-2 and plasma NOM concentrations was significantly higher in the obese subjects and in obese T2DM patients than in normal subjects. The expression of IL-4, LIGHT, MMP-9, and CCR-2 expression was related to BMI and HOMA-IR. The expression of IL-4, LIGHT, LTBR, ADAM-33, MMP-9, and CCR-2 fell after RYGB surgery as did plasma concentrations of MMP-9 and NOM. CONCLUSIONS: Obesity with and without T2DM is associated with an increase in the expression of IL-4, LIGHT, MMP-9 and CCR-2; plasma NOM and MMP-9 concentrations are also increased. Following RYGB surgery and weight loss, the expression of these factors in MNC and plasma concentrations falls significantly.

A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal.

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, NF-E2-related factor-2 (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 toll-like receptor 4 (TLR-4), CD14, IL-1ß, TNFα, SOCS-3, Keap-1, NAD(P)H:quinone oxidoreductase-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 p47(phox), TLR-4, CD14, SOCS-3, IL-1ß, 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 suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1ß and SOCS-3 in mononuclear cells 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.

Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations.

OBJECTIVE: To determine (1) whether long-term treatment with exenatide is associated with reductions in C-reactive protein (CRP), systolic blood pressure (BP), and triglyceride concentrations in addition to reductions in body weight and hemoglobin A(1c) (A1C) levels and (2) whether these beneficial results persist without any loss of effect while exenatide is being used, and whether they reverse after its cessation. METHODS: We conducted a retrospective review of 141 patients with type 2 diabetes mellitus treated with exenatide at a tertiary clinic. RESULTS: Exenatide (mean duration of treatment, 1.4 years) decreased A1C (0.7%), weight (5 kg), systolic BP (8 mm Hg), and triglyceride concentrations (46 mg/dL) (P<.05 for all). Sixty-one patients continued exenatide therapy throughout the study (mean duration of use, 2.4 years). Exenatide treatment reduced their mean weight by 7 kg, systolic BP by 8 mm Hg, triglycerides by 52 mg/dL, A1C by 1.3%, and CRP by 2.4 mg/L (P<.05 for all). Reductions in systolic BP and CRP were not related to weight loss. The reduction in CRP concentration was significantly related to the baseline CRP concentration (r = 0.78; P<.001) and to change in A1C (r = 0.68; P = .02). Patients who stopped taking exenatide had a reversal of the benefits within 6 months after cessation of treatment. CONCLUSION: Exenatide treatment in patients with type 2 diabetes has durable and persistent beneficial effects on A1C, weight, CRP, systolic BP, and triglyceride concentrations. Cessation of treatment reverses all these beneficial effects within 6 months. There was no evidence of loss of its effects while exenatide treatment was continued.

Suppressive effect of insulin infusion on chemokines and chemokine receptors.

OBJECTIVE: In view of the previously described anti-inflammatory effects of insulin, we investigated the potential suppressive effect of insulin on plasma concentrations and expression of the chemokines, monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normal T-cell expressed and secreted (RANTES) and their receptors, chemokine receptor (CCR)-2 and CCR-5, in mononuclear cells (MNCs). We also investigated the effect of insulin on other chemokines. RESEARCH DESIGN AND METHODS: Ten obese type 2 diabetic patients were infused with insulin (2 units/h with 100 ml of 5% dextrose/h) for 4 h. Another 8 and 6 type 2 diabetic patients were infused with 100 ml of 5% dextrose/h or saline for 4 h, respectively, and served as control subjects. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS: Insulin infusion significantly suppressed the plasma concentrations of MCP-1, eotaxin, and RANTES and the expression of RANTES, macrophage inflammatory protein (MIP)-1beta, CCR-2, and CCR-5 in MNCs at 2 and 4 h. Dextrose and saline infusions did not alter these indexes. CONCLUSIONS: A low-dose infusion of insulin suppresses the plasma concentration of key chemokines, MCP-1, and RANTES, and the expression of their respective receptors, CCR-2 and CCR-5, in MNCs. Insulin also suppresses the expression of RANTES and MIP-1beta in MNCs. These actions probably contribute to the comprehensive anti-inflammatory effect of insulin.