Background-Circulating levels of interleukin-6 (IL-6) and tumor necrosis factor-␣ (TNF-␣) are elevated in diabetic patients. We assessed the role of glucose in the regulation of circulating levels of IL-6, TNF-␣, and interleukin-18 (IL-18) in subjects with normal or impaired glucose tolerance (IGT), as well as the effect of the antioxidant glutathione. Methods and Results-Plasma glucose levels were acutely raised in 20 control and 15 IGT subjects and maintained at 15 mmol/L for 5 hours while endogenous insulin secretion was blocked with octreotide. In control subjects, plasma IL-6, TNF-␣, and IL-18 levels rose (PϽ0.01) within 2 hours of the clamp and returned to basal values at 3 hours. In another study, the same subjects received 3 consecutive pulses of intravenous glucose (0.33 g/kg) separated by a 2-hour interval. Plasma cytokine levels obtained at 3, 4, and 5 hours were higher (PϽ0.05) than the corresponding values obtained during the clamp. The IGT subjects had fasting plasma IL-6 and TNF-␣ levels higher (PϽ0.05) than those of control subjects. The increase in plasma cytokine levels during the clamping lasted longer (4 hours versus 2 hours, PϽ0.01) in the IGT subjects than in the control subjects, and the cytokine peaks of IGT subjects after the first glucose pulse were higher (PϽ0.05) than those of control subjects. On another occasion, 10 control and 8 IGT subjects received the same glucose pulses as above during an infusion of glutathione; plasma cytokine levels did not show any significant change from baseline after the 3 glucose pulses. Conclusions-Hyperglycemia acutely increases circulating cytokine concentrations by an oxidative mechanism, and this effect is more pronounced in subjects with IGT. This suggests a causal role for hyperglycemia in the immune activation of diabetes.
Context Obesity is an independent risk factor for cardiovascular disease, which may be mediated by increased secretion of proinflammatory cytokines by adipose tissue. Objective To determine the effect of a program of changes in lifestyle designed to obtain a sustained reduction of body weight on markers of systemic vascular inflammation and insulin resistance. Design and Setting Randomized single-blind trial conducted from February 1999 to February 2002 at a university hospital in Italy. Patients One hundred twenty premenopausal obese women (body mass index Ն30) aged 20 to 46 years without diabetes, hypertension, or hyperlipidemia. Interventions The 60 women randomly assigned to the intervention group received detailed advice about how to achieve a reduction of weight of 10% or more through a low-energy Mediterranean-style diet and increased physical activity. The control group (n=60) was given general information about healthy food choices and exercise. Main Outcome Measures Lipid and glucose intake; blood pressure; homeostatic model assessment of insulin sensitivity; and circulating levels of interleukin 6 (IL-6), interleukin 18 (IL-18), C-reactive protein (CRP), and adiponectin. Results After 2 years, women in the intervention group consumed more foods rich in complex carbohydrates (9% corrected difference; PϽ.001), monounsaturated fat (2%; P=.009), and fiber (7 g/d; PϽ.001); had a lower ratio of omega-6 to omega-3 fatty acids (−5; PϽ.001); and had lower energy (−310 kcal/d; PϽ.001), saturated fat (−3.5%; P=.007), and cholesterol intake (−92 mg/d; PϽ.001) than controls. Body mass index decreased more in the intervention group than in controls (−4.2; PϽ.001), as did serum concentrations of IL-6 (−1.1 pg/mL; P=.009), IL-18 (−57 pg/mL; P=.02), and CRP (−1.6 mg/L; P=.008), while adiponectin levels increased significantly (2.2 µg/mL; P=.01). In multivariate analyses, changes in free fatty acids (P=.008), IL-6 (P=.02), and adiponectin (P=.007) levels were independently associated with changes in insulin sensitivity. Conclusion In this study, a multidisciplinary program aimed to reduce body weight in obese women through lifestyle changes was associated with a reduction in markers of vascular inflammation and insulin resistance.
Long-term vascular complications still represent the main cause of morbidity and mortality in diabetic patients. Although prospective randomized long-term clinical studies comparing the effects of conventional and intensive therapy have demonstrated a clear link between diabetic hyperglycemia and the development of secondary complications of diabetes, they have not defined the mechanism through which excess glucose results in tissue damage. Evidence has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications. This hypothesis is supported by evidence that many biochemical pathways strictly associated with hyperglycemia (glucose autoxidation, polyol pathway, prostanoid synthesis, protein glycation) can increase the production of free radicals. Furthermore, exposure of endothelial cells to high glucose leads to augmented production of superoxide anion, which may quench nitric oxide, a potent endothelium-derived vasodilator that participates in the general homeostasis of the vasculature. In further support of the consequential injurious role of oxidative stress, many of the adverse effects of high glucose on endothelial functions, such as reduced endothelial-dependent relaxation and delayed cell replication, are reversed by antioxidants. A rational extension of this proposed role for oxidative stress is the suggestion that the different susceptibility of diabetic patients to microvascular and macrovascular complications may be a function of the endogenous antioxidant status.
OBJECTIVE—To explore the possibility that oscillating glucose may outweigh A1C levels in determining the risk for cardiovascular diabetes complications. RESEARCH DESIGN AND METHODS—A euinsulinemic hyperglycemic clamp at 5, 10, and 15 mmol/l glucose was given in increasing steps as a single “spike” or oscillating between basal and high levels over 24 h in normal subjects and type 2 diabetic patients. Flow-mediated dilatation, a marker of endothelial function, and plasma 3-nitrotyrosine and 24-h urinary excretion rates of free 8-iso PGF2α, two markers of oxidative stress, were measured over 48 h postclamp. RESULTS—Glucose at two different levels (10 and 15 mmol/l) resulted in a concentration-dependent fasting blood glucose–independent induction of both endothelial dysfunction and oxidative stress in both normal and type 2 diabetic patients. Oscillating glucose between 5 and 15 mmol/l every 6 h for 24 h resulted in further significant increases in endothelial dysfunction and oxidative stress compared with either continuous 10 or 15 mmol/l glucose. CONCLUSIONS—These data suggest that oscillating glucose can have more deleterious effects than constant high glucose on endothelial function and oxidative stress, two key players in favoring cardiovascular complications in diabetes. Concomitant vitamin C infusion can reverse this impairment.
Background-Visceral fat is a key regulator site for the process of inflammation, and atherosclerotic lesions are essentially an inflammatory response. Methods and Results-Fifty-six healthy premenopausal obese women (age range 25 to 44 years, body mass index 37.2Ϯ2.2, waist to hip ratio range 0.78 to 0.92) and 40 age-matched normal weight women were studied. Compared with nonobese women, obese women had increased basal concentrations of tumor necrosis factor-␣ (TNF-␣, PϽ0.01), interleukin-6 (IL-6, PϽ0.01), P-selectin (PϽ0.01), intercellular adhesion molecule-1 (ICAM-1, PϽ0.02), and vascular adhesion molecule-1 (VCAM-1, PϽ0.05). Vascular responses to L-arginine (3 g IV), the natural precursor of nitric oxide, were impaired in obese women: reductions in mean blood pressure (PϽ0.02), platelet aggregation to adenosine diphosphate (PϽ0.05), and blood viscosity (PϽ0.05) were significantly lower as compared with those in the nonobese group. Concentrations of TNF-␣ and IL-6 were related (PϽ0.01) to visceral obesity, as well as to adhesin levels and responses to L-arginine. After 1 year of a multidisciplinary program of weight reduction (diet, exercise, behavioral counseling), all obese women lost at least 10% of their original weight (9.8Ϯ1.5 kg, range 7.5 to 13 kg).
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