Biomedical subjects
Publications and source records attributed to Ahmad Aljada.
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Fasting hyperinsulinemia is associated with an increased risk of atherosclerotic complications, namely heart attack and stroke, which has led to the concept that insulin may promote atherosclerosis despite the absence of any evidence that insulin is atherogenic either in humans or in experimental models. Recent evidence shows that insulin exerts vasodilatory, antiplatelet, and anti-inflammatory effects at the cellular level in vitro and in humans in vivo. Because atherosclerosis is an inflammatory process, insulin is probably antiatherosclerotic in the long-term. Recent data on experimental atherosclerosis in mice show that (a) insulin administration reduces the number and the size of atherosclerotic lesions in apolipoprotein E null mice; and (b) in insulin receptor substrate-2 null mice, the interruption in insulin signal transduction results in enhanced atherogenicity. The use of a low dose of insulin infusion in patients with acute myocardial infarction (AMI) has been shown to markedly improve clinical outcomes both in diabetic and nondiabetic patients. The authors' most recent data show that a low-dose infusion of insulin in patients with AMI induces a reduction in inflammation (C-reactive protein and serum amyloid A) and oxidative stress and may have a role in myocardial protection. The authors conclude that insulin is both anti-inflammatory and antiatherogenic and may be of use in the treatment of cardiovascular inflammatory conditions, including AMI.
In view of the pro-oxidant and proinflammatory effects of angiotensin II, we have tested the hypothesis that valsartan, an angiotensin receptor blocker, may exert a suppressive action on reactive oxygen species (ROS) generation, nuclear factor kappa B (NF-kappa B) in mononuclear cells. Four groups of eight normal subjects were given 1) 160 mg daily of valsartan, 2) 80 mg daily of simvastatin, 3) 40 mg quinapril, or 4) no treatment. Fasting blood samples were obtained before treatment and at d 1, 8, and 14 (7 d after the cessation of the drug). After valsartan, ROS generation by polymorphonuclear cells and mononuclear cells fell significantly by more than 40% (P < 0.01). NF-kappa B binding activity and the expression of total cellular p65, a protein component of NF-kappa B, fell significantly (P < 0.01). The expression of inhibitor kappa B (I kappa B) increased significantly (P < 0.05). Plasma C-reactive protein (CRP) concentration fell significantly (P < 0.01). All indices, except I kappa B, reverted toward baseline, 7 d after the cessation of the drug. I kappa B persisted in an elevated state. Neither quinapril nor simvastatin given for 7 d produced a suppression of ROS generation, intranuclear NF-kappa B, p65, or CRP, and these two agents did not alter cellular I kappa B either. The untreated controls also did not demonstrate a change in their ROS generation or NF-kappa B binding activity or plasma CRP concentration. We conclude that valsartan at a modest dose exerts a profound and rapid ROS and inflammation-suppressive effect that may be relevant to its potential beneficial effects in atherosclerosis, diabetes, and congestive cardiac failure. In contrast, quinapril and simvastatin produced no similar effect over the period of 1 wk. Our observations may also have implications to clinical situations in which a rapid antiinflammatory effect is required.
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To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-kappaB (NF-kappaB) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-kappaB, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-kappaB binding activity in the MNC nuclear extracts increased to 163 +/- 17% and 144 +/- 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-kappaB p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 +/- 1.1% at baseline to 4.3 +/- 1.9% and 2.7 +/- 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flow-mediated vasodilation of the brachial artery.
OBJECTIVE: We recently demonstrated a potent anti-inflammatory and thus a potential antiatherogenic effect of insulin in human aortic endothelial cells and mononuclear cells at physiologically relevant concentrations. We have now further investigated the anti-inflammatory suppressive action of insulin on vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. VEGF and MMP-9 play a central regulatory role in angiogenesis, contribute to the pathogenesis of proliferative retinopathy, and have also been found to accelerate atherosclerosis. RESEARCH DESIGN AND METHODS: Insulin was infused (2 IU/h) in 5% dextrose (100 ml/h) and KCl (8 mmol/h) into 10 fasting, obese, nondiabetic subjects for 4 h. Subjects were also infused with 5% dextrose without insulin and with saline on two separate occasions. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS: Plasma insulin concentrations increased from a basal level of 12.5 +/- 2.2 to 28.2 +/- 3.3 micro U/ml at 2 h and 24.4 +/- 3.7 micro U/ml at 4 h after insulin infusion. VEGF concentration decreased from 307.2 +/- 163.8 pg/ml (100%) at 0 h to 73.5 +/- 20.9% of the basal level at 2 h and 67.1 +/- 23.2% at 4h. Plasma MMP-9 concentrations decreased from 375 +/- 196.3 ng/ml (100%) at 0 h to 83 +/- 22% of the basal level at 2 h and to 82 +/- 21% of the basal level at 4 h (P < 0.05). Dextrose infusion alone did not change plasma VEGF concentration. However, plasma MMP-9 concentration increased significantly at 4 h following dextrose infusion alone (P < 0.05). Saline infusions without insulin caused no alteration in glucose, insulin, VEGF, or MMP-9. CONCLUSIONS: These observations may have implications for a potential antiretinopathic and antiatherosclerotic effect of insulin in the long term.
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Type 2 diabetes and obesity are major risk factors for the development of coronary artery disease (CAD) and premature atherosclerosis. Both conditions are associated with insulin resistance, oxidative stress, and inflammation. Inflammatory mediators, including plasma interleukin 6, tumor necrosis factor alpha, and tumor necrosis factor R are elevated in these individuals. The elevations of inflammatory mediators may contribute to the pathogenesis of atherosclerosis, because atherosclerosis is an inflammation of the arterial wall. There is evidence that the thiazolidinedione (TZD) class of drugs may alleviate some of the adverse atherosclerotic effects common in patients with type 2 diabetes. Considerable recent data suggest that the TZDs possess anti-inflammatory properties and exert an effect on the atherogenic process, including effects on endothelial function, monocyte/macrophage function, lipid abnormalities, smooth muscle cell migration, and fibrinolysis, all functions that are abnormal in the presence of insulin resistance. These actions of TZDs are consistent with the recently described anti-inflammatory effects of insulin. The use of TZDs as potent anti-inflammatory agents in patients with type 2 diabetes is an approach that would normalize glucose levels, as well as potentially alleviate the long-term risk of atherosclerosis.
AIM: The purpose of this study was to assess the response of diabetics to scaling and root planing treatment and subgingival oral irrigation as adjunctive therapy. METHOD: A total of 52 type 1 and 2 diabetics (mean age 51.3+/-14) with adult periodontitis were randomized to two groups. Treatment included ultrasonic scaling and scaling and root planing in both groups (control and test) plus subgingival water irrigation 2x daily for the test group. Assessments were made prior to and at 6 and 12 weeks after treatment. Parameters measured were modified gingival index (MGI), probing pocket depth (PPD), plaque index (PI), clinical attachment level (CAL), and bleeding on probing (BOP). Systemic measurement of Reactive Oxygen Species (ROS) generation, cytokines (TNF-alpha, IL-1beta, IL-10, and PGE2), and glycated hemoglobin (HbA1C). RESULTS: After treatment, analysis of data showed that both groups had clinical and systemic improvement. The test group had a statistically significant reduction for MGI, PI, and BOP compared to controls (p<0.03) at 12 weeks and for ROS generation at 12 weeks (p<0.012). Unlike controls, systemic analysis of cytokines showed a statistically significant reduction from baseline for IL-1beta at 6 weeks and PGE2 at 6 and 12 weeks (p<0.05) within test group. CONCLUSION: These results suggest that scaling and root planing and adjunctive therapy may be of value in establishing a healthy periodontium in diabetics.
Insulin exerts a vasodilatory effect through the release of nitric oxide (NO) from the endothelium. We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. The inhibition of ICAM-1 by insulin is NO dependent. Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. TNF-alpha (1 to 5 ng/mL) caused e-NOS inhibition in a dose-dependent fashion as measured by Western blotting. This inhibition was reduced with insulin addition. TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. Our data demonstrate that TNF-alpha may exert its effect by inhibiting IR autophosphorylation in HAEC and also by reducing IR protein (IRP) expression. Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel.
BACKGROUND: It was recently shown that glucose challenge leads to increased generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs). OBJECTIVE: To further elucidate the relation between nutrition and ROS generation, we investigated the effect of lipid and protein challenges on ROS generation by leukocytes. DESIGN: After having fasted overnight, one group of healthy subjects consumed a carbohydrate- and protein-free cream preparation (1257 kJ) and another group of healthy subjects consumed an equienergetic pure preparation of casein. Sequential blood samples were obtained after the intake of cream and casein. ROS were measured by chemiluminescence after stimulation by N-formyl-methionyl-leucinyl-phenylalanine. Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) and alpha-tocopherol was measured by HPLC. RESULTS: ROS generation by MNCs and PMNs increased significantly 1, 2, and 3 h after cream intake and 1 h after protein intake. Cholesterol concentrations did not change significantly, whereas triacylglycerol concentrations increased significantly 2 h after cream intake. Total TBARS concentrations increased 1 h after cream intake and remained elevated 3 h after intake, but the increase was not significant when corrected for changes in triacylglycerol. After casein intake, total cholesterol, triacylglycerol, and TBARS concentrations did not change significantly. alpha-Tocopherol concentrations did not change significantly after either cream or casein intake. CONCLUSIONS: Both fat and protein intakes stimulate ROS generation. The increase in ROS generation lasted 3 h after cream intake and 1 h after protein intake. Cream intake also caused a significant and prolonged increase in lipid peroxidation. These data are important because increased ROS generation and lipid peroxidation are key events in atherogenesis.
We have recently demonstrated that an infusion of a low dose of insulin reduces the intranuclear NF-kappa B (a pro-inflammatory transcription factor) content in MNC while also reducing the plasma concentration of NF-kappa B dependent pro-inflammatory cytokines and adhesion molecules. We have now tested the effect of insulin on the pro-inflammatory transcription factor, early growth response-1 (Egr-1) and plasma concentration of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), two major proteins whose expression is modulated by Egr-1. Insulin was infused at the rate of 2 IU/h in 5% dextrose (100 mL/h) and KCI (8 mmol/h) for 4 h in the fasting state in ten obese subjects. Blood samples were obtained at 0, 2, 4 and 6 h. MNC were isolated and their total homogenates and nuclear fractions were prepared and Egr-1 was measured by electrophoretic mobility shift assay (EMSA). Plasma TF and PAI-1 were assayed by ELISA. There was a significant fall in Egr-1 at 2 (66 +/- 14% of basal level) and 4 h (47 +/- 17% of the basal level; P<0.01). PAI-1 levels (basal = 100%) decreased significantly after insulin infusion at 2 h (57 +/- 6.7% of the basal level) and at 4 h (58 +/- 8.3% of the basal level; P<0.001). Plasma TF levels (basal = 100%) decreased to 76 +/- 7.7% of the basal level at 2 h and to 85 +/- 10.4% of the basal level at 4 h (P<0.05). Thus, insulin reduces intranuclear Egr-1 and the expression of TF and PAI-1. These data provide further evidence that insulin has an anti-inflammatory effect including the inhibition of TF and PAI-1 expression. These effects suggest a potential beneficial effect of insulin in thrombin formation and fibrinolysis in atherothrombosis.
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Lipid hydroperoxides (LHP) at high concentrations are cytotoxic, but at sublethal concentration, they induce synthesis of cytokine vascular growth factors. Intracorneal injections of 30 μg LHP placed 5 mm from the superior limbus stimulated early vasodilation of limbal vasculature and a rapidly developing, sustained neovascularization. Under these conditions, vessels grew at the rate of 0.3 mm/day to a total length of 7.5 mm, 25 days after injection. Cholesterol peroxides were less effective. Developing vessels were oriented towards the stimulus. Around the developing vessel there was dissolution of the stromal extracellular matrix. The most distal endothelial cells displayed prominent endoplasmic reticulum, a lack of basement membrane or tight junction complexes and leakage of fluorescein dye. Both the injection site and superior quadrant showed increased levels of tumor necrosis factor (TNF)-alpha and vascular endothelial growth factor after exposure to LHP. The neovascular response was inhibited by simultaneous administration of TNF-alpha antibody or pentoxifylline, an inhibitor of TNF-alpha synthesis. This corneal model of peroxide-induced neovascularization should prove useful for temporal studies of events in the initiation and propagation of signals leading to neovascularization, and for evaluating effects of treatment on neovascular growth.
Endothelial dysfunction is increasingly recognised as a key event in the pathogenesis of atherosclerosis, which occurs in association with insulin resistance early in the course of type 2 diabetes mellitus (T2DM). Thiazolidinediones (TZDs), such as rosiglitazone, are a class of oral antidiabetic agents that act primarily as insulin sensitisers, reducing insulin resistance with associated improvements in glycemic control. Available data indicate that thiozolidinediones also have beneficial effects on numerous markers of endothelial function and profound antiinflammatory activity, indicative of potential antiatherogenic activity. These effects may be of considerable clinical significance if sustained during long-term therapy, given the morbidity and mortality associated with atherosclerosis in T2DM patients.