Health sciences, College of Arts and Science

Supplementary key words diabetic retinopathy • 12-and 15-HETEs • retinal vascular leakage • reduced nicotinamide adenine dinucleotide phosphate oxidase • retinal infl ammation • lipoxygenase • bioactive lipids Diabetic retinopathy (DR), the most prevalent micro-vascular complication of diabetes, is responsible for over 10,000 new cases of blindness every year in the United States alone (1). The risk of vision loss increases with the development of diabetic macular edema and/or retinal neovascularization (NV), the former being a direct consequence of blood-retinal barrier (BRB) dysfunction and the latter the result of widespread retinal ischemia (2). For years, signifi cant effort has been invested in elucidating the mechanisms that underlie destructive prereti-nal NV in DR (3). Nonetheless, considerably less is known about the molecular events that lead to BRB dysfunction that is characterized by enhanced retinal vascular perme-ability and recruitment of infl ammatory cells. Moreover, existing regimens of treatment carry nonspecifi c adverse effects. These include increased risk of thromboembolic incidence, neuronal toxicity, and geographic atrophy with anti-vascular endothelial growth factor (VEGF) therapies Abstract Retinal hyperpermeability and subsequent macu-lar edema is a cardinal feature of early diabetic retinopathy (DR). Here, we investigated the role of bioactive lipid me-tabolites, in particular 12/15-lipoxygenase (LOX)-derived metabolites, in this process. LC/MS lipidomic screen of human retinal endothelial cells (HRECs) demonstrated that 15-HETE was the only signifi cantly increased metabolite (2.4 ± 0.4-fold, P = 0.0004) by high glucose (30 mM) treatment. In the presence of arachidonic acid, additional eicosanoids generated by 12/15-LOX, including 12-and 11-HETEs, were signifi cantly increased. Fluorescein angiog-raphy and retinal albumin leakage showed a signifi cant decrease in retinal hyperpermeability in streptozotocin-induced diabetic mice lacking 12/15-LOX compared with diabetic WT mice. Our previous studies demonstrated the potential role of NADPH oxidase in mediating the permeability effect of 12-and 15-HETEs, therefore we tested the impact of intraocular injection of 12-HETE in mice lacking the catalytic subunit of NADPH oxidase (NOX2). The permeability effect of 12-HETE was signifi cantly reduced in NOX2 / mice compared with the WT mice. In vitro experiments also showed that 15-HETE induced HREC migration and tube formation in a NOX-dependent manner. Taken together our data suggest that 12/15-LOX is implicated in DR via a NOX-dependent mechanism. —Ibrahim,

Background: Activation of Toll-like-receptor 4 (TLR4) causes chronic inflammation that can result in obesity and metabolic syndrome (MeS). Aim: This study aimed to investigate the role of TLR4 polymorphisms of TLR4D299G/T399I, and its impact on protein expression of TLR4 in obese female subjects. Methodology: A prospective cross-sectional association study was performed on Arab female subjects from Qatar University. The subjects were categorized according to BMI classifications into two groups: "obese; n = 69" and "non-obese; n = 136". Anthropometric measurements, weight (kg), height (m) and waist circumference (WC) were evaluated, and the body mass index (BMI) was calculated. Fasting blood samples were collected, and assessment of glucose, lipid profile, C-reactive protein (CRP), leptin, IL-6 and insulin was performed. Insulin resistance was computed using HOMA-IR. Genotyping of the TLR4 polymorphisms of TLR4D299G (rs4986790) and TLR4T399I (rs4986791) was performed by the 5 nuclease assay by TaqMan MGB probe. Flow cytometry was used to evaluate the monocyte cell surface expression of TLR4. Results: The frequency distribution of the genotype revealed that homozygous AA is the most frequent among obese subjects (86.4%) for (TLR4D299G, A > G) and the homozygous CC genotype is the most frequent (92.4%) for (TLR4T399I, C > T). Haplotype analysis of TLR4 D299G/T399I showed that GT carriers had a significant association with increased probability of insulin resistance (odds ratio = 4.73; 95% CI 1.19-18.90; p-value = 0.016). The monocyte cell surface of TLR4 was significantly higher by 1.3 folds in obese compared to non-obese subjects. Conclusions: TLR4 D299G/T399I haplotype polymorphism is associated with an increased risk of insulin resistance with the upregulation of TLR4 protein expression in obese subjects.

The state of Qatar suffers from diabetes epidemic due to obesity-associated metabolic syndrome. However, the prevalence of insulin resistance prior to obesity, which could play an important role in the high prevalence of diabetes, has not yet been described. This study aims to compare the prevalence of insulin resistance in apparently healthy non-obese and obese participants from Qatar and identify the predictors of insulin resistance in different body mass index (BMI)-groups. In this cross-sectional study, 150 young healthy females from Qatar were dichotomized into four groups (underweight, normal weight, overweight and obese) based on their BMI. Anthropometric measures as well as fasting plasma levels of lipids, adipokines, blood glucose and insulin were recorded. The prevalence of insulin resistance as per homeostatic model assessment of insulin resistance (HOMA-IR) was estimated and differences between insulin sensitive and insulin resistant were compared. Linear models were used to identify predictors of insulin resistance in every BMI group. Prevalence of insulin resistance in non-obese healthy females from Qatar ranges between 7% and 37% and increases with BMI. Overall, predictors of insulin resistance in the Qatari population are triglycerides/high-density lipoprotein (HDL) ratio and free fat mass but vary according to the BMI group. The main predictors were triglycerides in normal weight, triglycerides/HDL in overweight and triglycerides/HDL and interleukin-6 (IL-6) in obese individuals. The high prevalence of insulin resistance in non-obese Qataris may partially explain diabetes epidemic. Larger studies are warranted to confirm these findings and identify underlying causes for insulin resistance in non-obese individuals in Qatar, aiming at targeted intervention before diabetes onset.

BACKGROUND: Serum adiponectin inversely correlates with the extent of coronary artery disease (CAD). OBJECTIVES: To investigate the clinical significance of measuring high molecular weight (HMW) adiponectin in addition to total adiponectin from different samples (peripheral veins and ostia of coronary arteries) in patients with CAD. METHODS: We studied 134 patients; 57 with acute coronary syndrome (ACS), 44 with stable angina and 33 healthy patients. Total and HMW adiponectin were measured in the coronary ostia and peripheral veins simultaneously. Venous levels of lipid profile, C-reactive protein, tumour necrosis factor-alpha, interleukin-6 and insulin were measured. RESULTS: Mean levels of HMW adiponectin in the coronary ostia were significantly correlated with the venous levels of total (r = 0.33, P = 0.002) and HMW (r = 0.37, P = 0.002) adiponectin. Mean levels of total and HMW adiponectin were lower in CAD patients versus controls (6.9 +/- 0.5 versus 7.9 +/- 0.7 microg/ml, P = 0.3 and 1.9 +/- 0.2 versus 3.1 +/- 0.3 microg/ml, P = 0.003). In the coronary ostia, levels of HMW adiponectin were higher in ACS than those with stable angina (1.1 +/- 0.1 versus 0.8 +/- 0.1 microg/ml, P = 0.2). In patients with CAD, levels of ostial adiponectin (total and HMW) were significantly lower in diabetic than non-diabetic patients (6.5 +/- 0.8 versus 9.4 +/- 1.1 microg/ml, P = 0.04 and 0.8 +/- 0.12 versus 1.2 +/- 0.1 microg/ml, P = 0.03). Mean levels of venous adiponectin (total and HMW) were non-significantly lower in diabetic patients (5.9 +/- 0.7 versus 7.7 +/- 0.7, P = 0.12 and 1.8 +/- 0.4 versus 1.9 +/- 0.1, P = 0.8). CONCLUSION: Measurement of HMW adiponectin and its ratio to total adiponectin may be a better marker for CAD than total adiponectin levels. Ostial levels of adiponectin in ACS may indicate re-distribution of adiponectin molecules towards the acute lesions. The low HMW adiponectin levels in diabetes mellitus may in part explain the worse outcome of CAD in diabetics.