Type 2 Diabetes Is Associated with Reduced ATP-Binding Cassette Transporter A1 Gene Expression, Protein and Function

Objective Increasing plasma glucose levels are associated with increasing risk of vascular disease. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT). We studied the influence of plasma glucose on expression and function of a key mediator in RCT, the ATP binding cassette transporter-A1 (ABCA1) and expression of its regulators, liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor–γ (PPARγ). Methods and Results Leukocyte ABCA1, LXRα and PPARγ expression was measured by polymerase chain reaction in 63 men with varying degrees of glucose homeostasis. ABCA1 protein concentrations were measured in leukocytes. In a sub-group of 25 men, ABCA1 function was quantified as apolipoprotein-A1-mediated cholesterol efflux from 2–3 week cultured skin fibroblasts. Leukocyte ABCA1 expression correlated negatively with circulating HbA1c and glucose (rho = −0.41, p<0.001; rho = −0.34, p = 0.006 respectively) and was reduced in Type 2 diabetes (T2DM) (p = 0.03). Leukocyte ABCA1 protein was lower in T2DM (p = 0.03) and positively associated with plasma HDL cholesterol (HDL-C) (rho = 0.34, p = 0.02). Apolipoprotein-A1-mediated cholesterol efflux correlated negatively with fasting glucose (rho = −0.50, p = 0.01) and positively with HDL-C (rho = 0.41, p = 0.02). It was reduced in T2DM compared with controls (p = 0.04). These relationships were independent of LXRα and PPARγ expression. Conclusions ABCA1 expression and protein concentrations in leukocytes, as well as function in cultured skin fibroblasts, are reduced in T2DM. ABCA1 protein concentration and function are associated with HDL-C levels. These findings indicate a glycaemia- related, persistent disruption of a key component of RCT

Effects of Xanthine Oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: Results from 2 placebo-controlled studies

Background - In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results - In 10 CHF patients with normal serum uric acid (UA) levels (315±42 μmol/L) and 9 patients with elevated UA (535±54 μmol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 μg/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (P120 μmol/L in all patients (mean reduction 217±15 μmol/L, P<0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (+24%, P=0.027) and legs (+23%, P=0.029). Flow-dependent flow improved by 58% in arms (P=0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (P<0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (r=0.63, P<0.05). Conclusions - In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically

Intrahepatic insulin exposure, intrahepatocellular lipid and regional body fat in non-alcoholic fatty liver disease

The liver is the primary site of insulin clearance in humans (1). In passing from the portal vein into the systemic circulation, a substantial and variable proportion of newly secreted insulin is extracted by the liver (2). The metabolic role of this process is unclear. Early reports (3) suggested that hepatic insulin extraction might contribute to the control of systemic insulin concentrations, and more recently it has been suggested that reduction in hepatic insulin extraction could be part of the compensatory hyperinsulinemic response to maintain normal glucose levels in the presence of insulin resistance (4, 5). Alternatively, hepatic insulin extraction may contribute to the control of insulin-sensitive metabolic pathways in the liver, such as glucose production and lipogenesis (6, 7). The liver plays a pivotal role in lipid metabolism, importing serum free fatty acids and manufacturing, storing, and exporting lipids and lipoproteins (8). Insulin exposure is an integral part of hepatic lipid homeostasis. In the liver, insulin resistance seems, paradoxically, to be associated with a reduced ability of insulin signaling to inhibit glucose production, whereas insulin-stimulated lipogenesis is enhanced (9). Nonalcoholic fatty liver disease (NAFLD) is a common condition characterized by the deposition of fat, mainly triglyceride, within the liver, and it is associated with both whole body and hepatic insulin resistance (10, 11). Close, but complex relationships might therefore be expected between hepatic lipid accumulation, hepatic insulin exposure, and insulin resistance. Further levels of complexity may be anticipated if basal or post-glucose hepatic insulin exposure, hepatic or peripheral glucoregulatory insulin sensitivity, or antilipolytic insulin sensitivity and adiposity in different regional fat depots are taken into account. These considerations justify an investigation in which variation in a sophisticated measure of intrahepatocellular lipid (IHCL) is related to equally differentiated measures of hepatic insulin exposure, adiposity, and insulin sensitivity. To our knowledge, the relationship between hepatic lipid accumulation, hepatic insulin exposure, and insulin resistance has not previously been studied in a group of males with NAFLD and age- and gender-matched controls. We hypothesized that NAFLD is associated with increased exposure of the liver to insulin, and the aim of this study was to confirm this in the above cohort