By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas ␤-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for ␤-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6·2, peroxisome proliferator-activated receptor ␥, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of antihyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy. Glucose concentration in venous plasma (mmol/L) Diabetes mellitusFasting у7·0 or 2-h post-glucose load у11·1 Impaired glucose tolerance Fasting (if measured) Ͻ7·0 and 2-h post-glucose load у7·8 and Ͻ11·1 Impaired fasting glucose Fasting у6·1 and Ͻ7·0 and 2 h post-glucose load (if measured) Ͻ7·8Glucose load=75 g glucose orally. 10

The classical perception of adipose tissue as a storage place of fatty acids has been replaced over the last years by the notion that adipose tissue has a central role in lipid and glucose metabolism and produces a large number of hormones and cytokines, e.g. tumour necrosis factor-alpha, interleukin-6, adiponectin, leptin, and plasminogen activator inhibitor-1. The increased prevalence of excessive visceral obesity and obesity-related cardiovascular risk factors is closely associated with the rising incidence of cardiovascular diseases and type 2 diabetes mellitus. This clustering of vascular risk factors in (visceral) obesity is often referred to as metabolic syndrome. The close relationship between an increased quantity of visceral fat, metabolic disturbances, including low-grade inflammation, and cardiovascular diseases and the unique anatomical relation to the hepatic portal circulation has led to an intense endeavour to unravel the specific endocrine functions of this visceral fat depot. The objective of this paper is to describe adipose tissue dysfunction, delineate the relation between adipose tissue dysfunction and obesity and to describe how adipose tissue dysfunction is involved in the development of diabetes mellitus type 2 and atherosclerotic vascular diseases. First, normal physiology of adipocytes and adipose tissue will be described.

Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 ؎ 0.2 vs. 1.7 ؎ 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 ؎ 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 ؎ 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 ؎ 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 ؎ 6 to 112 ؎ 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 ؉ 2: from 0.4 ؎ 0.1 to 1.1 ؎ 0.2 nmol/l; D-dimer: from 0.27 ؎ 0.1 to 0.55 ؎ 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia. Diabetes 55:480 -486, 2006 P atients with diabetes have increased vascular vulnerability to atherogenic insults, leading to accelerated atherogenesis. Although atherogenesis is in part due to the increased prevalence of traditional cardiovascular risk factors, these factors cannot fully explain the propensity toward vascular complications in diabetic patients (1). Hyperglycemia itself has been shown to induce a wide array of downstream effects that adversely affect the protective capacity of the vessel wall (2). Hyperglycemia has been associated with enhanced endothelial permeability, increased leukocyte-endothelium adhesion, and impaired nitric oxide (NO) bioavailability (3-5). Despite clear progress in understanding the underlying pathophysiological mechanisms contributing to this vascular dysfunction, it has proven difficult to unravel a final common pathway for the increased vascular vulnerability under hyperglycemic conditions (6).The glycocalyx covers the endothelium and consists of endothelial cell-derived proteoglycans, glycoproteins, and adsorbed plasma proteins. This layer has been shown to orchestrate vascular homeostasis (7). Its thickness (up to 1 m) may explain its potent antiadhesive effects on leukocytes and platelets (8,9). Hyaluronan glycosaminoglycans, one of the major constituents of the glycocalyx, are crucial for maintaining endothelial barrier properties for plasma macromolecules (10). The glycocalyx also serves as a mechanosensor of shear stress, mediating shear-induced release of NO by endothelial cells (11-13). In fact, selective perturbation of the g...

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.