To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

, and the complex formation between eNOS and heat shock protein 90, resulting in a marked reduction of NO production. Adenovirus-mediated overexpression of a constitutively active version of AMPK reversed these changes. In db/db diabetic mice, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased compared with their lean littermates. Taken together, these results suggest that APPL1 acts as a common downstream effector of AdipoR1 and -R2, mediating adiponectin-evoked endothelial NO production and endothelium-dependent vasodilation. Diabetes 56: [1387][1388][1389][1390][1391][1392][1393][1394] 2007 E ndothelial dysfunction, characterized by decreased production and/or bioactivity of nitric oxide (NO) and impaired endothelium-dependent vasodilation, is a key mediator that links obesity, diabetes, and cardiovascular diseases (1). Dysfunction of the endothelium in conduit arteries is a well-established antecedent of hypertension and atherosclerosis, whereas dysfunction of peripheral vascular endothelium at the arteriolar and capillary level contributes to the pathogenesis of insulin resistance and the metabolic syndrome (2). On the other hand, insulin resistance aggravates endothelial dysfunction. Therapeutic interventions in animal models and humans have demonstrated that improving endothelial function ameliorates insulin resistance, while increasing insulin sensitivity alleviates endothelial dysfunction (3).Adiponectin, an insulin-sensitizing adipokine secreted predominantly from adipocytes, possesses potent protective effects against endothelial dysfunction (4). Unlike most adipokines, plasma levels of adiponectin are decreased in obese individuals and patients with insulin resistance, type 2 diabetes, and cardiovascular diseases. An independent association between serum levels of adiponectin and endothelium-dependent vasodilation has been repeatedly documented (5-7). Hypoadiponectinemia has been closely linked to impairment in endotheliumdependent vasodilation in both normal subjects and patients with hypertension and type 2 diabetes. Consistent with these clinical findings, adiponectin-deficient mice exhibit reduced endothelium-dependent vasodilation on an atherogenic diet (6), increased neointimal hyperplasia after acute vascular injury (8,9), and elevated blood pressure compared with their wild-type littermates (10). On the other hand, both adenovirus-mediated overexpression of full-length adiponectin and transgenic overexpression of globular adiponectin result in a marked alleviation of atherosclerotic lesion in apolipoprotein E-deficient mice (11) and also cause a significant amelioration of endothelial dysfunction and hypertension (10) in obese mice.The endothelium-protective functions of adiponectin are mediated, at least in part, by its ability to increase the production of NO, a vasodilator synthesized by endothelial NO synthase (eNOS) from the precursor L-arginine (4,7,12). NO protects the vascular system by enhancing vasodilation and inhibiting platelet aggregation,...

Adiponectin is a major adipocyte-secreted adipokine abundantly present in the circulation as three distinct oligomeric complexes. In addition to its role as an insulin sensitizer, mounting evidence suggests that adiponectin is an important player in maintaining vascular homoeostasis. Numerous epidemiological studies based on different ethnic groups have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for endothelial dysfunction, hypertension, coronary heart disease, myocardial infarction and other cardiovascular complications. Conversely, elevation of circulating adiponectin concentrations by either genetic or pharmacological approaches can alleviate various vascular dysfunctions in animal models. Adiponectin exerts its vasculoprotective effects through its direct actions in the vascular system, such as increasing endothelial NO production, inhibiting endothelial cell activation and endothelium-leucocyte interaction, enhancing phagocytosis, and suppressing macrophage activation, macrophage-to-foam cell transformation and platelet aggregation. In addition, adiponectin reduces neointima formation through an oligomerization-dependent inhibition of smooth muscle proliferation. The present review highlights recent research advances in unveiling the molecular mechanisms that underpin the vascular actions of adiponectin and discusses the potential strategies of using adiponectin or its signalling pathways as therapeutic targets to combat obesity-related metabolic and vascular diseases.

Hepatic insulin resistance is the major contributor to fasting hyperglycemia in type 2 diabetes. Here we report that the endosomal adaptor protein APPL1 increases hepatic insulin sensitivity by potentiating insulin-mediated suppression of the gluconeogenic program. Insulin-stimulated activation of Akt and suppression of gluconeogenesis in hepatocytes are enhanced by APPL1 overexpression, but are attenuated by APPL1 knockdown. APPL1 interacts with Akt and blocks the association of Akt with its endogenous inhibitor tribble 3 (TRB3) through direct competition, thereby promoting Akt translocation to the plasma membrane and the endosomes for further activation. In db/db diabetic mice, the blockage of the augmented interaction between Akt and TRB3 by hepatic overexpression of APPL1 is accompanied by a marked attenuation of hyperglycemia and insulin resistance. These results suggest that the potentiating effects of APPL1 on insulin-stimulated suppression of hepatic glucose production are attributed to its ability in counteracting the inhibition of Akt activation by TRB3.