Abstract-Human obesity is associated with an increased tumor necrosis factor-␣ (TNF-␣) mRNA expression in adipose tissue. TNF-␣ decreases insulin-dependent glucose uptake by inhibiting autophosphorylation of the insulin receptor, suggesting that TNF-␣ may play a role in insulin resistance. In this study, we analyzed plasma levels of TNF-␣ in 40 70-year-old men with newly detected non-insulin-dependent diabetes mellitus and in 20 age-matched controls. Twenty of the patients had a moderate level of insulin resistance and 20 were severely insulin resistant. The plasma levels of TNF-␣ were higher in patients (4.00Ϯ1.53 pg/mL in moderately insulin resistant and 4.91Ϯ1.43 pg/mL in severely insulin resistant subjects) than in controls (3.27Ϯ0.79 pg/mL, PϽ0.001). TNF-␣ was significantly related to body mass index, fasting glucose levels, and serum triglyceride levels and inversely related to the high density lipoprotein cholesterol level. The finding of an association between high plasma levels of TNF-␣ and several metabolic abnormalities characteristic for the insulin resistance syndrome suggests that TNF-␣ may be involved in the pathogenesis of non-insulin-dependent diabetes mellitus.

Abstract-Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been discussed as a part of the insulin resistance syndrome. However, it is not clear whether the relationship between PAI-1 and insulin resistance is independent of or mediated by increased triglycerides levels. The aim of this study was to investigate whether PAI-1 activity is associated with insulin sensitivity independently of serum triglycerides (sTG) and of other potential confounders. Seventy-year-old men (nϭ871), participating in a cohort study undergoing extensive metabolic investigations, had blood samples taken for determination of PAI-1 activity. Insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp. In multivariate correlation and regression analyses, insulin sensitivity was a statistically significant determinant of PAI-1 activity (partial rϭϪ.12; PϽ.001), independent of sTG, body mass index, waist-hip ratio, and other potential confounders.The levels of sTG were also independently related to PAI-1 activity (partial rϭ.18; PϽ.001). The relationships between PAI-1 and insulin sensitivity and sTG were independent of fasting glucose levels. Aggregation of risk factors of the insulin resistance syndrome was associated with increased activity of PAI-1 in men with normal glucose tolerance. We conclude that PAI-1 activity is related to insulin sensitivity and sTG, independently of each other and of other potential confounders, and that increased levels of PAI-1 should be regarded as a component of the insulin resistance syndrome. (Arterioscler Thromb Vasc Biol. 1998;18:258-264.)Key Words: plasminogen activator inhibitor-1 Ⅲ insulin sensitivity Ⅲ triglycerides Ⅲ hyperglycemia Ⅲ cardiovascular disease N on-insulin-dependent diabetes mellitus has a high and increasing prevalence, especially in countries that are rapidly becoming affluent. In white and South Asian populations, NIDDM is associated with a twofold to threefold increase in cardiovascular disease.1 An early characteristic in the development of NIDDM is "insulin resistance," a state in which the promoting effect of insulin on glucose uptake is decreased. The "insulin resistance syndrome" comprises several cardiovascular risk factors, including elevated blood pressure, glucose intolerance, central obesity, and an atherogenic lipoprotein pattern characterized by elevated concentrations of plasma triglycerides, decreased HDL cholesterol, and increased levels of small, dense LDL particles.2 The insulin resistance syndrome is associated with an increased risk for cardiovascular disease, even at normoglycemia. 3 Although insulin has been associated with an increased risk of ischemic heart disease, 4 it is possible that elevated levels of the major rapid inhibitor of fibrinolysis in blood, PAI-1, is an important mediator of the increased incidence of cardiovascular disease in insulin-resistant states.5 Both insulin and triglyceride-rich lipoproteins stimulate the production of PAI-1 in cultured cells.6 -12 PAI-1 has been shown to be associated with insulin re...

We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and >25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) ‫؍‬ 1.5, P ‫؍‬ 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR ‫؍‬ 3.4, P ‫؍‬ 0.001). The finding was subsequently replicated in two independent collections (combined OR ‫؍‬ 1.4, P < 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR ‫؍‬ 1.4, P ‫؍‬ 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.