The status of fasting triglycerides as a risk factor for coronary artery disease (CAD) has been considered weak because in multivariate analyses, triglycerides tend to be eliminated by high density lipoprotein (HDL) cholesterol. To further evaluate the role of triglycerides in CAD, we employed postprandial lipemia as a more informative means of characterizing triglyceride metabolism. In 61 male subjects with severe CAD and 40 control subjects without CAD as verified by angiography, we measured cholesterol; triglycerides; HDL cholesterol; HDL 2 cholesterol; and apolipoproteins A-I, A-II, and B in fasting plasma and triglycerides before and 2, 4, 6, and 8 hours after a standardized test meal. Both the maximal triglyceride increase and the magnitude of postprandial lipemia (area under the triglyceride curve over 8 hours after the meal) were higher in cases than in control subjects. Single postprandial triglyceride levels 6 and 8 hours after the meal were highly discriminatory (p<0.001), and by logistic-regression analysis displayed an accuracy of 68% in predicting the presence or absence of CAD. In this respect, accuracy was higher than that of HDL 2 cholesterol (64%) and equal to that of apolipoprotein B (68%), the most discriminatory fasting parameter. Multivariate logistic-regression analysis was performed to reduce the number of risk factors to those that were statistically independent. This statistical procedure selected postprandial but not fasting triglycerides into the most accurate multivariate model, which also contained the accepted risk factors HDL 2 cholesterol, apolipoprotein B, and age. This model classified 82% of subjects correctly. We conclude that triglycerides are independent predictors of CAD in multivariate analyses including HDL cholesterol, provided that a challenge test of triglyceride metabolism such as postprandial lipemia is used. The study suggests that the metabolism of triglycerides is a critical determinant of cholesterol metabolic routing. The findings support the concept that the negative association between HDL cholesterol levels and CAD actually originates in part from a positive relation between CAD and plasma triglycerides, as ascertained in the postprandial state. (

Background-Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse. Methods and Results-After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. Conclusions-Optimal LDL-C values are Ͻ100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

We identified a childhood obesity locus on chromosome 6q16.3-q24.2 1 that includes 2.4 Mb common to eight genome scans for Type 2 diabetes (T2D) or obesity 1-8 . Analysis of the ENPP1 (PC-1) gene, a candidate for insulin resistance 9,10 in 6,147 subjects revealed association between a three allele risk haplotype (K121Q/IVS20 delT-11/A>G +1044 TGA, QdelTG) and childhood obesity (OR=1.69, p=0.0006), and in adults with morbid or moderate obesity (OR= 1.50, p= 0.006, OR= 1.37, p= 0.02) and also with T2D (OR=1.56, p=0.00002). The Genotype IBD Sharing Test suggested a contribution of this obesity-associated ENPP1 risk haplotype to the observed chromosome 6q linkage with childhood obesity. The haplotype confers a higher risk of glucose intolerance and T2D to obese children and to their parents and associates with increased serum levels of soluble ENPP1 protein in children. Expression of a long ENPP1 mRNA isoform, which includes the obesityassociated A>G +1044 TGA SNP, was found to be specific for pancreatic islet beta-cells, adipocytes and liver. These findings suggest a primary role for several variants of ENPP1 in mediating insulinresistance, in the development of both obesity and type 2 diabetes, suggesting an underlying molecular mechanism common to both widespread afflictions. Competing interests statementThe authors declare that they have no competing financial interests. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2007 October 4. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptInitially, the phenotypic characteristics of 62 "6q-evidence" families (defined by an individual pedigree Zscore > 1.0 in the 2-LOD drop interval flanked by markers D6S434 and D6S1704) were compared with the remaining 35 families from our previously published genome scan for childhood obesity 1 . The "6q-evidence" obese children have a trend towards higher area under the glycemia curve after glucose administration and a significantly lower insulinogenic index (Supplementary Table 1). Compared to none of the other families, 3.1% of the "6q-evidence" obese children are glucose intolerant or diabetic and 13.8% of 6q linked obese children parents have type 2 diabetes mellitus (T2D) compared to 3.2% of parents in other families (p=0.018). Thus, the obesity susceptibility gene(s) on chromosome 6q may be also involved in glucose homeostasis.The "6q-evidence" 2-LOD drop interval 1 covers 41.4 Mb and includes 166 referenced genes. This was narrowed to a 2.4 Mb interval between markers D6S1656 and D6S270 using overlapping published linkage results on chromosome 6q16.1-q27 with either obesity 2 , insulin secretion 3,4 or T2D 5-8 . Within this interval, the best candidate was ectonucleotide pyrophosphatase phosphodiesterase ENPP1 (also known as the Plasma Cell glycoprotein-1 PC-1). ENPP1 is believed to directly inhibit insulin-induced conformational changes of the insulin receptor, thereby affecting its activation and downstream signaling 9,11 .The microsatellite marker D6S1656 in...

A randomized trial is needed to eliminate possible selection biases in our observational study that are related to the prescription of replacement hormones. Nevertheless, hormone-replacement therapy appears to be associated with a favorable physiologic profile, which probably mediates its protective effects on cardiovascular disease. The use of estrogen combined with progestin appears to be associated with a better profile than the use of estrogen alone.

TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger's regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2.

OBJECTIVETo assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.RESEARCH DESIGN AND METHODSTo characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.RESULTSObese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4+FoxP3+ Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8+CD69+ T cells in visceral adipose tissue and kidneys of Treg-treated animals.CONCLUSIONSData suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

SUMMARY Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of “healthy” versus “unhealthy” obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal. Here, we tested a hypothesized anti-inflammatory role for heme oxygenase-1 (HO-1) in the development of metabolic disease. Surprisingly, in matched biopsies from “healthy” versus insulin-resistant obese subjects we find HO-1 to be among the strongest positive predictors of metabolic disease in humans. We find that hepatocyte and macrophage conditional HO-1 deletion in mice evokes resistance to diet-induced insulin resistance and inflammation, dramatically reducing secondary disease such as steatosis and liver toxicity. Intriguingly, cellular assays show that HO-1 defines prestimulation thresholds for inflammatory skewing and NF-κB amplification in macrophages and for insulin signaling in hepatocytes. These findings identify HO-1 inhibition as a potential therapeutic strategy for metabolic disease.