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BACKGROUND Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. METHODS A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (non-surgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. RESULTS The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was −45.0 kg (95% confidence interval [CI], −47.2 to −42.9; mean percent change, −35.0) at 2 years, −36.3 kg (95% CI, −39.0 to −33.5; mean percent change, −28.0) at 6 years, and −35.0 kg (95% CI, −38.4 to −31.7; mean percent change, −26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was −2.9 kg (95% CI, −6.9 to 1.0; mean percent change, −2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, −3.5 to 3.5; mean percent change, −0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). CONCLUSIONS This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

HE PREVALENCE OF EXTREMEobesity in the United States is increasing at a rate greater than moderate obesity. 1 , 2 Unfortunately, lifestyle therapy is generally insufficient as a weight management intervention for patients who are extremely obese. To date, effective long-term weight loss through pharmacological therapy has been marginal, leaving bariatric For editorial comment see p 1160.

At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores. IntroductionIncreased iron stores are associated with increased risk of type 2 diabetes (1-4), gestational diabetes (5), prediabetes (6), metabolic syndrome (MetS) (7), central adiposity (8), and cardiovascular disease (9, 10). The mechanisms underlying these associations are poorly understood. The commonly used marker for total body iron stores, serum ferritin, is also responsive to inflammatory stress (11, 12), so increased ferritin in diabetes could simply reflect the inflammatory component of that disease (13). On the other hand, phlebotomy improves glycemia and MetS traits (14-17), arguing that iron may play a causal role in diabetes.The possible mediators of the association between iron and diabetes risk are not known. Decreases in both insulin secretion and sensitivity have been linked to iron. Excess iron impairs pancreatic β cell function and causes β cell apoptosis (18-21). Recent studies have also found a negative correlation between serum ferritin and the insulin-sensitizing adipokine, adiponectin (3,(22)(23)(24). The hypothesis that adiponectin links iron and insulin resistance is appealing, as decreased adiponectin levels are associated with obesity and type 2 diabetes (25) and are causally linked with insulin resistance (26).We therefore investigated the mechanisms underlying the relationships among serum ferritin, adiponectin, and MetS in mice and humans. We demonstrate in humans that the association between serum ferritin and adiponectin is independent of inflammation and that serum ferritin, even within its normal ranges, is among the best predictors of serum adiponec...

Despite weight loss recommendations to prevent cancer, cancer outcome studies after intentional weight loss are limited. Recently, reduced cancer mortality following bariatric surgery has been reported. This study tested whether reduced cancer mortality following gastric bypass was due to decreased incidence. Cancer incidence and mortality data through 2007 from the Utah Cancer Registry (UCR) were compared between 6,596 Utah patients who had gastric bypass (1984–2002) and 9,442 severely obese persons who had applied for Utah Driver's Licenses (1984–2002). Study outcomes included incidence, case‐fatality, and mortality for cancer by site and stage at diagnosis of all gastric bypass patients, compared to nonoperated severely obese controls. Follow‐up was over a 24‐year period (mean 12.5 years). Total cancer incidence was significantly lower in the surgical group compared to controls (hazard ratio (HR) = 0.76; confidence interval (CI) 95%, 0.65–0.89; P = 0.0006). Lower incidence in surgery patients vs. controls was primarily due to decreased incidence of cancer diagnosed at regional or distant stages. Cancer mortality was 46% lower in the surgery group compared to controls (HR = 0.54; CI 95%, 0.37–0.78; P = 0.001). Although the apparent protective effect of surgery on risk of developing cancer was limited to cancers likely known to be obesity related, the inverse association for mortality was seen for all cancers. Significant reduction in total cancer mortality in gastric bypass patients compared with severely obese controls was associated with decreased incidence, primarily among subjects with advanced cancers. These findings suggest gastric bypass results in lower cancer risk, presumably related to weight loss, supporting recommendations for reducing weight to lower cancer risk.

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Background: Primary aldosteronism is a nonsuppressible renin-independent aldosterone production that causes hypertension and cardiovascular disease.Objective: To characterize the prevalence of nonsuppressible renin-independent aldosterone production, as well as biochemically overt primary aldosteronism, in relation to blood pressure.