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ATIENTS WITH TYPE 2 DIABETES mellitus (DM) have a marked increase in the risk of myocardial infarction (MI), and a substantially worse prognosis after MI compared with patients without diabetes. [1][2][3] In recent years, it has become apparent that optimal control of blood pressure and low-density lipoprotein cholesterol (LDL-C) level can substantially reduce excess cardiovascular risk in patients with diabetes. 4-6 However, even with optimal control of these potent cardiovascular risk factors, incremental risk for cardiovascular events remains high compared with individuals without diabetes. 2,3,6 New approaches are, therefore, needed to further reduce cardiovascular risk in patients with diabetes.Emerging evidence suggests that thiazolidinediones could be useful for reducing cardiovascular risk. In isolated vessel-wall cells, troglitazone, pioglitazone, and rosiglitazone have been shown to modulate gene expression in a manner that would be predicted to be atheroprotective in vivo. 7,8 In hu-mans, these agents have been shown to have beneficial effects on systemic inflammatory and coagulation markers, lipoprotein profile, and endothelial cell function. 9-12 Some of these beneficial ef-Author Affiliations are listed at the end of this article.

Subjects with diabetes have increased cardiovascular disease risk compared to those without diabetes. Addressing residual cardiovascular disease risk in this disease, beyond blood pressure and LDL cholesterol control, remains important as the prevalence of diabetes increases worldwide. The accelerated atherosclerosis and cardiovascular disease in diabetes is likely multifactorial and there are numerous therapeutic approaches that can be considered. Results of mechanistic studies conducted in isolated cells, animals, or humans can provide important insights with potential to influence clinical management decisions and improve outcomes. In this review, we focus on three areas in which pathophysiologic considerations could be particularly informative in this regard; the roles of hyperglycemia, diabetic dyslipidemia (beyond LDL cholesterol level), and inflammation (including that in adipose tissue) for accelerating vascular injury and the rates of cardiovascular disease in Type 2 diabetes are outlined and evaluated.

These findings suggest that SDB is pathophysiologically related to impaired glucose homeostasis, and that CPAP can be an important therapeutic approach for diabetic patients with SDB.

Abstract-The prevalence of obesity, especially among the young, is dramatically increasing in the United States. Obesity is associated with accelerated atherosclerosis and increased rates of cardiovascular death. There are many plausible mechanisms by which an increase in adipose tissue could adversely affect the vessel wall. These include the changes in blood pressure, glucose level, lipid/lipoprotein metabolism, and systemic inflammation. In addition, factors secreted by adipose tissue may directly influence vessel wall homeostasis by influencing the function of endothelial cells, arterial smooth muscle cells, and macrophages in the vessel wall. There is general agreement that central, as opposed to peripheral, adipose tissue confers the most cardio-metabolic risk. Although the basis of this differential risk has not been not established, the pattern of gene expression and secretory products in visceral fat would be predicted to be more atherogenic compared with that in subcutaneous peripheral fat. Numerous studies have shown the beneficial effects of weight loss on markers of cardiovascular risk but fewer have demonstrated improvement in direct measures of large vessel disease. The unfolding role of adipose tissue as an important metabolic and secretory organ provides new opportunities for developing more effective approaches for preventing obesity and its atherosclerotic complications. Key Words: obesity Ⅲ atherosclerosis Ⅲ adipocytokines Ⅲ lipoprotein metabolism Ⅲ visceral fat T he prevalence of obesity is dramatically increasing in the United States. [1][2][3] Of special concern is the sharp increase in obesity among children and adolescents. In to 2004.1% of US children were obese (as defined by being greater than the 95th percentile of sex-specific body mass index (BMI) for age growth charts); significantly increased compared with 1999 to 2000. Approximately 32.2% of US adults are obese as defined by a BMIՆ30 kg/m 2 . Extreme obesity (defined as a BMIՆ40 kg/m 2 ) affects 2.8% of men and 6.9% of women in the United States. Many studies have demonstrated that obesity increases mortality from all causes, including cardiovascular death. This review focuses on the contribution of excess adipose tissue to the major underlying cause of cardiovascular death, large vessel atherosclerosis. Studies measuring the effect of obesity on direct measures of large vessel atherosclerosis in humans are considered, along with evidence regarding potential mechanisms by which excess adipose tissue could adversely affect the vessel wall. Obesity and AtherosclerosisNumerous studies have demonstrated the effect of excess adipose tissue for increasing cardiovascular death for adolescents and adults up to 75 years of age. 4 -7 A number of more recent studies have specifically reported on the effect of excess adipose tissue on direct measures of macrovascular disease. Using the measurement of coronary artery calcium as a marker for coronary atherosclerosis, Cassidy et al studied 443 asymptomatic white individuals who had quantitatio...

Apolipoprotein E (apoE) is highly expressed in adipose tissue and adipocytes in which its expression is regulated by peroxisome proliferator-activated receptor (PPAR)-␥ agonists and tumor necrosis factor-␣. There is, however, no information regarding a role for endogenous apoE in differentiated adipocyte function. In this report, we define a novel role for apoE in modulating adipocyte lipid metabolism. ApoE ؊/؊ mice have less body fat and smaller adipocytes compared with wild-type controls. Freshly isolated adipose tissue from apoE ؊/؊ mice contains lower levels of triglyceride and free fatty acid, and these differences are maintained in cultured adipocytes derived from preadipocytes. Adenoviral expression of apoE in apoE ؊/؊ -cultured adipocytes increases triglyceride and fatty acid content. During incubation with apoE-containing triglyceride-rich lipoproteins, apoE ؊/؊ adipose tissue accumulates less triglyceride than wild type. The absence of apoE expression in primary cultured adipocytes also leads to changes in the expression of genes involved in the metabolism/turnover of fatty acids and the triglyceride droplet. Markers of adipocyte differentiation were lower in freshly isolated and cultured apoE ؊/؊ adipocytes. Importantly, PPAR-␥-mediated changes in lipid content and gene expression are markedly altered in cultured apoE ؊/؊ adipocytes. These results establish a novel role for endogenous apoE in adipocyte lipid metabolism and have implications for constructing an integrated model of adipocyte physiology in health and disease. Diabetes 55:3394 -3402, 2006 O besity and its consequent insulin resistance are major health problems in the U.S., imparting significant risk for diabetes and cardiovascular disease (1-4). The prevalence of obesity is predicted to substantially increase over the next several decades, and there is a need to better understand adipocyte and adipose tissue physiology. In the past several years, it has become apparent that adipocytes and adipose tissue actively modulate systemic substrate availability and produce a number of protein factors with endocrine, paracrine, and autocrine regulatory activity (5,6). Apolipoprotein E (apoE), which was first described as a product of hepatocytes and a surface component of lipoproteins, e.g., in humans, chylomicrons, VLDL, remnant lipoproteins, and HDL, has been shown to be highly expressed in adipocytes and adipose tissue (7). Interestingly, apoE has been shown to be highly expressed in a number of cell types that experience high lipid flux (8 -15). The physiologic role of apoE expression in other cell types has been intensively studied and characterized (8 -15). In macrophages and steroidogenic cells, for example, endogenous apoE expression plays an important role in cellular lipid balance. Adipocytes and adipose tissue, like macrophages and steroidogenic cells, also experience large lipid fluxes integral to their differentiated function, yet there is no information regarding a potential physiologic role of apoE expressed in the adipocyte. Our lab...

BackgroundInability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.MethodsWe developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21).ResultsStem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6) and patients with no residual pancreatic islet β cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.ConclusionsStem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01350219.

BackgroundIt is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. MethodsIn this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. ResultsThe cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P = 0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P = 0.85). ConclusionsAmong patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)Copyright © 2010 Massachusetts Medical Society. All rights reserved.Downloaded from www.nejm.org by JEAN-CHRISTOPHE PHILIPS on May 3, 2010 .T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 362;16 nejm.org april 22, 2010 1478 P atients with impaired glucose tolerance have an increased risk of type 2 diabetes mellitus and cardiovascular disease. [1][2][3] Interventions that might reduce the incidence of diabetes and associated rates of death and complications from cardiovascular causes in such patients are therefore of importance. 3 Several trials have shown that lifestyle modification, including increased physical activity and weight loss, reduces the risk of diabetes, although these trials did not evaluate cardiovascular outcomes. [3][4][5][6][7][8] Certain drugs, including metformin, acarbose, and rosiglitazone, also reduce the incidence of diabetes, although their effect on cardiovascular events is uncertain. 6,9,10 Another pharmacologic approach to reducing the risk of diabetes and cardiovascular disease is inhibition of the renin-angiotensin system. Some studies have shown that angiotensin-convertingenzyme (ACE) inhibitors and ang...