Perspectives of Health-Care Providers Toward Advance Care Planning in Patients With Advanced Cancer and Congestive Heart Failure.

BACKGROUND: Advance care planning (ACP) discussions afford patients and physicians a chance to better understand patients' values and wishes regarding end-of-life care; however, these conversations typically take place late in the course of a disease. The goal of this study was to clarify attitudes of oncologists, cardiologists, and primary care physicians (PCPs) toward ACP and to identify persistent barriers to timely ACP discussion following a quality improvement initiative at our health system geared at improvement in ACP implementation. METHODS: A 20-question, cross-sectional online survey was created and distributed to cardiologists, oncologists, PCPs, and cardiology and oncology support staff at the NorthShore University HealthSystem (NorthShore) from February to March 2015. A total of 117 individuals (46% of distributed) completed the surveys. The results were compiled using an online survey analysis tool (SurveyMonkey, Inc., Palo Alto, California, USA). RESULTS: Only 15% of cardiologists felt it was their responsibility to conduct ACP discussions with their patients having congestive heart failure (CHF). In contrast, 68% of oncologists accepted this discussion as their responsibility in patients with terminal cancer ( P < .01). These views were mirrored by PCPs, as 68% of PCPs felt personally responsible for ACP discussion with patients having CHF, while only 34% felt the same about patients with cancer. Reported documentation of these discussions in the electronic health record was inconsistent between specialties. Among all surveyed specialties, lack of time was the major barrier limiting ACP discussion. Perceived patient discomfort and discomfort of the patient's family toward these discussions were also significant reported barriers. CONCLUSION: Attitudes toward ACP implementation vary considerably by medical specialty and medical condition, with oncologists in this study tending to feel more personal responsibility for these discussions with patients having cancer than cardiologists with their patients having heart failure. Robust implementation of ACP across the spectrum of medical diagnoses is likely to require a true collaboration between office-based PCPs and specialists in both the inpatient and the ambulatory settings.

Metabolic dysfunction in obese Hispanic women with polycystic ovary syndrome.

STUDY QUESTION: Are certain ethnic groups with polycystic ovary syndrome (PCOS) at increased risk of metabolic disorders? SUMMARY ANSWER: Obese Hispanic women with PCOS are at increased risk of metabolic disorders compared with age- and BMI-matched obese non-Hispanic white women with PCOS in the USA. WHAT IS KNOWN ALREADY: Ethnic differences in body composition and metabolic risk are well established. PCOS is a common disorder in women of reproductive age and is associated with high rates of insulin resistance, glucose intolerance and dyslipidemia. STUDY DESIGN, SIZE, DURATION: A cross-sectional observational study was performed at an Academic Medical Center on 60 women of reproductive age with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood was obtained after fasting from 17 Hispanic, 22 non-Hispanic black and 21 non-Hispanic white women with PCOS who were similar in age and BMI. Anthropometric parameters, insulin, lipid and lipoprotein levels (measured by nuclear magnetic resonance) were compared between the three groups. MAIN RESULTS AND THE ROLE OF CHANCE: Age and BMI did not differ between the groups. Hispanic women with PCOS had higher waist-to-hip ratio (WHR) (P = 0.02), homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.03) and a more atherogenic lipid and lipoprotein profile consisting of lower high-density lipoprotein (HDL) (P = 0.02), higher low-density lipoprotein (LDL) particle number (P = 0.02), higher very low-density lipoprotein particle (VLDL) size (P = 0.03) and lower LDL (P = 0.03) and HDL particle size (P = 0.005) compared with non-Hispanic white women. The differences in HDL, HOMA-IR, VLDL and LDL size did not persist after adjustment for WHR while differences in LDL particle number (P = 0.04) and HDL size (P = 0.01) persisted. LIMITATIONS, REASON FOR CAUTION: The sample size for the three groups was small but the findings were still significant. The women were mostly obese so the ethnic differences in metabolic disorders may not apply to non-obese women with PCOS. WIDER IMPLICATIONS OF THE FINDINGS: Independent of BMI, obese, reproductive age, Hispanic women with PCOS in the USA had a greater degree of abdominal obesity, insulin resistance and dyslipidemia. Hispanic women with PCOS may benefit from more focused management of metabolic parameters. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the following National Institutes of Health grants: K23 DK080988-01A1 to S.S. and UL1RR029879 to CTSA at University of Illinois. None of the authors report any conflict of interests.

PCOS is associated with increased CD11c expression and crown-like structures in adipose tissue and increased central abdominal fat depots independent of obesity.

CONTEXT: Adipose tissue macrophage (ATM) infiltration is a major pathway for obesity-induced insulin resistance but has not been studied as a mechanism for insulin resistance in PCOS. OBJECTIVE: We tested whether polycystic ovary syndrome (PCOS) is associated with increased ATM infiltration, especially of inflammatory subtype identified by the CD11c marker. DESIGN AND SETTING: We conducted a case-control study at an academic medical center in the United States. PARTICIPANTS AND INTERVENTIONS: Fourteen PCOS and 14 control women of similar age and body mass index (BMI) underwent a gluteal fat biopsy. Markers of ATM, integrins, TNF-α, and adiponectin, were analyzed by quantitative RT-PCR using a standard curve method. Crown-like structures (CLS) were identified by immunohistochemistry. Abdominal magnetic resonance imaging and frequently sampled i.v. glucose tolerance test were performed to assess abdominal fat and insulin sensitivity (SI). MAIN OUTCOME: Women with PCOS were compared with control women of similar age and BMI for ATM markers, CLS density, adipose tissue expression of inflammatory cytokines and adiponectin, SI, and abdominal fat depots. RESULTS: Women with PCOS had an increase in CD11c expression (P = 0.03), CLS density (P = 0.001), α5 expression (P = 0.009), borderline increase in TNF-α expression (P = 0.08), and a decrease in adiponectin expression (P = 0.02) in gluteal adipose tissue. Visceral (P = 0.009) and sc abdominal fat (P = 0.005) were increased in PCOS. SI was lower in PCOS (P = 0.008). CONCLUSIONS: PCOS is associated with an increase in CD11c expression and CLS density and a decrease in adiponectin expression in sc adipose tissue. Additionally, PCOS is associated with higher central abdominal fat depots independent of BMI. These alterations are present among mostly nonobese women and could represent mechanisms for insulin resistance.

ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice.

The synthesis of apoE by adipocytes has profound effects on adipose tissue lipid flux and gene expression. Using adipose tissue transplantation from wild-type (WT) to apoE knockout (EKO) mice, we show that adipose tissue also contributes to circulating apoE. Different from circulating apoE produced by bone marrow transplantation (BMT), however, adipose tissue-derived apoE does not correct hyperlipidemia or suppress atherosclerosis. ApoE secreted by macrophages has a more acidic isoform distribution, and it increases binding of reconstituted VLDL particles to hepatocytes and fibroblasts more effectively than apoE secreted by adipocytes. The incremental binding can be entirely accounted for by binding to the LDL receptor. After BMT into EKO hosts, plasma cholesterol and macrophage-derived apoE are largely within IDL/LDL- and HDL-sized particles. After adipose tissue transplantation, most cholesterol and adipocyte apoE remain in VLDL. After BMT, circulating apoE no longer demonstrates predominance of acidic isoforms compared with that circulating after fat transplantation. In conclusion, fat transplantation provides circulating apoE levels similar to those provided by bone marrow transplantation, but it does not suppress hyperlipidemia or atherosclerosis. A potential mechanism contributing to this difference is differential binding to cell surface lipoprotein receptors.

Predictors of cardiovascular events in a contemporary population with impaired glucose tolerance: an observational analysis of the Nateglinide and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial.

OBJECTIVES: Risk factors for cardiovascular events are well established in general populations and those with diabetes but have been sparsely studied in impaired glucose tolerance (IGT). We sought to identify predictors of (1) a composite cardiovascular outcome (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and (2) cardiovascular death, among patients with IGT. DESIGN: We studied participants enrolled in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Predictors of cardiovascular events were identified in observational analyses. SETTING: Clinical trial participants in 40 countries. PARTICIPANTS: 9306 participants with biochemically confirmed IGT at high risk of cardiovascular events participated in NAVIGATOR. PRIMARY AND SECONDARY OUTCOME MEASURES: Cox proportional hazard regression models were constructed using variables (demographic data, medical history, clinical features, biochemical results and ECG findings) recorded at baseline to identify variables associated with and predictive of cardiovascular events. RESULTS: Over 6.4 years, 639 (6.9%) participants experienced a cardiovascular event, and 244 (2.6%) cardiovascular death. While predictors of both outcomes included established risk factors such as existing cardiovascular disease, male gender, older age, current smoking status and higher low-density lipoprotein cholesterol, other variables such as reduced estimated glomerular filtration rate, previous thromboembolic disease, atrial fibrillation, higher urinary albumin/creatinine ratio and chronic obstructive pulmonary disease were also important predictors. Glycaemic measures were not predictive of cardiovascular events. c-Statistics for predicting cardiovascular events and cardiovascular death were 0.74 and 0.82, respectively. This compares with c-statistics for cardiovascular events and cardiovascular death of 0.65 and 0.71, respectively, using the classical Framingham risk factors of age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, treatment for hypertension and smoking status. CONCLUSIONS: The most powerful independent predictors of cardiovascular events in IGT included both established risk factors and other variables excluding measures of glycaemia, allowing effective identification of high-risk individuals.

Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase.

Apolipoprotein E (apoE) is widely expressed in mammalian tissues, and one of the important tissue-specific effects is the atheroprotection ascribed to macrophage-derived apoE in the arterial wall. However, underlying mechanisms are not well understood. In this study, using subcellular fractionation, confocal microscopy, and coimmunoprecipitation, we demonstrated that macrophage-derived apoE is internalized by endothelial cells and impacts the subcellular distribution/interaction of caveolin 1 (cav-1) and endothelial NO synthase (eNOS). The addition of apoE disrupts the heteromeric complex formed between cav-1 and eNOS, and increases NO production. Sterol and oxysterol enhance endothelial cav-1/eNOS interaction and suppress NO production, but these effects are reversed by apoE. Silencing endothelial cav-1 attenuates apoE-induced NO production, establishing the importance of the cav-1-eNOS interaction for the increment in endothelial NO produced by apoE. Consistent with these observations, macrophage-derived apoE significantly improves vasodilation to acetylcholine in resistance arteries isolated from adipose tissue of obese humans. We conclude that macrophage-derived apoE enhances endothelial NO production by disrupting the inhibitory interaction of eNOS with cav-1. These results establish a novel mechanism by which apoE modulates endothelial cell function.

Risk of obstructive sleep apnea in obese and nonobese women with polycystic ovary syndrome and healthy reproductively normal women.

OBJECTIVE: To study the risk for obstructive sleep apnea (OSA) in a group of nonobese and obese polycystic ovary syndrome (PCOS) and control women. DESIGN: Prospective study. SETTING: Academic tertiary care medical center. PATIENT(S): Forty-four women with PCOS and 34 control women. INTERVENTION(S): All of the women completed the Berlin questionnaire for assessment of OSA risk. MAIN OUTCOME MEASURE(S): All of the women underwent fasting determination of androgens, glucose, and insulin. RESULT(S): Women with PCOS were more obese compared with control women. However, there were no differences in BMI once subjects were divided into nonobese (PCOS: n = 17; control: n = 26) and obese (PCOS: n = 27; control: n = 8) groups. Women with PCOS had higher prevalence of high-risk OSA compared with control women (47% vs. 15%). However, none of the nonobese PCOS and control women screened positively for high-risk OSA. Among the obese group, the risk did not differ between groups (77% vs. 63%). CONCLUSION(S): Our findings indicate that even though the risk for OSA in PCOS is high, it is related to the high prevalence of severe obesity. The risk for OSA among nonobese women with PCOS is very low. However, our findings are limited by lack of polysomnographic confirmation of OSA.

Adipose tissue depot-specific differences in adipocyte apolipoprotein E expression.

Important differences in gene expression have been documented in adipocytes derived from specific adipose tissue depots. We have previously documented an important role for adipocyte apolipoprotein E (apoE) in modulating adipocyte and adipose tissue triglyceride and lipoprotein metabolism. We now evaluate the endogenous expression of apoE in adipocytes isolated from unique adipose tissue depots in 4 different species. Adipocyte apoE expression is higher in subcutaneous fat compared with visceral fat in humans, mice, rats, and baboons. In baboons, evaluation of apoE expression in 5 adipose tissue depots (subcutaneous abdominal, subcutaneous gluteal, visceral, pericardial, epicardial) showed that, compared with subcutaneous abdominal adipocytes, the level of apoE expression is similar in subcutaneous gluteal, lower in visceral and pericardial, and higher in epicardial adipocytes. Consistent with previously demonstrated suppression of adipocyte apoE by adipose tissue inflammation, adipose tissue depots with lower apoE expression demonstrated greater infiltration of macrophages and an increased expression of tumor necrosis factor-α messenger RNA. Depot-specific differences in apoE expression were maintained after in vitro differentiation. Adipocytes isolated from depots with lower apoE expression manifested lower rates of triglyceride synthesis in the absence and presence of triglyceride-rich lipoproteins. Adenoviral-mediated increase of apoE expression in omental adipocytes increased triglyceride synthesis in these cells. Our results demonstrate significant heterogeneity in adipocyte apoE expression across adipose tissue depots in several species. Because of its role in modulating adipocyte triglyceride and lipoprotein metabolism, depot-specific differences in endogenous adipocyte apoE could have important implications for modulating the accumulation of lipid in these depots.

Polycystic ovary syndrome is associated with atherogenic changes in lipoprotein particle number and size independent of body weight.

OBJECTIVE: Adverse changes in lipoprotein particle number and size are common with insulin resistance and are associated with increased cardiovascular risk. Comprehensive information regarding lipoprotein particle number and size, and how these parameters relate to body weight, insulin resistance and hyperandrogenemia is lacking in polycystic ovary syndrome (PCOS). We tested the hypothesis that PCOS is associated with atherogenic changes in lipoprotein profile independent of body weight and examined the role of insulin resistance and androgens in these atherogenic changes. DESIGN: Case-control study performed at Clinical Research Center at an Academic Medical Center in the United States. PATIENTS AND MEASUREMENTS: Fasting blood was obtained from 25 PCOS and 25 control women of similar age and body mass index (BMI). Lipoprotein particle number and size was determined by nuclear magnetic resonance and compared between the groups. RESULTS: The mean BMI for both groups was <30 kg/m(2) (P = 0·33). Women with PCOS had an increase in very low-density lipoprotein (VLDL) particle number (P = 0·005), low-density lipoprotein (LDL) particle number (P = 0·02) and a decrease in high-density lipoprotein (HDL) size (P = 0·04). LDL size was borderline decreased (P = 0·09). These differences persisted after adjustment for ethnicity, alcohol and tobacco intake and exercise. In stepwise regression models, bioavailable testosterone was the only predictor of LDL cholesterol, triglyceride, VLDL and LDL particle number. Sex hormone binding globulin (SHBG) was the only predictor of LDL and HDL size. CONCLUSIONS: Independent of body weight, PCOS was associated with changes in lipoprotein profile that increases risk for cardiovascular disease. These changes were present in a mostly nonobese group of women and were more closely related to androgens than fasting insulin.

Human cord blood stem cells and the journey to a cure for type 1 diabetes.

Umbilical cord blood contains several types of stem cells that are of interest to a wide range of disciplines in regenerative medicine. The translational potential to the clinical applications of cord blood stem cells has increased enormously in recent years, mainly because of its advantages including no risk to the donor, no ethical issues, low risk of graft-versus-host disease (GVHD) and rapid availability. Type 1 diabetes (T1D) is an autoimmune disease caused by an autoimmune destruction of pancreatic islet ß cells. Understanding the nature and function of cord blood stem cells is an exciting challenge that might set the stage for new approaches to the treatment of T1D. Here, we review progress in this field and draw conclusions for the development of future therapeutics in T1D. New insights are provided on a unique type of cord blood-derived multipotent stem cells (CB-SC), including the molecular mechanisms underlying immune modulation by CB-SC, protection of ß-cell mass, and promotion of islet ß-cell neogenesis.

Hyperglycemia and advanced glycosylation end products suppress adipocyte apoE expression: implications for adipocyte triglyceride metabolism.

Endogenous adipocyte apolipoprotein E (apoE) plays an important role in adipocyte lipoprotein metabolism and lipid flux. A potential role for hyperglycemia in regulating adipocyte apoE expression and triglyceride metabolism was examined. Exposure of adipocytes to high glucose or advanced glycosylation end product-BSA significantly suppressed apoE mRNA and protein levels. This suppression was significantly attenuated by antioxidants or inhibitors of the NF-κB transcription pathway. Hyperglycemia in vivo led to adipose tissue oxidant stress and significant reduction in adipose tissue and adipocyte apoE mRNA level. Incubation with antioxidant in organ culture completely reversed this suppression. Hyperglycemia also reduced adipocyte triglyceride synthesis, and this could be completely reversed by adenoviral-mediated increases in apoE. To more specifically evaluate an in vivo role for adipocyte apoE expression on organismal triglyceride distribution in vivo, WT or apoE knockout (EKO) adipose tissue was transplanted in EKO recipient mice. After 12 wk, WT adipocytes transplanted in EKO mice accumulated more triglyceride compared with transplanted EKO adipocytes. In addition, EKO recipients of WT adipose tissue had reduced hepatic triglyceride content compared with EKO recipients transplanted with EKO adipose tissue. Our results demonstrate that hyperglycemia and advanced glycosylation end products suppress the expression of adipocyte apoE in vitro and in vivo and thereby reduce adipocyte triglyceride synthesis. In vivo results using adipose tissue transplantation suggest that reduction of adipocyte apoE, and subsequent reduction of adipocyte triglyceride accumulation, could influence lipid accumulation in nonadipose tissue.

Pioglitazone versus glimepiride on coronary artery calcium progression in patients with type 2 diabetes mellitus: a secondary end point of the CHICAGO study.

OBJECTIVE: To compare coronary artery calcium (CAC) progression between 2 treatment groups, pioglitazone versus glimepiride. METHODS AND RESULTS: The CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study demonstrated that pioglitazone significantly decreased carotid intima-media thickness progression compared with glimepiride in patients with type 2 diabetes mellitus. The CAC level was determined at baseline and at the end of 72 weeks of treatment in the pioglitazone (n=146) and glimepiride (n=153) treatment groups using electron beam computed tomography. There was no difference in CAC progression between the treatment groups. By using backward and forward selection models, age, race/ethnicity, and baseline apolipoprotein B level predicted CAC progression. There was no relationship between carotid intima-media thickness and CAC progression during the study. CONCLUSIONS: There was no difference in CAC progression in patients with type 2 diabetes mellitus treated with pioglitazone or glimepiride. Age, race/ethnicity, and baseline apolipoprotein B level predicted CAC progression in patients with type 2 diabetes mellitus.

Relation of abdominal fat depots to systemic markers of inflammation in type 2 diabetes.

OBJECTIVE: Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C. RESULTS: VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI. CONCLUSIONS: In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.

Oxidative stress regulates adipocyte apolipoprotein e and suppresses its expression in obesity.

OBJECTIVE: Endogenous expression of apolipoprotein E (apoE) has a significant impact on adipocyte lipid metabolism and is markedly suppressed in obesity. Adipose tissue oxidant stress is emerging as an important mediator of adipocyte dysfunction. These studies were undertaken to evaluate the role of oxidant stress for regulation of adipocyte apoE. RESEARCH DESIGN AND METHODS: ApoE gene and protein expression in 3T3-L1 adipocytes or mature adipocytes and adipose tissue from C57/BL6 mice was evaluated after induction of oxidant stress. The response of adipose tissue and adipocytes from obese compared with lean mice to antioxidants was also assessed. RESULTS: Oxidant stress in 3T3-L1 cells or adipocytes and adipose tissue from lean mice significantly reduced apoE mRNA and protein level. Inclusion of an antioxidant eliminated this reduction. Oxidant stress was accompanied by activation of the nuclear factor-kappaB (NF-kappaB) transcription complex, and its effect on apoE was eliminated by an NF-kappaB activation inhibitor. Treatment of freshly isolated adipose tissue or mature adipocytes from obese mice with antioxidant increased apoE expression but had no effect on cells or tissue from lean mice. Incubation of freshly isolated adipocytes from lean mice with stromovascular cells from obese mice significantly suppressed adipocyte apoE compared with incubation with stromovascular cells from lean mice, but this suppression was reversed by inclusion of antioxidant or a neutralizing antibody to tumor necrosis factor-alpha. CONCLUSIONS: Oxidant stress significantly modulates adipose tissue and adipocyte apoE expression. Furthermore, oxidant stress contributes to suppression of adipocyte apoE in obesity. This suppression depends on interaction between adipose tissue stromovascular cells and adipocytes.

Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.

Tumor necrosis factor-alpha-mediated suppression of adipocyte apolipoprotein E gene transcription: primary role for the nuclear factor (NF)-kappaB pathway and NFkappaB p50.

The adipose tissue inflammation accompanying obesity has important consequences for adipocyte lipid metabolism, and increased adipose tissue TNFalpha plays an important role for mediating the effect of inflammation on adipocyte function. Recent studies have shown that apolipoprotein E (apoE) is highly expressed in adipose tissue where it plays an important role in modulating adipocyte triglyceride metabolism, triglyceride mass, and adipocyte size. We have previously reported that TNFalpha reduces adipocyte apoE, and the current studies were undertaken to evaluate the molecular mechanism for this regulation. TNFalpha repression of adipocyte apoE gene expression required an intact nuclear factor (NF)-kappaB binding site at -43 in the apoE promoter. Site-directed mutagenesis at this site completely eliminated TNFalpha regulation of an apoE gene reporter. TNFalpha treatment activated binding of NFkappaB p50, isolated from adipocyte nuclei, to the apoE promoter. Two structurally distinct inhibitors of NFkappaB complex activation or translocation abrogated the TNFalpha effect on the apoE gene. Using chromatin immunoprecipitation assays, we demonstrated that treatment of adipocytes with TNFalpha led to increased binding of NFkappaB p50, and decreased binding of p65 and Sp1, to this region of the apoE promoter in living cells. The key role played by increased p50 binding was confirmed by p50 knockdown experiments. Reduction of p50 expression using small interference RNA completely eliminated TNFalpha-mediated reduction of endogenous adipocyte apoE gene expression. These results establish the molecular link between adipose tissue inflammation and apoE gene expression in adipocytes. The suppression of adipocyte apoE by the proinflammatory adipose tissue milieu associated with obesity will have important downstream effects on adipocyte triglyceride turnover and content.

Relationship of abdominal visceral and subcutaneous adipose tissue with lipoprotein particle number and size in type 2 diabetes.

OBJECTIVE: Insulin resistance and type 2 diabetes are associated with an atherogenic lipoprotein profile. We examined the role of visceral and subcutaneous fat depots, independent of BMI, on the dyslipidemia associated with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 382 subjects with type 2 diabetes underwent abdominal computed tomography to evaluate subcutaneous (SAT) and visceral adipose tissue (VAT) distribution and had anthropometric measurements to determine BMI and waist and hip circumference. Fasting blood was obtained for lipoprotein particle number and size using nuclear magnetic resonance spectroscopy. The relationship of lipoprotein particle number and size with BMI, SAT, and VAT was examined using multivariable regression models adjusted for age, sex, diabetes therapy, duration of diabetes, smoking, statin use, and A1C levels. The relation of VAT to lipoprotein particle number and size was further evaluated after the addition of BMI, BMI plus SAT, or BMI plus homeostatis is model assessment of insulin resistance (HOMA-IR) to the model. RESULTS: VAT was positively related to VLDL particle number (P < 0.0001), LDL particle number (P < 0.01), and VLDL size (P < 0.0001) and negatively related to LDL size (P < 0.0001) and HDL size (P < 0.0001). These relationships remained unchanged after addition of BMI and SAT to the model. After addition of HOMA-IR, VAT remained positively related to VLDL particle number (P < 0.0001) and size (P < 0.01) and negatively related to LDL and HDL particle size (P < 0.0001 for both comparisons). Neither BMI nor SAT was independently related to lipoprotein parameters. CONCLUSIONS: In patients with type 2 diabetes, higher VAT independent of BMI was associated with higher VLDL and LDL particle number, larger VLDL particles, and smaller LDL and HDL particles. This lipoprotein pattern has been associated with increased risk for atherosclerosis and cardiovascular disease.

Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism.

Hyperglycemia is common and associated with markedly increased mortality rates in patients hospitalized with acute coronary syndromes (ACS). Despite the fact that several studies have documented this association, hyperglycemia remains underappreciated as a risk factor, and it is frequently untreated in ACS patients. This is in large part due to limitations of prior studies, and the remaining critical gaps in our understanding of the relationship between hyperglycemia and poor outcomes. The main objective of the present statement is to summarize the current state of knowledge regarding the association between elevated glucose and patient outcomes in ACS and to outline the most important knowledge gaps in this field. These gaps include the need to specifically define hyperglycemia, develop optimal ways of measuring and tracking glucose values during ACS hospitalization, and better understand the physiological mechanisms responsible for poor outcomes associated with hyperglycemia. The most important issue, however, is whether elevated glucose is a direct mediator of adverse outcomes in ACS patients or just a marker of greater disease severity. Given the marked increase in short- and long-term mortality associated with hyperglycemia, there is an urgent need for definitive large randomized trials to determine whether treatment strategies aimed at glucose control will improve patient outcomes and to define specific glucose treatment targets. Although firm guidelines will need to await completion of these clinical trials, the present statement also provides consensus recommendations for hyperglycemia management in patients with ACS on the basis of the available data.

Cellular sphingolipids regulate macrophage apolipoprotein E secretion.

Macrophage-derived apolipoprotein E (apoE) in the vessel wall has important effects on the vessel-wall response to atherogenic injury. The current studies characterize a novel post-transcriptional pathway for the regulation of apoE secretion from macrophages. Treatment of J774 macrophages transfected to constitutively express a human apoE3 cDNA (to constitutively secrete a physiologic level of apoE) with sphingomyelinase led to a reduction of apoE secretion by nearly 50%. Increasing cellular ceramide by inhibiting ceramide degradation or by the direct treatment of cells with exogenous ceramide also reduced apoE secretion without a concomitant increase in cellular retention of newly synthesized apoE. Reducing cellular sphingomyelin (SM) by inhibiting its synthesis also reduced apoE secretion, but in this case, reduced apoE secretion was accompanied by increased cellular retention of apoE. The effect of sphingomyelin depletion to decrease apoE secretion and increase its cellular retention was dependent upon the presence of intact C-terminal amphipathic lipid-binding domains in apoE. ApoE expression also increased sphingomyelin secretion from macrophages, and this sphingomyelin was co-localized with apoE in secreted lipoprotein particles. The importance of sphingomyelin for apoE secretion and cell retention was confirmed using a Chinese hamster ovary model, in which cellular sphingolipids (both ceramide and sphingomyelin) are reduced secondary to absent serine palmitoyltransferase activity. Our results show that cellular sphingolipids, ceramide and sphingomyelin, have important effects on the post-transcriptional handling of nascent apoE by macrophages. Increased cellular ceramide reduces apoE secretion without increased cell retention, consistent with enhanced degradation of newly synthesized apoE. Reduction of cell SM also reduces apoE secretion, but this is associated with increased cellular retention of newly synthesized apoE. The dependence for this effect on the C-terminal domain of apoE suggests a model in which the SM content of intracellular membranes modulates the secretion of nascent apoE via the interaction with amphipathic lipid-binding domains.