A role for protein kinase B beta/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes

Insulin stimulates glucose uptake into muscle and fat cells by promoting the translocation of glucose transporter 4 (GLUT4) to the cell surface. Phosphatidylinositide 3-kinase (PI3K) has been implicated in this process. However, the involvement of protein kinase B (PKB)/Akt, a downstream target of PI3K in regulation of GLUT4 translocation, has been controversial. Here we report that microinjection of a PKB substrate peptide or an antibody to PKB inhibited insulin-stimulated GLUT4 translocation to the plasma membrane by 66 or 56%, respectively. We further examined the activation of PKB isoforms following treatment of cells with insulin or platelet-derived growth factor (PDGF) and found that PKB beta is preferentially expressed in both rat and 3T3-L1 adipocytes, whereas PKB alpha expression is down-regulated in 3T3-L1 adipocytes. A switch in growth factor response was also observed when 3T3-L1 fibroblasts were differentiated into adipocytes. While PDGF was more efficacious than insulin in stimulating PKB phosphorylation in fibroblasts, PDGF did not stimulate PKB beta phosphorylation to any significant extent in adipocytes, as assessed by several methods. Moreover, insulin, but not PDGF, stimulated the translocation of PKB beta to the plasma membrane and high-density microsome fractions of 3T3-L1 adipocytes. These results support a role for PKB beta in insulin-stimulated glucose transport in adipocytes.

A new formation model for M32: a threshed early-type spiral galaxy?

The origin of M32, the closest compact elliptical galaxy (cE), is a long-standing puzzle of galaxy fort-nation in the Local Group. Our N-body/smoothed particle hydrodynamics simulations suggest a new scenario in which the strong tidal field of M31 can transform a spiral galaxy into a compact elliptical galaxy. As a low-luminosity spiral galaxy plunges into the central region of M31, most of the outer stellar and gaseous components of its disk are dramatically stripped as a result of M31's tidal field. The central bulge component, on the other hand, is just weakly influenced by the tidal field, owing to its compact configuration, and retains its morphology. M31's strong tidal field also induces rapid gas transfer to the central region, triggers a nuclear starburst, and consequently forms the central high-density and more metal-rich stellar populations with relatively young ages. Thus, in this scenario, M32 was previously the bulge of a spiral galaxy tidally interacting with M31 several gigayears ago. Furthermore, we suggest that cE's like M32 are rare, the result of both the rather narrow parameter space for tidal interactions that morphologically transform spiral galaxies into cE's and the very short timescale (less than a few times 10(9) yr) for cE's to be swallowed by their giant host galaxies (via dynamical friction) after their formation.

Social structures, genetic structures and dispersal strategies in Australian rabbit (Oryctolagus cuniculus) populations

In this study, the pattern of movement of young male and female rabbits and the genetic structures present in adult male and female populations in four habitats was examined. The level of philopatry in young animals was found to vary between 18-90% for males and 32-95% for females in different populations. It was skewed, with more males dispersing than females in some but not all populations. Analysis of allozyme data using spatial autocorrelation showed that adult females from the same social group, unlike males, were significantly related in four of the five populations studied. Changes in genetic structure and rate of dispersal were measured before and during the recovery of a population that was artificially reduced in size. There were changes in the rate and distance of dispersal with density and sex. Subadults of both sexes moved further in the first year post crash (low density) than in the following years. While the level of dispersal for females was lower than that of the males for the first 3 years, thereafter (high density) both sexes showed similar, low levels of dispersal (20%). The density at which young animals switch behaviour between dispersal and philopatry differed for males and females. The level of genetic structuring in adult females was high in the precrash population, reduced in the first year post crash and undetectable in the second year. Dispersal behaviour of rabbits both affects the genetic structure of the population and changes with conditions. Over a wide range of levels of philopatry, genetic structuring is present in the adult female, but not the male population. Consequently, though genetic structuring is present, it does not lead to inbreeding. More long-distance movements are found in low-density populations, even though vacant warrens are available near birth warrens. The distances moved decreased as density increased. Calculation of the effective population size (N-e) shows that changes in dispersal distance offset changes in density, so that N-e remains constant.

Serum triglycerides as a risk factor for cardiovascular diseases in the Asia-Pacific Region

Background-The importance of serum triglyceride levels as a risk factor for cardiovascular diseases is uncertain. Methods and Results-We performed an individual participant data meta-analysis of prospective studies conducted in the Asia-Pacific region. Cox models were applied to the combined data from 26 studies to estimate the overall and region-, sex-, and age-specific hazard ratios for major cardiovascular diseases by fifths of triglyceride values. During 796 671 person-years of follow-up among 96 224 individuals, 670 and 667 deaths as a result of coronary heart disease (CHD) and stroke, respectively, were recorded. After adjustment for major cardiovascular risk factors, participants grouped in the highest fifth of triglyceride levels had a 70% (95% CI, 47 to 96) greater risk of CHD death, an 80% (95% CI, 49 to 119) higher risk of fatal or nonfatal CHD, and a 50% (95% CI, 29% to 76%) increased risk of fatal or nonfatal stroke compared with those belonging to the lowest fifth. The association between triglycerides and CHD death was similar across subgroups defined by ethnicity, age, and sex. Conclusions-Serum triglycerides are an important and independent predictor of CHD and stroke risk in the Asia-Pacific region. These results may have clinical implications for cardiovascular risk prediction and the use of lipid-lowering therapy.

A comparison of lipid variables as predictors of cardiovascular disease in the Asia Pacific Region

PURPOSE: Many guidelines advocate measurement of total or low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides (TG) to determine treatment recommendations for preventing coronary heart disease (CHD) and cardiovascular disease (CVD). This analysis is a comparison of lipid variables as predictors of cardiovascular disease. METHODS: Hazard ratios for coronary and cardiovascular deaths by fourths of total cholesterol (TC), LDL, HDL, TG, non-HDL, TC/HDL, and TG/HDL values, and for a one standard deviation change in these variables, were derived in an individual participant data meta-analysis of 32 cohort studies conducted in the Asia-Pacific region. The predictive value of each lipid variable was assessed using the likelihood ratio statistic. RESULTS: Adjusting for confounders and regression dilution, each lipid variable had a positive (negative for HDL) log-linear association with fatal CHD and CVD. Individuals in the highest fourth of each lipid variable had approximately twice the risk of CHD compared with those with lowest levels. TG and HDL were each better predictors of CHD and CVD risk compared with TC alone, with test statistics similar to TC/HDL and TG/HDL ratios. Calculated LDL was a relatively poor predictor. CONCLUSIONS: While LDL reduction remains the main target of intervention for lipid-lowering, these data support the potential use of TG or lipid ratios for CHD risk prediction. (c) 2005 Elsevier Inc. All rights reserved.

Effects of Perilipin (PLIN) Gene Variation on Metabolic Syndrome Risk and Weight Loss in Obese Children and Adolescents

Context: Genetic polymorphisms at the perilipin (PLIN) locus have been investigated for their potential utility as markers for obesity and metabolic syndrome (MS). We examined in obese children and adolescents (OCA) aged 7-14 yr the association of single-nucleotide polymorphisms (SNP) at the PLIN locus with anthropometric, metabolic traits, and weight loss after 20-wk multi-disciplinary behavioral and nutritional treatment without medication. Design: A total of 234 OCA [body mass index (BMI = 30.4 +/- 4.4 kg/m(2); BMI Z-score = 2.31 +/- 0.4) were evaluated at baseline and after intervention. We genotyped four SNPs (PLIN1 6209T -> C, PLIN4 11482G -> A, PLIN5 13041A -> G, and PLIN6 14995A -> T). Results: Allele frequencies were similar to other populations, PLIN1 and PLIN4 were in linkage disequilibrium (D` = 0.999; P < 0.001). At baseline, no anthropometric differences were observed, but minor allele A at PLIN4 was associated with higher triglycerides (111 +/- 49 vs. 94 +/- 42 mg/dl; P = 0.003), lower high-density lipoprotein cholesterol (40 +/- 9 vs. 44 +/- 10 mg/dl; P = 0.003) and higher homeostasis model assessment for insulin resistance (4.0 +/- 2.3 vs. 3.5 +/- 2.1; P +/- 0.015). Minor allele A at PLIN4 was associated with MS risk (age and sex adjusted) hazard ratio 2.4 (95% confidence interval = 1.1-4.9) for genotype GA and 3.5 (95% confidence interval = 1.2-9.9) for AA. After intervention, subjects carrying minor allele T at PLIN6 had increased weight loss (3.3 +/- 3.7 vs. 1.9 +/- 3.4 kg; P = 0.002) and increased loss of the BMI Z-score (0.23 +/- 0.18 vs. 0.18 +/- 0.15; P +/- 0.003). Due to group size, risk of by-chance findings cannot be excluded. Conclusion: The minor A allele at PLIN4 was associated with higher risk of MS at baseline, whereas the PLIN6 SNP was associated with better weight loss, suggesting that these polymorphisms may predict outcome strategies based on multidisciplinary treatment for OCA. (J Clin Endocrinol Metab 93: 4933-4940, 2008)

Laparoscopic treatment of metabolic syndrome in patients with type 2 diabetes mellitus

Background Metabolic syndrome refers to risk factors for cardiovascular disease. Hyperglycemia is a critical component contributing to the predictive power of the syndrome. This study aimed to evaluate the results from the laparoscopic interposition of an ileum segment into the proximal jejunum for the treatment of metabolic syndrome in patients with type 2 diabetes mellitus and a body mass index (BMI) lower than 35. Methods Laparoscopic procedures were performed for 60 patients (24 women and 36 men) with a mean age of 51.7 +/- 6.4 years (range, 27-66 years) and a mean BMI of 30.1 +/- 2.7 (range, 23.6-34.4). All the patients had a diagnosis of type 2 diabetes mellitus (T2DM) given at least 3 years previously and evidence of stable treatment using oral hypoglycemic agents, insulin, or both for at least 12 months. The mean duration of type 2 diabetes mellitus was 9.6 +/- 4.6 years (range, 3-22 years). Metabolic syndrome was diagnosed for all 60 patients. Arterial hypertension was diagnosed for 70% of the patients (mean number of drugs, 1.6) and hypertriglyceridemia for 70%. High-density lipoprotein was altered in 51.7% of the patients and the abdominal circumference in 68.3%. Two techniques were performed: ileal interposition (II) into the proximal jejunum and sleeve gastrectomy (II-SG) or ileal interposition associated with a diverted sleeve gastrectomy (II-DSG). Results The II-SG procedure was performed for 32 patients and the II-DSG procedure for 28 patients. The mean postoperative follow-up period was 7.4 months (range, 3-19 months). The mean BMI was 23.8 +/- 4.1 kg/m(2), and 52 patients (86.7%) achieved adequate glycemic control. Hypertriglyceridemia was normalized for 81.7% of the patients. An high-density lipoprotein level higher than 40 for the men and higher than 50 for the women was achieved by 90.3% of the patients. The abdominal circumference reached was less than 102 cm for the men and 88 cm for the women. Arterial hypertension was controlled in 90.5% of the patients. For the control of metabolic syndrome, II-DSG was the more effective procedure. Conclusions Laparoscopic II-SG and II-DSG seem to be promising procedures for the control of the metabolic syndrome and type 2 diabetes mellitus. A longer follow-up period is needed.

Microsurgical anatomy and approaches to the cavernous sinus

OBJECTIVE: The aim of this article is to describe the anatomy of the cavernous sinus and to provide a guide for use when performing surgery in this complex area. Clinical cases are used to illustrate routes to the cavernous sinus and its contents and to demonstrate how the cavernous sinus can be used as a pathway for exposure of deeper structures. METHODS: Thirty cadaveric cavernous sinuses were examined using X3 to X40 magnification after the arteries and veins were injected with colored silicone. Distances between the entrance of the oculomotor and trochlear nerves and the posterior clinoid process were recorded. Stepwise dissections (if the cavernous sinuses, performed to demonstrate the intradural and extradural routes, are accompanied by intraoperative photographs of those approaches. RESULTS: The anatomy of the cavernous sinus is complex because of the high density of critically important neural and vascular structures. Selective cases demonstrate how a detailed knowledge of cavernous sinus anatomy can provide for safer surgery with low morbidity. CONCLUSION: A precise understanding of the bony relationships and neurovascular contents of the cavernous sinus, together with the use of cranial base and microsurgical techniques, has allowed neurosurgeons to approach the cavernous sinus with reduced morbidity and mortality, changing the natural history of selected lesions in this region. Complete resection of cavernous sinus meningiomas has proven to be difficult and, in many cases, impossible without causing significant morbidity. However, surgical reduction of such lesions enhances the chances for success of subsequent therapy.

Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity

The metabolic syndrome (MetS) phenotype is typically characterized by visceral obesity, insulin resistance, atherogenic dyslipidemia involving hypertriglyceridemia and subnormal levels of high density lipoprotein-cholesterol (HDL-C), oxidative stress and elevated cardiovascular risk. The potent antioxidative activity of small HDL3 is defective in MetS [Hansel B, et al. J Clin Endocrinol Metab 2004;89:4963-71]. We evaluated the functional capacity of small HDL3 particles from MetS subjects to protect endothelial cells from apoptosis induced by mildly oxidized low-density lipoprotein (oxLDL). MetS subjects presented an insulin-resistant obese phenotype, with hypertriglyceridemia, elevated apolipoprotein B and insulin levels, but subnormal HDL-C concentrations and chronic low grade inflammation (threefold elevation of C-reactive protein). When human microvascular endothelial cells (HMEC-1) were incubated with oxLDL (200 jig apolipoprotein B/ml) in the presence or absence of control HDL subfiractions (25 mu g protein/ml), small, dense HDL3b and 3c significantly inhibited cellular annexin V binding and intracellular generation of reactive oxygen species. The potent anti-apoptotic activity of small HDL3c particles was reduced (-35%; p < 0.05) in MetS subjects (n = 16) relative to normolipidemic controls (n = 7). The attenuated anti-apoptotic activity of HDL3c correlated with abdominal obesity, atherogenic dyslipidemia and systemic oxidative stress (p < 0.05), and was intimately associated with altered physicochemical properties of apolipoprotein A-I (apoA-I-poor HDL3c, involving core cholesteryl ester depletion and triglyceride enrichment. We conclude that in MetS, apoA-I-poor, small, dense HDL3c exert defective protection of endothelial cells from oxLDL-induced apoptosis, potentially reflecting functional anomalies intimately associated with abnormal neutral lipid core content. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Lipid goals among patients with diabetes or metabolic syndrome: Lipid Treatment Assessment Project (L-TAP) 2

Objective: This analysis of the Lipid Treatment Assessment Project 2 population compared lipid goal attainment by diabetes and metabolic syndrome status. Research design and methods: Dyslipidaemic patients aged >= 20 years on stable lipid lowering therapy had their lipid levels determined once during enrolment at investigation sites in nine countries between September 2006 and April 2007. Achievement of low-density lipoprotein (LDL) cholesterol success, triglycerides < 150 mg/dl (1.7 mmol/l), and high-density lipoprotein (HDL) cholesterol success (> 40 mg/dl [1.0 mmol/l] in men or > 50 mg/dl [1.3 mmol/l] in women) was compared using logistic regression. Results: A total of 9955 patients were evaluated. Patients with diabetes, compared with those without diabetes, had lower achievement of LDL cholesterol goals (according to National Cholesterol Education Program Adult Treatment Panel [NCEP ATP] III guidelines; 67% vs. 75%), triglycerides < 150 mg/dl (55% vs. 64%), and HDL cholesterol success (61% vs. 74%; p < 0.0001 for all comparisons). The significantly lower lipid goal attainment in patients with diabetes was consistent across participating world regions. Patients with metabolic syndrome, compared with those without metabolic syndrome, had lower achievement of NCEP ATP III LDL cholesterol goals (69% vs. 76%), triglycerides < 150 mg/dl (36% vs. 83%), and HDL cholesterol success (49% vs. 89%; p < 0.0001 for all comparisons). As the number of metabolic syndrome components increased, lipid success rates progressively decreased (p < 0.0001 for LDL cholesterol success, triglycerides < 150 mg/dl, and HDL cholesterol success). Conclusions: This analysis indicates that despite their increased cardiovascular risk, patients with diabetes or metabolic syndrome remain undertreated.

Impact on Dyslipidemia of the Laparoscopic Ileal Interposition Associated to Sleeve Gastrectomy in Type 2 Diabetic Patients

Dyslipidemia is known to increase significantly the odds of major cardiovascular events in the general population. Its control becomes even more important in the type 2 diabetic (T2DM) population. Bariatric surgeries, especially gastric bypass, are effective in achieving long-term control of dyslipidemia in morbidly obese patients. The objective of the study was to evaluate the control of dyslipidemia in patients with T2DM and BMI below 30 that were submitted to the laparoscopic ileal interposition associated to sleeve gastrectomy. An observational transversal study was performed in a tertiary care hospital, between June 2005 and August 2007. Mean follow-up was 24.5 months (range 12-38). The procedure was performed in 72 patients: 51 were men and 21 were women. Mean age was 53.1 years (38-66). Mean BMI was 27 kg/m(2) (22.1-29.4). Mean duration of T2DM was 10.5 years (3-22). Mean HbA1c was 8.5%. Hypercholesterolemia was diagnosed in 68% of the patients and hypertriglyceridemia in 63.9%. Mean postoperative BMI was 21.2.kg/m(2) (17-26.7). Mean postoperative HbA1c was 6.1%, ranging 4.4% to 8.3%. Overall, 86.1% of the patients achieved an adequate glycemic control (HbA1c < 7) without anti-diabetic medication. HbA1c below 6 was achieved by 50%, 36.1% had HbA1c between 6 and 7, and 13.9% had HbA1c above 7. Total hypercholesterolemia was normalized in 91.8% and hypertriglyceridemia in 89.1% of patients. Low-density lipoprotein below 100 mg/dl was seen in 85.7%. The laparoscopic ileal interposition associated to sleeve gastrectomy was an effective operation for the regression of dyslipidemia and T2DM in a non-obese population.

HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN EXPRESSION ENHANCES THE MOUSE SURVIVAL RATE IN AN EXPERIMENTAL SYSTEMIC INFLAMMATION MODEL: A NOVEL ROLE FOR CETP

Mice expressing human cholesteryl ester transfer protein (huCETP) are more resistant to Escherichia coli bacterial wall LIPS because death rates 5 days after intraperitoneal inoculation of LIPS were higher in wild-type than in huCETP(+/-) mice, whereas all huCETP(+/+) mice remained alive. After LIPS inoculation, plasma concentrations of TNF-alpha and IL-6 increased less in huCETP(+/+) than in wild-type mice. LPS in vitro elicited lower TNF-alpha production by CETP expressing than by wild-type macrophages. In addition, TNF-alpha production by RAW 264.7 murine macrophages increased on incubation with LPS but decreased in a dose-dependent manner when human CETP was added to the medium. Human CETP in vitro enhanced the LIPS binding to plasma high-density lipoprotein/low-density lipoprotein. The liver uptake of intravenous infused C-14-LPS from Salmonella typhimurium was greater in huCETP(+/+) than in wild-type mice. Present data indicate for the first time that CETP is an endogenous component involved in the first line of defense against an exacerbated production of proinflammatory mediators.

Anti-Lipoprotein Lipase Antibodies in Patients with Hypertriglyceridemia without Associated Autoimmune Disease

Background: Anti-lipoprotein lipase antibodies have been described in rare cases of patients with hypertriglyceridemia. However, no systematic study evaluating these antibodies in patients with this lipid abnormality has been undertaken. Objectives: To analyze the correlation of anti-lipoprotein lipase (anti-LPL) antibodies with other laboratory findings in patients with hypertriglyceridemia but no autoimmune disease. Methods: We evaluated 44 hypertriglyceridemic patients without autoimmune disease. Clinical and laboratory evaluations included analyses of comorbidities, fasting lipid profile and anti-LPL antibodies. Results: Mean patient age was 55 +/- 10 years; 46% of the patients were female and 64% were Caucasian. The mean disease duration was 94.4 months and mean body mass index 28.7 +/- 3.6 kg/m(2); 34.0% were diabetic, 25.0% were obese, 72.7% had systemic arterial hypertension, 75% were sedentary, 15.9% were smokers, 56.8% had a family history of dyslipidemia, 45.5% had a family history of coronary insufficiency, 20.5% had acute myocardial infarction, 9.0% had undergone revascularization and 11.0% angioplasty, 79.5% were being treated with statins and 43.2% were taking fibrates. Median triglyceride levels were 254 mg/dl (range 100-3781 mg/dl), and total cholesterol level was 233 +/- 111 mg/dl. High-density lipoprotein was 42.6 +/- 15.4 mg/dl, low-density lipoprotein 110.7 +/- 42.4 mg/dl and very low-density lipoprotein 48 +/- 15 mg/dl. Anti-LPL antibodies were identified in 2 patients (4.5%), both of whom had a family history of dyslipidemia, coronary insufficiency and acute myocardial infarction; one had undergone myocardial revascularization and percutaneous transluminal coronary angioplasty, and both were using fibrates and had normal triglyceride levels. Conclusions: Our findings demonstrate a correlation between the immune response and dyslipoproteinemia in hypertriglyceridemic patients, suggesting that autoimmune disease contributes to the dyslipidemia process.

Systemic lupus erythematosus and ""lupus dyslipoproteinemia""

A growing body of evidences reinforces the close link between systemic lupus erythematosus (SLE) and atherosclerosis which is due to traditional and nontraditional risk factors for cardiovascular diseases. It is now recognized that SLE has a particular pattern of dyslipoproteinemia characterized by low HDL levels and increased triglycerides, which is aggravated by flares. Multiple mechanisms can induce an altered lipoprotein metabolism in SLE such as cytokines produced during systemic inflammation, autoantibodies and therapy. (C) 2007 Elsevier B.V. All rights reserved.

Cardiovascular risk factors associated with migraine among the elderly with a low income: The Sao Paulo Ageing & Health Study (SPAH)

Background: To investigate the association between cardiovascular risk-factor profile and migraine in the elderly, we evaluated a population sample of ageing men and women (65 years or more) living in a low-income area in the city of Sao Paulo, Brazil. Patients and Methods: We investigated migraine status and cardiovascular profile from a baseline of 1450 participants (65-102 years of age) of the Sao Paulo Ageing & Health Study (SPAH), a longitudinal population-based study with low-income elderly in Brazil. The following age and sex-adjusted cardiovascular risk factors were analyzed: blood pressure, pulse pressure, serum total and high-density lipoprotein cholesterol, body mass index, smoking, history of hypertension, diabetes and the 10-year risk of myocardial infarction or coronary heart disease death based on the Framingham Risk Score. Results: The overall prevalence of migraine was 11.4%, and it was 3 times more frequent among women than men (15.3% vs 5.4%; P < 0.0001). Migraineurs were younger than non-migraineurs (mean age 70.6 years vs 72.1 years; P = 0.001, respectively). There was no statistically significant difference regarding the cardiovascular risk-factor profile after adjustment for age and sex among migraineurs and non-migraineurs. Only a decrease in the risk of hypertension among women (OR 0.58; 95% CI 0.38-0.90; P = 0.01) was also observed even after adjustment for age. Conclusions: Overall, we did not find a worse cardiovascular risk profile among elderly migraineurs. An inverse association between hypertension and migraine in women warrants further investigation.