Fernando Flexa Ribeiro-Filho

The New Adipose Tissue and Adipocytokines

Obesity is a well-known risk factor for the development of insulin resistance, type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. Rather than the total amount of fat, central distribution of adipose tissue is very important in the pathophysiology of this constellation of abnormalities termed metabolic syndrome. Adipose tissue, regarded only as an energy storage organ until the last decade, is now known as the biggest endocrine organ of the human body. This tissue secretes a number of substances--adipocytokines--with multiple functions in metabolic profile and immunological process. Therefore, excessive fat mass may trigger metabolic and hemostatic disturbances as well as CVD. Adipocytokines may act locally or distally as inflammatory, immune or hormonal signalers. In this review we discuss visceral obesity, the potential mechanisms by which it would be related to insulin resistance, methods for its assessment and focus on the main adipocytokines expressed and secreted by the adipose tissue. Particularly, we review the role of adiponectin, leptin, resistin, angiotensinogen, TNF-alpha, and PAI-1, describing their impact on insulin resistance and cardiovascular risk, based on more recent findings in this area.

Continuous positive airway pressure therapy improves hypoadiponectinemia in severe obese men with obstructive sleep apnea without changes in insulin resistance.

BACKGROUND Obstructive sleep apnea (OSA) is associated with several conditions that could facilitate the onset of cardiovascular and metabolic dysfunctions. Continuous positive airway pressure (CPAP) therapy has been shown to improve cardiovascular morbidity and mortality related to OSA, but the mechanisms underlying this association are not fully understood. OBJECTIVE The aim of the present study was to evaluate whether sleep apnea contributes to insulin resistance and inflammatory marker alterations and to evaluate the benefits of nasal CPAP therapy in severe obese patients with OSA. METHODS Plasma inflammatory cytokines and the homeostasis model assessment of insulin resistance index (HOMA-IR, Insulin Sensitivity Index [ISI]) were measured in severe obese male with OSA (n = 16) and compared with body mass index (BMI)-matched male controls without OSA (n = 13). Seven patients with severe sleep apnea (apnea-hypopnea index >30 events/h) were reevaluated after 3 months of nasal CPAP therapy. RESULTS OSA patients had a significantly lower adiponectin levels than obese controls (8.7 +/- 1.18 ng/mL vs. 15.0 +/- 2.55 ng/mL, P = 0.025). HOMA-IR, ISI, tumor necrosis factor-alpha (TNF-alpha, C-reactive protein (CRP), and interleukin-6 (IL-6) levels were not different between groups. Although insulin resistance index and BMI values did not change after 3 months of nCPAP therapy, adiponectin levels increased (P = 0.036) and the levels of TNF-alpha tended to decrease (P = 0.065). Changes in adiponectin levels during nCPAP therapy were positively correlated with an improvement in minimum oxygen saturation (r = 0.773; P = 0.041) and negatively correlated with changes in TNF-alpha levels (r = -0.885; P = 0.008). CONCLUSIONS nCPAP therapy reverses hypoadiponectinemia levels present in obese men with OSA, probably through reductions in hypoxia and inflammation activity.

Effect of continuous positive airway pressure therapy on hypothalamic-pituitary-adrenal axis function and 24-h blood pressure profile in obese men with obstructive sleep apnea syndrome

Obstructive sleep apnea syndrome (OSAS) increases the risk of cardiovascular events. Sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA) axis activation may be the mechanism of this relationship. The aim of this study was to evaluate HPA axis and ambulatory blood pressure monitoring in obese men with and without OSAS and to determine whether nasal continuous positive airway pressure therapy (nCPAP) influenced responses. Twenty-four-hour ambulatory blood pressure monitoring and overnight cortisol suppression test with 0.25 mg of dexamethasone were performed in 16 obese men with OSAS and 13 obese men controls. Nine men with severe apnea were reevaluated 3 mo after nCPAP therapy. Body mass index and blood pressure of OSAS patients and obese controls were similar. In OSAS patients, the percentage of fall in systolic blood pressure at night (P = 0.027) and salivary cortisol suppression postdexamethasone (P = 0.038) were lower, whereas heart rate (P = 0.022) was higher compared with obese controls. After nCPAP therapy, patients showed a reduction in heart rate (P = 0.036) and a greater cortisol suppression after dexamethasone (P = 0.001). No difference in arterial blood pressure (P = 0.183) was observed after 3 mo of nCPAP therapy. Improvement in cortisol suppression was positively correlated with an improvement in apnea-hypopnea index during nCPAP therapy (r = 0.799, P = 0.010). In conclusion, men with OSAS present increased postdexamethasone cortisol levels and heart rate, which were recovered by nCPAP.

Association between carotid intima-media thickness and adiponectin in participants without diabetes or cardiovascular disease of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Objective The study assessed the association of adiponectin concentration with carotid intima-media thickness (CIMT) in middle-aged participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) without diabetes or cardiovascular disease. Design Cross-sectional analyses. Methods A sample of 687 individuals (35–54 years old) without diabetes or cardiovascular disease was stratified into two categories according to CIMT (< or ≥ 75th percentile). Traditional risk factors, C-reactive protein and adiponectin values were compared between categories by Student’s t-test and frequencies by chi-square test. In linear regression models, associations of CIMT with adiponectin, adjusted for adiposity, blood pressure, C-reactive protein and homeostasis model assessment–insulin resistance were tested. Mean CIMT values were compared across quartiles of adiponectin concentrations using analysis of variance. Results Three hundred and forty-one individuals (49.6%) were women and 130 (19.0%) had three traditional cardiovascular risk factors. Those with elevated CIMT (21.8%) had greater mean values of body mass index (26.2(3.8) vs. 27.7(4.0)kg/m2, p < 0.001), waist circumference (86.9(10.1) vs. 90.1(10.8) cm, p = 0.001), systolic blood pressure (116.2(13.6) vs.121.2(16.1) mmHg, p < 0.001), homeostasis model assessment index (1.4(0.9–2.4) vs. 1.8(1.1–2.9), p = 0.011), C-reactive protein (1.2 (0.6–2.6) vs. 1.4(0.8–3.2) mg/l, p = 0.054) and adiponectin (9.9 (6.0–14.7) vs. 8.9 (5.3–13.8) µg/ml, p = 0.002) levels than the counterpart, while plasma glucose and lipids were not different between groups. In the adjusted model, blood pressure (directly) and adiponectin (inversely) persisted associated with high CIMT. Mean CIMT was greater in the first quartile of adiponectin when compared with the other three quartiles (p = 0.019). Conclusions Lower adiponectin levels together with higher blood pressure were independently associated with elevated CIMT. Adiponectin concentration may be an independent marker of early structural damage in individuals at low-to-moderate cardiovascular risk.

Novel biomarkers of cardiometabolic risk are associated with plasma glucose within non-diabetic range. The Brazilian Longitudinal Study of Adult Health - ELSA-Brasil.

Abnormal glucose metabolism preceding overt diabetes is associated with increased cardiovascular risk. Whether novel biomarkers are useful to identify this condition is unclear. The objective was to investigate associations of biomarkers of atherogenesis with plasma glucose within non-diabetic range. 998 participants (35-54 years) of the Brazilian Longitudinal Study of Adult Health without diabetes or cardiovascular disease were classified as normal glucose tolerance (NGT), impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT). Traditional risk factors and markers of atherogenesis were evaluated among groups and across plasma glucose concentrations. IFG and IGT had worse profile considering traditional cardiovascular risk factors than the NGT group, although these values were within the reference range. NGT, IFG and IGT groups differed (medians and interquartile intervals) regarding transforming growth factor-β1 [12.2 (6.4-22.3), 16.8 (8.4-26.5), and 15.5 (8.0-26.1)pg/mL, p<0.05], C-reactive protein [1.1 (0.6-2.9), 1.2 (0.6-2.7), and 1.4 (0.8-3.7)ng/mL, p<0.001] and monocyte chemoattractant protein-1 [35.9 (21.2-57.8), 32.2 (18.7-55.8), and 34.1 (18.6-52.4)pg/mL, p<0.05]. TGF-β1 and E-selectin concentrations increased while MCP-1 decreased across quartiles of fasting plasma glucose. C-reactive protein increased with increments in 2-h plasma glucose. In linear regression, TGF-β1 was independently associated with fasting plasma glucose, and C-reactive protein with 2-h plasma glucose after adjustments. In conclusion, association of TGF-β1, E-selectin, C-reactive protein and MCP-1 with slight elevations in glycemia may be anticipating alterations in traditional cardiovascular risk factors. Independent association of TGF-β1 with plasma glucose suggests that this may be useful to identifying atherogenic process, deserving further investigation on the prediction of cardiovascular outcomes.

IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea.

STUDY OBJECTIVES This study examined insulin-like growth factor-1 (IGF-1) production and its association with the metabolic syndrome (MS) in men with obstructive sleep apnea (OSA). METHODS In total, 47 overweight and obese men who had been referred for suspected OSA underwent polysomnography and were classified based on the apnea-hypopnea index (AHI) into three groups: no OSA, < 5 events/h (n = 11); mild OSA, ≥ 5 to < 15 events/h (n = 8); and moderate-severe OSA, ≥ 15 events/h (n = 28). The assessment of the somatotropic axis function included IGF-1 measurement. MS was diagnosed according to the National Cholesterol Education Program guidelines. RESULTS IGF-1 level in the moderate-severe OSA group was lower than in the no-OSA group (156.8 ± 54.3 μg/L versus 225.5 ± 80.5 μg/L; p = 0.013). IGF-1 level was negatively correlated with body mass index, waist circumference (WC), AHI, and sleep duration with oxygen (O2) saturation < 90% and positively correlated with the average and minimum O2 saturation (p = 0.027). In a multivariable linear regression, considering WC and minimum O2 saturation as independent variables, only the minimum O2 saturation was a predictor of low IGF-1 levels. The proportions of patients with MS were different between the three groups (18.2% in no OSA; 25% in mild OSA, and 57.1% in moderate-severe OSA; p = 0.047). Furthermore, in the lowest tertile of IGF-1 value, 66.7% of patients were affected by MS (p = 0.049). Hemoglobin (Hb)A1c correlated negatively with the minimum O2 saturation and IGF-1 levels. However, in multivariable linear regression only IGF-1 levels were a predictor of HbA1c levels. CONCLUSION The occurrence of OSA is associated with a reduction in IGF-1 levels. IGF-1 alterations in OSA also seem to be associated with a higher prevalence of MS.

Leptin is associated with insulin resistance in Japanese migrants.

BACKGROUND Leptin and insulin are both influenced by body adiposity. Insulin plays an important role in the context of the metabolic syndrome (MS). We evaluated whether leptin was associated with insulin resistance and MS after adjusting for confounders in Japanese-Brazilian women. METHODS A total of 717 Japanese-Brazilian women aged >/=30 years were investigated for the presence of MS. They were submitted to clinical examination and laboratory measurements, including oral GTT, lipid profile, uric acid, C-reactive protein (CRP), insulin, and leptin levels. Insulin sensitivity was assessed by HOMA. Diagnosis of MS was based on the National Cholesterol Education Program criteria modified for Asians. Pearson correlation coefficient and logistic regression analysis were used. RESULTS MS was diagnosed in 56% (95% CI 52-59); these subjects were older and had higher body mass index (BMI) and fat mass, and worse metabolic profile. Leptin and CRP levels were statistically greater in women with MS when compared to those without the syndrome (8.6 +/- 8.0 vs. 7.2 +/- 5.9 ng/mL and 0.219 +/- 0.848 vs. 0.360 +/- 0.852 mg/dL, p < 0.05). Leptin was significantly correlated to BMI, fat mass, waist circumference, HOMA-IR, and insulin but not to other components of MS, such as fasting plasma glucose, blood pressure, HDL-cholesterol, triglyceride, and CRP levels. Correlation between leptin and HOMA-IR or fasting insulinemia was maintained after adjustments for body adiposity. However, in logistic regression model, age, BMI, 2-h glucose, and uric acid were independently associated with MS, but not leptin. CONCLUSIONS Adiposity-adjusted correlation of leptin with HOMA-IR and fasting insulinemia suggested that the former is associated with insulin resistance, despite the lack of independent association with the definition of the MS according to NCEP-ATP III. These findings in such Japanese-Brazilian population of high prevalence of MS need to be confirmed in other populations.

Circulating early biomarkers of atherogenesis in participants of the Longitudinal Study of Adult Health (ELSA-Brasil) without diabetes or cardiovascular disease

Objective Our aim was to describe the distribution of selected biomarkers according to age and sex, adjusted for HOMA-IR and adiposity, in a subset of middle-aged individuals of Brazilian Longitudinal Study of Adult Health-ELSA without diabetes mellitus or CVD. Subjects and methods This cross-sectional study was conducted in 998 participants of the ELSA-Brasil without diabetes and/or cardiovascular disease. In addition to the traditional risk factors, several biomarkers concentrations were compared according to sex, age groups (35-44; 45-54 yrs) and HOMA-IR tertiles. Linear regression was used to examine independent associations of sex and age with selected novel biomarkers, adjusted for body adiposity and HOMA-IR. Results Fifty-five percent were women. Men had higher mean values of body mass index, waist circumference, blood pressure, plasma glucose, HOMA-IR, worse lipid profile and higher E-selectin and lower leptin concentrations than women; while women had higher levels of HDL-cholesterol and leptin than men. Mean values of waist circumference, systolic BP, plasma glucose and apolipoprotein B (Apo B) increased with age in both sexes. Leptin and E-selectin concentrations increased across HOMA-IR tertiles. Independent associations of Apo B with age were found only in male sex, while of leptin with body mass index and HOMA-IR, and of E-selectin with HOMA-IR in both sexes. Conclusions In conclusion, our data indicate age, sex, adiposity and, consequently, insulin resistance, influence circulating levels of Apo B, leptin and E-selectin, suggesting that those aspects should be taken into consideration when assessing these parameters for research or clinical purposes in individuals at relatively low cardiometabolic risk.