Background: Adipose tissue is a veritable "endocrine organ" due to its adipocytokines secretion implied in insulin sensitivity modulation and cardiovascular complications.
Objective: To identify the adipocytokines' plasmatic profile (adiponectin, leptin, resistin, IL-6, TNFα) in obese children and adolescents and to assess their relationship with "classic" clinical/paraclinical markers of metabolic syndrome and insulin resistance.
Material and Methods: A case-control study comparing a study group of 38 obese children and adolescents (age 13.5±2.3 years) to a normal weight age matched control group of 24 children.
We measured body mass index (BMI) and waist circumference (WC), systolic and diastolic blood pressure (BP). The classical metabolic parameters (fasting glycemia, total cholesterol and its fractions, serum triglycerides) were measured in both groups. Insulin sensitivity was evaluated using fasting insulinemia, HOMA-index and insulin-resistance summary score (IRS). Adiponectin, leptin, resistin, IL-6 and TNFα were measured using ELISA method.
Outcomes: Serum levels of leptin, resistin and IL-6 were signficantly higher (42.42±22.58 ng/ml versus 14.4±14.49 ng/ml, p <0.001; 9.69±3.47 ng/ml versus 7.92±2.13ng/ml, p = 0.029 and 2.66 ±2.87 pg/ml versus 0.89 ± 1.16 pg/ml, p = 0.006 respectively), while adiponectin levels were significantly lower (9.05±4.61 µg/ml versus 15.93±9.24 μg/ml, p <0.001) in the obese group compared to control group. TNFα was not statistical different between groups.
In multivariate regression analysis adiponectin was negatively and significantly correlated with WC (r = - 0.463, p = 0.003); leptin was positively and significantly related to WC, diastolic BP, fasting insulinemia and resistin (r = 0.775, p <0.001); resistin was positively related to leptin and IL-6 (r = 0.499, p <0.001), IL-6 was positively and significantly related to diastolic blood pressure (r = 0.333, p = 0.008).
Conclusions: Serum levels of adiponectin, leptin, resistin and IL-6 are significantly different in obese children compared to normal weight controls; leptin was the only adipokine correlated with insulin resistance in children. There are significant correlations between plasmatic levels of leptin, resistin and IL-6.
Simple plasmatic determination of TNFα is not a marker of the degree of obesity or its metabolic complications in pediatric population.
adipokine; cytokine; obesity; children
Adipose-derived cytokines, including tumor necrosis factor α, may contribute to the inflammation that occurs in the metabolic syndrome. We investigated the effects of inhibition of tumor necrosis factor α with etanercept in patients with the metabolic syndrome.
Fifty-six subjects with the metabolic syndrome were randomized to administration of either etanercept or identical placebo, 50 mg subcutaneously once a week for 4 weeks. The C-reactive protein level was the primary end point. Effects on other inflammatory markers (including fibrinogen, interleukin 6, and adiponectin), insulin sensitivity, lipid levels, and body composition were also determined.
Baseline characteristics were similar between the groups. Two subjects dropped out of each group, and etanercept was well tolerated throughout the study. The C-reactive protein levels decreased significantly in the treated compared with the placebo group (−2.4 ± 0.4 vs 0.5 ± 0.7 mg/L; P<.001). Adiponectin levels rose significantly in the etanercept group compared with the placebo group (0.8 ± 0.4 vs −0.3 ± 0.3 µg/mL; P=.03). Fibrinogen levels decreased (−68 ± 16 vs −2 ± 31 mg/dL [−2.0 ± 0.47 vs −0.06 ± 0.91 µmol/L]; P=.04) and interleukin 6 levels tended to decrease (−1.2 ± 0.8 vs 0.5 ± 0.5 ng/L; P=.07) in the etanercept-treated subjects compared with placebo, respectively. No changes occurred in body composition parameters or insulin sensitivity, but high-density lipoprotein levels tended to decrease in the etanercept group (−1 ± 1 vs 2 ± 1 mg/dL [−0.03 ± 0.03 vs 0.05 ± 0.03 mmol/L]; P=.06) compared with the placebo group.
Etanercept reduces C-reactive protein levels and tends to improve other inflammatory cardiovascular risk indexes in patients with the metabolic syndrome. Etanercept may interrupt the inflammatory cascade that occurs with abdominal obesity. Further, longer-term studies are needed to determine the effects of tumor necrosis factor α inhibition on cardiovascular disease in patients with the metabolic syndrome.
Obesity, insulin resistance, and dyslipidemia are associated with preeclampsia. Recently, “adipose tissue failure”, characterized by dysregulation of adipokine production, has been implicated in the pathophysiology of these metabolic complications. Adiponectin, an insulin-sensitizing, anti-atherogenic, anti-inflammatory and angiogenic adipokine, circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. These multimers exert differential biological effects, and HMW to total adiponectin ratio (SA) has been reported to be a specific marker of adiponectin activity. The aim of this study was to determine whether preeclampsia is associated with changes in circulating adiponectin multimers.
This cross-sectional study included women with: 1) normal pregnancy (n=225); and 2) patients with mild preeclampsia (n=111). The study population was further stratified by first trimester BMI (normal weight <25 kg/m2 vs. overweight/obese ≥25 kg/m2). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
1) The median maternal HMW and LMW adiponectin concentrations were lower in patients with preeclampsia than in those with normal pregnancies (p<0.001 and p=0.01, respectively); 2) patients with preeclampsia had a lower HMW/Total adiponectin ratio (p<0.001) and higher MMW/Total adiponectin and LMW/Total adiponectin ratios than those with a normal pregnancy (p<0.001 and p=0.009, respectively); 3) the presence of preeclampsia was independently associated with lower maternal serum HMW adiponectin concentrations (p=0.001) and with a low HMW/Total adiponectin ratio (p<0.001) after correction for maternal age, maternal BMI, the difference in BMI between the third and the first trimester, and gestational age at sampling; and 4) overweight/obese pregnant women had a lower median total and HMW adiponectin concentration than normal weight pregnant women among women with normal pregnancies, but not among those with preeclampsia.
1) Preeclampsia is associated with a lower median concentration of the HMW adiponectin isoform, the most active form of this adipokine, and a low HMW/Total adiponectin ratio, a specific marker of adiponectin biologic activity; 2) in contrast to normal pregnancy, preeclampsia is not associated with decreased circulating adiponectin multimers in overweight/obese individuals suggesting altered regulation of this adipokine in preeclampsia; 3) collectively, these findings suggest that preeclampsia is characterized by alterations in adiponectin multimers and their relative distribution implying a role for adiponectin multimers in the mechanism of disease in preeclampsia.
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; overweight; obesity
Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy (1H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m2) who underwent 1H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMAIR), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMAIR. Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.
Adiponectin, an adipokine with antidiabetic properties, forms multimers, and the high molecular weight (HMW) form most closely correlates with insulin sensitivity. Therefore, we hypothesize that HMW adiponectin levels are decreased in women with polycystic ovary syndrome (PCOS), a condition characterized by insulin resistance, compared to normal controls, and that HMW adiponectin correlates with testosterone and insulin sensitivity.
Design and patients
Cross-sectional study involving 13 women with PCOS and 13 age- and BMI-matched normal controls.
Waist-to-hip ratios (WHR), glucose, insulin, SHBG, total testosterone, total and HMW adiponectin levels were measured after an overnight fast. Free testosterone was calculated from SHBG and total testosterone, and insulin sensitivity (Si) was determined using a frequently sampled intravenous glucose tolerance test. The study’s primary outcomes were differences in total and HMW adiponectin between women with PCOS and normal control women.
Total adiponectin (p<0.01), HMW adiponectin (p<0.01), and the ratio of HMW to total adiponectin (SA) (p=0.03), were lower in women with PCOS compared to normal women. Total and HMW adiponectin levels correlated inversely with WHR (p<0.01) and free testosterone (p<0.01) and positively with Si (p<0.001). Using forward stepwise multivariate analysis, HMW adiponectin and WHR, but not PCOS status, were independent predictors of Si.
Women with PCOS have lower total and HMW adiponectin levels compared with normal women. HMW adiponectin also comprises a smaller proportion of total circulating adiponectin in women with PCOS. Alterations in HMW adiponectin levels in women with PCOS may contribute to the insulin resistance intrinsic to the syndrome.
adiponectin multimers; insulin sensitivity; testosterone; visceral adiposity
Intra-amniotic and systemic infection/inflammation have been causally linked to preterm parturition and fetal injury. An emerging theme is that adipose tissue can orchestrate a metabolic response to insults, but also an inflammatory response via the production of adipocytokines, and that these two phenomenon are interrelated. Adiponectin, an insulin-sensitizing, anti-inflammatory adipocytokine, circulates in multimeric complexes including low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. Each of these complexes can exert differential biological effects. The aim of this study was to determine whether spontaneous preterm labor (PTL) with intact membranes and intra-amniotic infection/inflammation (IAI) is associated with changes in maternal serum circulating adiponectin multimers.
This cross-sectional study included patients in the following groups: 1) normal pregnant women (n=158); 2) patients with an episode of preterm labor and intact membranes without IAI who delivered at term (n=41); 3) preterm labor without IAI who delivered preterm (n=27); and 4) preterm labor with IAI who delivered preterm (n=36). Serum adiponectin multimers (total, HMW, MMW and LMW) concentrations were determined by ELISA. Non-parametric statistics were used for analyses.
1) Preterm labor leading to preterm delivery or an episode of preterm labor which does not lead to preterm delivery, was associated with a lower median maternal serum concentration of total and HMW adiponectin, a lower median HMW/total adiponectin ratio, and a higher median LMW/total adiponectin ratio than normal pregnancy; 2) among patients with preterm labor, those with IAI had the lowest median concentration of total and HMW adiponectin, as well as the lowest median HMW/total adiponectin ratio; 3) The changes in maternal adiponectin and adiponectin multimers remained significant after adjusting for confounding factors such as maternal age, BMI, gestational age at sampling, and parity.
1) Preterm labor is characterized by a change in the profile of adiponectin multimers concentrations and their relative isoforms. These changes were observed in patients with an episode of preterm labor not leading to preterm delivery, in patients with intra-amniotic inflammation, or in those without evidence of intra-amniotic inflammation; 2) The changes in adiponectin multimer concentrations reported in preterm labor are different from those previously reported in spontaneous labor at term, suggesting that there is a fundamental difference between preterm labor and labor at term; 3) The findings reported herein, provide the first evidence for the participation of adiponectin multimer in preterm parturition. We propose that adiponectins and adipokines in general provide a mechanism to organize the metabolic demands generated by the process of preterm parturition regardless of the nature of the insult (intra-amniotic inflammation or not).
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW); Medium molecular weight (MMW); Low molecular weight (LMW); Preterm labor; Intra-amniotic infection; Inflammation; Chorioamnionitis; Preterm delivery; Energy Requirements; Energy Expenditure; Preterm Birth; Metabolism; Metaflammation
Adiponectin—an adipose tissue-derived protein—may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high-molecular weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite them being hypothesized to have differential biological activities, i.e. regulating insulin sensitivity (HMW adiponectin) versus inflammatory response (non-HMW adiponectin). In a prospective, nested case–control study, we investigated whether prediagnostic serum concentrations of total, HMW and non-HMW adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon and 451 rectal) were matched to 1206 controls using incidence-density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53–0.95, P
trend = 0.03 for total adiponectin and RR = 0.45, 95% CI = 0.34–0.61, P
trend < 0.0001 for non-HMW adiponectin]. HMW adiponectin concentrations were not associated with CRC risk (RR = 0.91, 95% CI = 0.68–1.22, P
trend = 0.55). Non-HMW adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR = 0.39, 95% CI = 0.26–0.60, P
trend < 0.0001), whereas the association with total adiponectin was no longer significant (RR = 0.81, 95% CI = 0.60–1.09, P
trend = 0.23). When stratified by cancer site, non-HMW adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms.
Adiponectin is an insulin sensitizing fat cell (FC) hormone whose levels are related to adipose tissue (AT) mass and depot distribution. We hypothesized that the nature of AT expansion (hypertrophy vs. hyperplasia) contributes to obesity-related reductions in serum adiponectin and that this effect is influenced by the regional distribution of AT to subcutaneous (S) and visceral (V) depots. Thirteen obese subjects provided paired AT biopsies. Serum total and high molecular weight (HMW) adiponectin levels were determined by ELISA. Secretion was quantified following 24-h explant culture. FC size, number, % large, and % small FC were determined by microscopic analysis. Secretion of total adiponectin was highest by SAT (P = 0.008) and correlated more strongly with serum adiponectin (total: P = 0.015, r = 0.77; HMW: P = 0.005, r = 0.83) than did secretion by VAT (P = 0.05, r = 0.66 for both). FC size was greatest in SAT and correlated negatively with both serum (total: P = 0.01, r = −0.74; HMW: P = 0.03, r = −0.69) and secreted (total: P = 0.05, r = −0.72; HMW: P = 0.02, r = −0.87) adiponectin. The % small FC in SAT correlated positively with both serum (total: P = 0.006, r = 0.87; HMW: P = 0.009, r = 0.79) and secreted (total: P = 0.03, r = 0.75; HMW: P = 0.01, r = 0.92) adiponectin. VAT FC size correlated negatively with serum HMW adiponectin (P = 0.01, r = −0.76) but not with any measure of secretion. VAT had the greatest % small FC, which related positively to serum HMW (P = 0.004, r = 0.81) and to secreted total adiponectin (P = 0.02, r = 0.78). These studies indicate that differences in fat cell size and depot distribution of AT expansion are important influences on adiponectin in obesity.
adipocyte; fat cell size; adiponectin; high molecular weight; insulin resistance; adipose tissue depots; subcutaneous adipose tissue; visceral adipose tissue
The aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood.
We studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk.
Leptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (p<0.0001) from L to OW to OB boys and girls. When compared with L peers, OW and OB girls exhibited lower (p<0.001) HMW adiponectin levels, while in boys the HMW multimers did not differ significantly across the BMI-stratified groups. OB girls displayed higher (p<0.05) IL-8, IL-18, monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 levels (sICAM-1) than L girls, whereas increased macrophage migration inhibitory factor (MIF) concentrations in OB vs OW boys were seen. HMW adiponectin (negatively), leptin or inflammatory markers (positively) correlated with adiposity and IR measures. In multivariate models, leptin represented a strong and independent determinant of HOMA-IR (R2 0.378; p<0.01). Adjustment for age, BMIz-score, lipids and inflammatory mediators abolished the association between leptin and HOMA-IR in boys, while in girls leptin remained still a significant predictor of IR (R2 0.513; p<0.01). Finally, in both sexes, the joint effect of the L/HMW did not improve the prediction of basal IR as compared with leptin levels alone, which were mainly explained by the BMIz-score.
In prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance.
Hyperglycemia and insulin resistance frequently occur in critically ill and in morbidly obese (MO) patients. Both conditions are associated with altered serum levels of cytokines and adipokines. In addition, obesity related alterations in adipokine expression contribute to insulin resistance in metabolic syndrome. In this study we examined the serum adipocytokine profile in critically ill patients, MO patients, and healthy blood donors.
33 patients who fulfilled the clinical criteria for severe sepsis or septic shock (SP) were prospectively enrolled in this study. A multiplex analysis was performed to evaluate plasma levels of adiponectin, resistin, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha in 33 critically ill patients, 37 MO patients and 60 healthy blood donors (BD).
In SP, adiponectin was significantly lowered and resistin, active PAI-1, MCP-1, IL-1 alpha, IL-6, IL-8, IL-10, and TNF-alpha were significantly elevated compared to BD. Leptin levels were unchanged. In MO, adiponectin and IL-8 were significantly lowered, leptin, active PAI-1, MCP-1, IL-1 alpha, IL-6, and IL-10 significantly elevated, whereas resistin was unaltered.
In SP, adiponectin correlated negatively with BMI, SAPS II and SOFA scores, while resistin correlated positively with SAPS II and SOFA scores and leptin correlated positively with the BMI. Adiponectin was approximately equally diminished in SP and MO compared to BD. With the exception of active PAI-1, cytokine levels in SP were clearly higher compared to MO.
A comparable adipocytokine profile was determined in critically ill and MO patients. As in MO, SP showed reduced adiponectin levels and elevated MCP-1, active PAI-1, IL-1 alpha, IL-6, and IL-10 levels. Leptin is only elevated in MO, while resistin, IL-8, and TNF-alpha is only elevated in SP. As in MO patients, increased levels of proinflammatory cytokines and altered levels of adipokines may contribute to the development of insulin resistance in critically ill patients.
Adiponectin, an abundant adipokine with insulin sensitizing properties, exists different multimeric forms, including low molecular weight (LMW), medium molecular weight (MMW), and high molecular weight (HMW) species. Alterations in the distribution of adiponectin multimers and the relationship between adiponectin multimers and insulin resistance (IR) in women with the polycystic ovary syndrome (PCOS) remain unclear. To compare adiponectin multimerization status and estimate of insulin sensitivity in Chinese women with PCOS compared with age and body mass index (BMI)-matched controls.
Cross-sectional study involving 64 Chinese women with PCOS and 59 normal women. Circulating total adiponectin and its multimeric forms were determined by ELISA and insulin resistance was estimated using the homeostasis assessment insulin resistance index (HOMA-IR).
After controlling for BMI status, levels of both total and HMW adiponectin were significantly lower in women with PCOS compared with normal women (P<0.05). Furthermore, HMW adiponectin provided a stronger contribution to models predicting insulin resistance than total adiponectin. Lastly, decreased HMW adiponectin was associated with increased HOMA-IR in both normal and PCOS women, and this association was independent of both overall adiposity and visceral adiposity.
Levels of both total and HMW adiponectin are decreased in Chinese women with PCOS compared with normal control women and the differences in HMW adiponectin persists after controlling for BMI. Furthermore, HMW adiponectin is a stronger predictor of insulin resistance in both women with PCOS and normal women than total adiponectin.
Polycystic ovary syndrome; adiponectin; insulin resistance; HMW-adiponectin
Ethnic-specific differences in insulin resistance (IR) are well described but the underlying mechanisms are unknown. Adiponectin is an insulin sensitizing adipocytokine that circulates as multiple isoforms, with high molecular weight (HMW) adiponectin associated with greatest insulin sensitivity. The objective of this study is to determine if plasma total and HMW adiponectin concentrations underlie ethnic-specific differences in IR.
Healthy Canadian Aboriginal, Chinese, European, and South Asian adults (N = 634) were assessed for sociodemographics; lifestyle; fasting plasma insulin, glucose, and total and HMW adiponectin; and adiposity measures [BMI, waist circumference, waist-to-hip ratio, percent body fat, and subcutaneous and visceral adipose tissue (quantified by computed tomography)]. The homeostasis model assessment-insulin resistance (HOMA-IR) assessed IR.
South Asians had the greatest HOMA-IR, followed by Aboriginals, Chinese, and Europeans (P < 0.001). Plasma total and HMW adiponectin concentrations were lower in Chinese and South Asians than Aboriginal and Europeans (P < 0.05). Total and HMW adiponectin were inversely associated with HOMA-IR (P < 0.001). Ethnicity modified the relationship between HMW adiponectin and HOMA-IR with stronger effects observed in Aboriginals (P = 0.001), Chinese (P = 0.002), and South Asians (P = 0.040) compared to Europeans. This was not observed for total adiponectin (P = 0.431). At mean total adiponectin concentrations South Asians had higher HOMA-IR than Europeans (P < 0.001).
For each given decrease in HMW adiponectin concentrations a greater increase in HOMA-IR is observed in Aboriginals, Chinese, and South Asians than Europeans. Ethnic-specific differences in HMW adiponectin may account for differences in IR.
High molecular weight adiponectin; Ethnicity; Insulin resistance; Visceral adipose tissue
Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High on-aspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2.
A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median.
Significant trends in age, body mass index (BMI), HOMA-IR, HMW adiponectin concentration, C-reactive protein concentration and the frequency of achieving target triglyceride levels were observed across increasing quartiles of TXB2. In a multivariate analysis, only younger age and higher BMI were independent predictors of TXB2 concentration above the upper quartile, while younger age and lower HMW adiponectin concentration were predictors of TXB2 concentration above the median.
These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA.
Aspirin; Platelet aggregation; Diabetes mellitus; Insulin resistance; Adipokines
Adipose tissue can release hormones into the blood stream in response to specific extracellular stimuli or changes in metabolic status. Resistin, an adipose-secreted factor, is primarily involved in the modulation of insulin sensitivity and adipocyte differentiation. Adiponectin, an adipocyte-specific hormone with insulin sensitizing, anti-inflammatory and anti-atherogenic effects, is reduced in obesity and type II diabetes. The aim of the study was to assess the influence of maternal pre-existing diabetes on cord blood resistin and adiponectin at birth in relation to neonatal anthropometric parameters and cord blood insulin levels.
Material and methods
A total of 60 term newborns were prospectively enrolled and categorized into three groups: 20 were macrosomic infants of pre-gestational diabetic mothers (group I), 20 were non-macrosomic infants of pre-gestational diabetic mothers (group II) and 20 were healthy non-macrosomic infants born to non-diabetic mothers serving as controls (group III). Infants’ anthropometric indices were recorded. Cord blood samples for glucose, insulin, resistin and adiponectin assay, together with maternal glycosylated haemoglobin were obtained.
Serum insulin was increased while resistin and adiponectin were significantly decreased in infants of diabetic mothers (IDMs) compared to the control group. Serum glucose, insulin, resistin and adiponectin were comparable in group I and II. Cord serum resistin correlated positively with cord blood glucose in IDMs in both macrosomic and non-macrosomic groups. Cord serum insulin correlated positively with triceps skinfold thickness in all studied neonates. Cord serum resistin and adiponectin showed no correlation with neonatal anthropometric indices. Multiple regression analysis demonstrated that insulin, resistin and adiponectin together were highly correlated with birth weight, with adiponectin as the one responsible for this positive correlation.
Infants of diabetic mothers had elevated levels of cord serum insulin and suppressed levels of cord serum resistin and adiponectin, suggesting that the regulation of these metabolic pathways is probably operational before birth. Levels were comparable in both macrosomic and non-macrosomic neonates.
infants of diabetic mothers; resistin; adiponectin; macrosomic; insulin
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are inflammatory rheumatic diseases that may modify body composition. Adipose tissue has the ability to release a wide range of products involved in physiologic functions, but also in various pathological processes, including the inflammatory/immune response. RA and AS are both associated with the development of cardiovascular complications. It is has been established that central/abdominal, and particularly intra-abdominal or visceral adiposity is closely linked to cardiovascular events. Thus, in this study, we aimed to evaluate the body composition of patients with RA or AS compared to healthy controls (HC), with a special emphasis on the visceral region. In parallel, we measured adipose products or adipokines, namely leptin, adiponectin and its high molecular weight (HMW) isoform, resistin, and ghrelin, a gastric peptide that plays a role in energetic balance. The homeostasis model assessment for insulin resistance (HOMA-IR) and atherogenic index were used to evaluate cardiovascular risk. One hundred and twelve subjects were enrolled (30 patients with RA, 31 with AS, and 51 HC). Body composition was measured using dual-energy X-ray absorptiometry to determine total fat mass and lean mass, adiposity, fat in the android and gynoid regions, and visceral fat. Patients and HC did not differ in terms of body mass index. On the contrary, adiposity was increased in RA (p = 0.01) while visceral fat was also increased, but only in women (p = 0.01). Patients with AS tended to have lower total fat mass (p = 0.07) and higher lean mass compared to HC (p = 0.07). Leptin and leptin/fat mass were decreased in male patients with AS (p < 0.01), while total adiponectin and the ratio of HMW to total adiponectin were both increased in RA (p < 0.01). There were no changes in serum resistin and ghrelin in any group of patients. HOMA-IR and the atherogenic index were not modified in RA and AS. These results confirm that body composition was altered in RA and AS, affecting distinct soft tissue compartments. The effect of the increased visceral adipose tissue on cardiovascular risk is presumably attenuated by the favorable cardiometabolic profile in women with RA, as suggested by the normal HOMA-IR and atherogenic index.
fat mass; body composition; visceral fat; leptin; adiponectin; cardiovascular risk
Even though there have been major advances in therapy, atherosclerosis and coronary artery disease retain their lead as one of the major causes of morbidity and mortality in the first decade of 21st century. To add to the woes, we have diabetes, obesity and insulin resistance as the other causes. The adipose tissue secretes several bioactive mediators that influence inflammation, insulin resistance, diabetes, atherosclerosis and several other pathologic states besides the regulation of body weight. These mediators are mostly proteins and are termed “adipocytokines”. Adiponectin, resistin, visfatin, retinol binding protein-4 (RBP-4) and leptin are a few such proteins. Adiponectin is a multimeric protein, acting via its identified receptors, AdipoR1 and AdipoR2. It is a potential biomarker for metabolic syndrome and has several antiinflammatory actions. Adiponectin increases insulin sensitivity and ameliorates obesity. Resistin, another protein secreted by the adipose tissue, derived its name due to its involvement in the development of insulin resistance. It plays a role in the pathophysiology of several conditions because of its robust proinflammatory activity mediated through the activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). In 2007, resistin was reported to have protective effect in ischemia-reperfusion injury and myocyte-apoptosis in the setting of myocardial infarction (MI). RBP-4 is involved in the developmental pathology of type 2 diabetes mellitus and obesity. Visfatin has been described as an inflammatory cytokine. Increased expression of visfatin mRNA has been observed in inflammatory conditions like atherosclerosis and inflammatory bowel disease. Leptin mainly regulates the food intake and energy homeostasis. Leptin resistance has been associated with development of obesity and insulin resistance. Few drugs (thiazolidinediones, rimonabant, statins, etc.) and some lifestyle modifications have been found to improve the levels of adipocytokines. Their role in therapy has a lot in store to be explored upon.
Adipokine; adiponectin; leptin; resistin; retinol binding protein-4; visfatin
Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high molecular weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered growth hormone (GH) signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH versus IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying the effects of GH on adiponectin are depot-specific. Interestingly rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity.
adiponectin; high molecular weight adiponectin; growth hormone receptor; growth hormone; growth hormone deficiency; growth hormone antagonist
Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.
Design, patients and measurements
We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11.35 years, body mass index (BMI) Z-score 2.15] and 14 BMI-matched controls (median age 11.97 years, BMI Z-score 2.34).
Despite comparable BMI Z-scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA-IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z-score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0.05), HOMA-IR (P < 0.01), BMI Z-score (P < 0.05), insulin (P < 0.01) and leptin (P < 0.05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls.
Relative to controls of similar age and BMI Z-score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI-matched controls.
Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue.
The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles.
Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined.
Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall.
We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity.
Diffferences in adipose tissue secretory profile, as measured by adipokine levels, may play a role in race-ethnic disparities in cardiovascular disease (CVD). We examined race-ethnic differences in adipokine levels in a group of mid-life Caucasian, African American (AA), Chinese and Japanese women, after accounting for adiposity.
Data on 1876 women from the Study of Women’s Health Across the Nation were analyzed. In multivariable adjustment, including total fat mass, differences in total and high molecular weight (HMW) adiponectin, leptin and soluble leptin receptor (sOB-R) levels were examined.
Despite intermediate levels of adiposity, Caucasian women had higher levels of both total and HMW adiponectin, when compared to both AA and Chinese and Japanese women. After multivariable adjustment, compared to Caucasian women, AA women had significantly lower total (β: −3.40; 95%CI: −4.29, −2.52; p < 0.001) and HMW adiponectin (β: −0.53; 95%CI: −0.64, −0.43; p<0.001) levels, higher leptin levels (β: 3.26; 95%CI: 1.36, 5.16; p<0.001) and lower sOB-R levels (β: −0.07; 95%CI: −0.11, −0.03; p<0.001). Compared to Caucasian women, both Chinese and Japanese women had lower total (Chinese: β: −5.50; 95%CI: −7.07, −3.93; p< 0.001; Japanese: β: −5.48; 95%CI: −6.95, −4.02; p<0.001) and HMW adiponectin (Chinese: β: −0.57; 95%CI: −0.75, −0.38; p<0.001; Japanese: β: −0.61; 95%CI: −0.78, −0.44; p<0.001) levels and lower sOB-R levels (Chinese: β: −0.13; 95%CI: −0.20, −0.06; p<0.001; Japanese: β: −0.09; 95%CI: −0.15, −0.02; p:0.008).
Significant race-ethnic differences exist in circulating adipokines, even after accounting for adiposity. Further research is needed to explicitly determine if such differences contribute to known racial differences in CVD risk.
Adiponectin; High Molecular Weight Adiponectin; Leptin; Soluble Leptin Receptor
Objective: This study aimed (a) to investigate the relationship between the degree of obesity and serum adiponectin, tumor necrosis factor (TNF)−α, leptin, insulin levels and the lipid profile; (b) to clarify the relationship between insulin resistance/glucose tolerance and adipocytokine levels; and (c) to investigate the value of adipocytokine levels as a marker of metabolic syndrome (MS).
Methods: We studied 151 obese children and adolescents (86 boys and 65 girls; mean age was 12.3±2.4 years). We defined obesity as a body−mass index (BMI) z−score more than 2 SD above the mean for age and sex. The control group consisted of 100 children (48 boys, 52 girls, mean age 12.4±2.5 years). Fasting glucose, insulin levels and lipid profiles were measured in all cases and controls after a 12−hour fast. Adiponectin, TNF−α, and leptin levels were measured in the subjects who participated in the adipocytokine branch of the study. An oral glucose tolerance test (OGTT) was also performed in all obese patients. Obese patients were grouped into three subgroups according to their glucose tolerance and insulin sensitivity assessment, and also according to whether they were grouped as MS or not.
Results: Serum levels of total cholesterol, LDL and VLDL cholesterol, log triglyceride, insulin, leptin and TNF−α were higher, whereas HDL and square root adiponectin levels were lower in the obese group when compared with controls. Multiple regression analysis among BMI−z score, LDL, triglyceride, HOMA−IR, leptin and TNF−α as determinants of adiponectin revealed that BMI−z score was the only determinant for adiponectin (r:−0.45, p<0.0001). Adiponectin levels in hyperinsulinemic and impaired glucose tolerance groups (IGT) tended to be lower than in normoinsulinemic obese children, however, the difference was not significant. There was a weak negative correlation between adiponectin levels and increasing severity of insulin resistance (r=−0.23, p=0.005) in the groups of obese subjects. Mean serum adiponectin level in subjects with MS was lower than in subjects without MS (p=0.008).
Conflict of interest:None declared.
children; obesity; Adiponectin; metabolic syndrome
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Steatosis, independently of its metabolic or viral origin, leads to liver injury and fibrosis. It is suggested that hepatitis C virus may contribute to a wide spectrum of metabolic disturbances—namely, steatosis, insulin resistance, increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus and lipid metabolism abnormalities. Adipokines, which are produced mainly by adipose tissue, may influence the inflammatory response and insulin sensitivity and contribute to the development of metabolic abnormalities in CHC and also regulate fibrogenesis and angiogenesis. Visfatin was described as an adipokine with immunomodulating and proinflammatory properties that promotes B-cell maturation and enhances activation of leukocytes, synthesis of adhesion molecules and production of proinflammatory cytokines. Visfatin exerts insulin-mimetic effects, decreases plasma glucose levels and regulates cell energy balance. Chemerin stimulates chemotaxis of dendritic cells, macrophages and natural killer (NK) cells toward the site of inflammation. On the other hand, it inhibits synthesis of proinflammatory mediators and enhances adiponectin production, influences adipocyte differentiation and maturation and regulates glucose uptake in adipocytes. Vaspin expression in human adipose tissue seems to be a compensatory mechanism associated with obesity and insulin resistance. Vaspin suppresses leptin, tumor necrosis factor (TNF)-α and resistin expression. Leptin protects against liver steatosis but accelerates fibrosis progression and exacerbates the inflammatory process. In contrast, adiponectin exerts a hepatoprotective effect. In this report, data indicating a possible role of these adipokines in the pathogenesis of chronic hepatitis are summarized.
AIM: To examine the association between obesity-related adipokines (adiponectin, leptin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) and colorectal cancer (CRC) risk.
METHODS: Serum levels of adipokines were measured in 100 CRC patients and age- and sex-matched controls for the data analysis. Unconditional logistic regression models were used for estimating ORs and 95%CIs related to each adipokine. For the meta-analysis, studies published before July 2013 available on Medline/PubMed and EMBASE were retrieved. The analysis included a total of 17 relevant studies (including the present case-control study): nine studies on adiponectin and eight on leptin. The effect sizes of ORs and 95%CIs were estimated using RevMan 5.1. Heterogeneity was evaluated using Cochran’s Q-test and I2 statistics.
RESULTS: Among the five adipokines, only resistin levels were significantly higher in cases than in controls (P < 0.001). The case-control study results showed no association between adiponectin and CRC and a negative association between leptin and CRC. However, the results of the meta-analysis showed a significant inverse association between adiponectin and CRC (OR = 0.91, 95%CI: 0.83-1.00, P = 0.04) and no association between CRC and leptin. After stratification by study design, an inverse association between adiponectin and CRC was observed in prospective studies only (OR = 0.90, 95%CI: 0.82-0.99, P = 0.03), whereas the association between leptin and CRC was inconsistent (prospective studies: OR = 1.14, 95%CI: 1.02-1.27, P = 0.02 and retrospective studies: OR = 0.47, 95%CI: 0.29-0.74, P = 0.001). The associations of resistin and TNF-α with CRC risk were positive, but no association was observed for IL-6.
CONCLUSION: Our results suggest a negative association of leptin, positive associations of resistin and TNF-α, and null associations of adiponectin and IL-6 with CRC. However, further studies with larger number of prospective approaches are needed.
Obesity; Colorectal cancer; Cancer risk; Adipokines; Obesity-related adipokines
Obesity is associated with a high risk of insulin resistance (IR) and its metabolic complications. It is still debated that distributions of adipose tissue relate to an excess risk of IR and chronic inflammation in different race. This study was designed to examine the relation between insulin sensitivity, chronic inflammation and central fat distribution in non-diabetic volunteers in Taiwanese.
There were 328 volunteers without family history of diabetes mellitus and with normal oral glucose tolerance test enrolled. Total body fat and abdominal fat were measured. Abdominal fat was categorized into intraperitoneal (IP), retroperitoneal (RP) and subcutaneous (SC) fat. The IR index was estimated by homeostatic model assessment. Five inflammatory markers: adiponectin, leptin, tumor necrosing factor-α (TNF-α), resistin and high sensitive CRP (hs-CRP) were measured.
IR was related to IP fat (r = 0.23, p < 0.001), but not RP fat, SC fat or total body fat. After correcting for age and sex, IP fat was the only significant predictor of IR (r2 = 58%, p = 0.001). Leptin showed the strongest relationship with all fat compartments (IP fat: r = 0.44, p = 0.001; RP fat: r = 0.36, p = 0.005, SC fat: r = 0.54, p < 0.001; total body fat: r = 0.61, p < 0.001). The hs-CRP and adiponectin were closely related both to IP (r = 0.29, p = 0.004; r = -0.20, p = 0.046, respectively) and total body fat (r = 0.29, p = 0.004; r = -0.29, p = 0.005, respectively), but not RP, or SC fat. TNF-α and resistin were not correlated to any fat compartment. After correcting for age and sex, leptin variance was mostly explained by SC fat (41.3%), followed by IP fat (33.6%) and RP fat (25.3%). The hs-CRP and adiponectin variance were mostly explained by IP fat (40% and 49% respectively).
IP fat is better predictors of IR and subclinical chronic inflammation in Taiwanese adults. A disproportionate accumulation of abdominal fat is associated with increased risk of cardiovascular diseases.
Subcutaneous fat; Intra-peritoneal fat; Retroperitoneal fat; Insulin resistance; High sensitive C-reactive protein; Adiponectin
Insulin resistance, which implies impairment of insulin signaling in the target tissues, is a common cause of type 2 diabetes. Adipose tissue plays an important role in insulin resistance through the dysregulated production and secretion of adipose-derived proteins, including tumor necrosis factor-α, plasminogen activator inhibitor-1, leptin, resistin, angiotensinogen, and adiponectin. Adiponectin was estimated to be a protective adipocytokine against atherosclerosis, and also to have an anti-inflammatory effect. In this study, the relationship between fasting plasma adiponectin concentration and adiposity, body composition, insulin sensitivity (ITT, HOMAIR, QUICK), lipid profile, fasting insulin concentration were examined in Korean type 2 diabetes. The difference in the adiponectin concentrations was also examined in diabetic and non-diabetic subjects, with adjustment for gender, age and body mass index. 102 type 2 diabetics and 50 controls were examined. After a 12-h overnight fast, all subjects underwent a 75gram oral glucose tolerance test. Baseline blood samples were drawn for the determinations of fasting plasma glucose, insulin, adiponectin, total cholesterol, triglyceride, LDL-cholesterol, and HDL-cholesterol. The body composition was estimated using a bioelectric impedance analyzer (Inbody 2.0). The insulin sensitivity was estimated using the insulin tolerance test (ITT), HOMAIR and QUICK methods. In the diabetic group, the fasting adiponectin concentrations were significantly lower in men than in women. They were negatively correlated with BMI (r=-0.453), hip circumference (r=-0.341), fasting glucose concentrations (r=-0.277) and HOMAIR (r=-0.233). In addition, they were positively correlated with systolic blood pressure (r=0.321) and HDL-cholesterol (r=0.291). The systolic blood pressure and HDL-cholesterol were found to be independent variables, from a multiple logistic regression analysis, which influenced the adiponectin concentration. Compared with the non-diabetic group, the adiponectin concentrations were significantly lower in the diabetic group, with the exception of obese males. In conclusion, the plasma adiponectin concentrations were closely related to the insulin resistance parameters in Korean type 2 diabetic patients.
Diabetes mellitus; insulin resistance; adiponectin