A transient increase in insulin resistance (IR) is a component of puberty. We investigated the impact of body composition and adipokines on IR during puberty in Chinese children. This study included 3223 schoolchildren aged 6–18 years. IR was calculated using homeostasis model assessment (HOMA-IR). We revealed that body mass index (BMI) and waist circumference increased gradually during puberty in both genders, while fat-mass percentage (FAT%) increased steadily only in girls. Change of leptin showed striking sexual dimorphisms: in girls leptin increased steadily during puberty, whereas in boys, after a transient rise at the beginning of puberty, leptin declined by Tanner staging even in those overweight or obese. Inversely, adiponectin level decreased significantly during puberty. In both genders, HOMA-IR started to increase at the beginning of puberty, peaked in the middle, and revised at late puberty in overweight/obesity boys while it stayed high till the end of puberty in girls and normal weight boys. Multivariate regression analysis revealed that leptin presented a stronger indicator of HOMA-IR than anthropometric measures during puberty. Our results demonstrated that gender-specific FAT% and leptin changed with pubertal development. Leptin emerged as a stronger predictor of IR than traditional anthropometric indices, suggesting a prominent role in the development of pubertal IR.
Osteocalcin (OC), a bone-derived protein, was recently shown to regulate metabolic pathways in mice. Undercarboxylated OC (ucOC), but not carboxylated OC (cOC), increases adiponectin and insulin secretion. It is unclear if carboxylation of OC affects its association with metabolic parameters in humans.
RESEARCH DESIGN AND METHODS
The associations between ucOC, cOC, total and high-molecular-weight (HMW) adiponectin, and insulin secretion (homeostasis model assessment [HOMA]-β) were investigated in a population-based sample of healthy prepubertal children (n = 103; 49 boys and 54 girls).
Weight-dependent associations were observed between the different forms of OC and metabolic parameters. Higher cOC was related to lower HMW adiponectin (with a stronger association in leaner children; P < 0.001). Higher ucOC-to-cOC ratio was associated with higher HOMA-β (P < 0.01) in leaner children and associated with higher HMW adiponectin (P < 0.001) in heavier children.
In a weight-dependent manner, cOC and the proportion of ucOC are differentially related to HMW adiponectin and insulin secretion in healthy children.
Body weight is positively associated with bone mineral density but the relationship between obesity and bone mineral density is unclear. Leptin and adiponectin are potential independent contributors to bone mineral density. We assessed the correlations of body composition, leptin and adiponectin with bone mineral density, and whether leptin, adiponectin and body composition determine bone mineral density independently in prepubertal girls. Forty-eight prepubertal girls were classified into obese and control groups by body mass index. Serum leptin and adiponectin levels were determined by enzyme immunoassay. Bone mineral density was measured using dual energy radiography absorptiometry and body composition was measured using bioelectrical impedance analysis. Lean and fat mass, and leptin were positively correlated with bone mineral density. Lean mass was a positive independent predictor of femoral and L-spine bone mineral density. Serum leptin was a postivie independent predictor of femoral bone mineral density. Fat mass was a negative independent predictor of femoral bone mineral density. In prepubertal girls, lean mass has a favorable effect on bone mineral density. Fat mass seems not to protect the bone structure against osteoporosis, despite increased mechanical loading. Serum leptin may play a biological role in regulating bone metabolism.
Bone Density; Body Composition; Leptin; Adiponectin; Obesity
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
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 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
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.
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
Adiponectin and lipocalin-2 are adipocyte-derived plasma proteins that have been proposed to have opposite effects on insulin sensitivity. Given the epidemiological, physiological and molecular links between sleep, the circadian timing system and glucose metabolism, the aim of this study was to assess effects of the sleep/wake cycle and the fasting/feeding cycle on high-molecular-weight adiponectin (HMW-adiponectin; the biologically active form) and lipocalin-2. We also aimed to compare the 24 h rhythms in the levels of these proteins with those of cortisol, leptin, leptin-binding protein and total adiponectin.
Lean men underwent a 3 day in-laboratory study, either in the fed state (n=8, age: 20.9±2.1 years, BMI: 22.8±2.3 kg/m2) or fasting state (3 day fast, n=4, 25.3±3.9 years, BMI: 23.3±2.2 kg/m2). The sleep episode was scheduled in darkness from 23:00 to 07:00 hours. Blood was sampled every 15 min for 24 h on the third day of each study.
While fed, HMW-adiponectin and lipocalin-2 had large daily rhythms with troughs at night (HMW-adiponectin: ~04:00 hours, peak-to-trough amplitude 36%, p<0.0001; lipocalin-2: ~04:00 hours, 40%, p<0.0001). On the third day of fasting, the timing and relative amplitudes were unchanged (HMW-adiponectin: ~04:00 hours, 38%, p=0.0014; lipocalin-2: ~05:00 hours, 38%, p=0.0043).
These data show that HMW-adiponectin and lipocalin-2 both have significant day/night rhythms, both with troughs at night, that these are not driven by the feeding/fasting cycle, and that it is important to report and/or standardise the time of day for such assays. Further studies are required to determine whether the daily rhythm of HMW-adiponectin levels influences the daily rhythm of insulin sensitivity.
Cortisol; Fasting; High-molecular-weight adiponectin; Leptin; Leptin-binding protein; Lipocalin-2; Nutrition; Sleep/wake cycle; Total adiponectin
In a prior study, we have shown that tumor necrosis factor (TNF)-α neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. In this study, we sought to extend our understanding of the effects of TNF-α neutralization in this human model of obesity by investigating the responses of high-molecular-weight (HMW) adiponectin, resistin, leptin, and muscle adiposity to etanercept in patients with the metabolic syndrome. Fifty-six men and women with the metabolic syndrome enrolled in a double-blind randomized placebo-controlled trial. Circulating concentrations of total and HMW adiponectin, resistin, and leptin were determined at baseline and after 4 wk of treatment with etanercept. Muscle adiposity was measured by computed tomography (CT). Although etanercept increased total adiponectin concentration, the HMW form, which is thought to mediate insulin sensitivity, was unchanged. Thus the ratio of HMW to total adiponectin decreased following etanercept treatment compared with placebo (−0.03 ± 0.03 vs. 0.06 ± 0.03, P = 0.02). Resistin tended to decrease in the etanercept-treated group compared with placebo (−0.6 ± 0.7 vs. 1.2 ± 0.7 ng/ml, P = 0.06), whereas leptin was not altered. Etanercept decreased muscle attenuation on CT [−0.61 ± 0.64 Hounsfield units (HU) vs. 1.54 ± 0.77 HU in placebo, P = 0.04], suggesting an increase in muscle adiposity. Together, these results demonstrate that neutralization of TNF-α in obese humans results in differential effects on critical adipokines and body composition indexes. These findings may help to explain the lack of effect on insulin sensitivity and extend our knowledge of the biological effects of TNF-α neutralization in obesity.
tumor necrosis factor-α; adiponectin; resistin; muscle adiposity; metabolic syndrome
Objective. To evaluate leptin and adiponectin as biomarkers of metabolic syndrome (MS) risk factors even in nonobese children/adolescents. Methods. Serum leptin, adiponectin, leptin:adiponectin ratio, lipids, glucose, and insulin concentrations as well as body size parameters and pubertal development were evaluated in a large population of Chinese children/adolescents (n = 3505, 6–18 years, 1722 girls and 1783 boys). Results. Leptin concentration increased while adiponectin decreased with obesity, both were influenced by pubertal development. Central obesity had an additive effect on leptin levels (above obesity alone). Leptin/adiponectin increased 8.4-fold and 3.2-fold in overweight/obesity, and 15.8- and 4.5-fold with obesity plus MS, in early and late puberty, respectively. Even in normal weight children/adolescents, higher leptin and lower adiponectin concentrations associated with increased risk profile. Conversely, overweight/obese with lower leptin or higher adiponectin concentrations had a less compromised metabolic profile. Conclusion. Leptin, adiponectin, and leptin:adiponectin ratio are informative biomarkers for obesity, central obesity, MS, and abnormal metabolic profile even in normal weight children/adolescents.
Adiponectin and leptin, adipokines associated with metabolic syndrome, type 2 diabetes, and cardiovascular disease, have not been well characterized in extreme pediatric obesity. Therefore, levels were compared in youth that were extremely obese (EO) to normal weight (NW), overweight (OW), and obese (OB) youth.
Leptin, adiponectin, body mass index (BMI), blood pressure, fasting glucose, insulin, and lipids were obtained in 277 children and adolescents (age 13.4±2.6 years; 152 boys). Participants were classified into four BMI groups (NW, OW, OB, EO). Variables were compared across groups using analysis of covariance (ANCOVA) adjusted for gender, age, and race.
Risk factors generally worsened across BMI groups. EO had significantly higher levels of leptin than OB (P<0.0001), OW (P<0.0001), and NW (P<0.0001). Leptin was higher in OB compared to OW (P<0.005) and NW (P<0.0001) and higher in OW compared to NW (P<0.0001). Adiponectin levels in EO did not significantly differ from OB or OW but were significantly lower than NW (P<0.0001). Adiponectin was not significantly different among the OB, OW, and NW groups.
Leptin was markedly elevated in EO children and adolescents, suggesting that this subset of obese youth may be at particularly high risk of future weight gain and potentially reduced response to weight-loss interventions.
Adiponectin is a circulating insulin-sensitizing hormone that homo-oligomerizes into trimers, hexamers, and higher molecular weight (HMW) species. Low levels of circulating HMW adiponectin appear to increase the risk for insulin resistance. Currently, assembly of adiponectin oligomers, and consequently mechanisms responsible for decreased HMW adiponectin in insulin resistance, are not well understood. In the work reported here, we analyzed the re-assembly of the most abundant HMW adiponectin species, the octadecamer, following its collapse to smaller oligomers in vitro. Purified bovine serum adiponectin octadecamer was treated with reducing agents at pH 5 to obtain trimers. These reduced trimers partially and spontaneously reassembled into octadecamers upon oxidative formation of disulfide bonds. Disulfide bonds appear to occupy a greater role in the process of oligomerization than in the structural stabilization of mature octadecamer. Stable octadecamers lacking virtually all disulfide bonds could be observed in abundance using native gel electrophoresis, dynamic light scattering, and collision-induced dissociation nano-electrospray ionization mass spectrometry. These findings indicate that while disulfide bonds help to maintain the mature octadecameric adiponectin structure, their more important function is to stabilize intermediates during the assembly of octadecamer. Adiponectin oligomerization must proceed through intermediates that are at least partially reduced. Accordingly, fully oxidized adiponectin hexamers failed to reassemble into octadecamers at a rate comparable to that of reduced trimers. As the findings from the present study are based on in vitro experiments, their in vivo relevance remains unclear. Nevertheless, they describe a redox environment-dependent model of adiponectin oligomerization that can be tested using cell-based approaches.
To delineate the associations of total adiponectin, high-molecular-weight (HMW) adiponectin, and the HMW-to-total adiponectin ratio with diabetes in older adults.
RESEARCH DESIGN AND METHODS
Total and HMW adiponectin were measured in a population-based study of older adults. The relations of total adiponectin, HMW adiponectin, and their ratio with incident diabetes (n = 309) were assessed in 3,802 individuals.
Total and HMW adiponectin were highly correlated (r = 0.94). Analysis using cubic splines revealed that the associations between total and HMW adiponectin and new-onset diabetes were not linear. Specifically, after adjustment for confounders, there were similar inverse relationships for total (hazard ratio per SD 0.49 [95% CI 0.39–0.63]) and HMW adiponectin (0.42 [0.32–0.56]) with diabetes up to values of 20 and 10 mg/L, respectively, above which the associations plateaued. These associations persisted after adjustment for potential mediators (blood pressure, lipids, C-reactive protein, and homeostasis model assessment of insulin resistance [HOMA-IR]). There was, however, evidence of interaction by HOMA-IR in the lower range of adiponectin, with stronger inverse associations among insulin-sensitive than insulin-resistant participants. HMW-to-total adiponectin ratio showed a linear adjusted association with outcome, but this was abolished by inclusion of mediating variables.
In this older cohort, increasing concentrations of total and HMW adiponectin were associated with comparably lower risks of diabetes, but these associations leveled off with further increases above concentrations of 20 and 10 mg/L, respectively. The more pronounced risk decreases at the lower range among participants without insulin resistance support a role for adiponectin that is independent of baseline hyperinsulinemia, but this will require further investigation.
Little is known regarding the associations between high-molecular-weight (HMW-) adiponectin, leptin and soluble leptin receptor (sOB-R) and metabolic syndrome (MetS) in Chinese. Also few studies elucidate the effects of inflammation and body fat mass on the relations.
Plasma HMW-adiponectin, leptin and sOB-R were measured among 1055 Chinese men and women (35∼54 yrs). Whole body and trunk fat mass were determined by Dual-energy X-ray absorptiometry. MetS was defined by the updated NCEP/ATPIII criterion for Asian-Americans.
HMW-adiponectin was inversely associated with MetS in multivariate model including fat mass index (FMI), inflammatory markers, leptin and sOB-R (OR in the highest quartile = 0.30, 95%CI 0.18∼0.50, P<.0001). Plasma sOB-R was also inversely associated with MetS independent of body fatness and inflammatory markers, whereas the association was somewhat attenuated after adjusting HMW-adiponectin (OR for the highest quartile = 0.78, 95%CI 0.47∼1.32, P = 0.15). In contrast, leptin was associated with increased odds of MetS independent of inflammatory markers, HMW-adiponectin, and sOB-R (OR for the highest quartile = 2.64, 95%CI 1.35∼5.18, P = 0.006), although further adjustment for FMI abolished this association.
HMW-adiponectin exhibited strong inverse associations with MetS independent of body composition, inflammation, leptin and sOB-R; while the associations of leptin and sOB-R were largely explained by fat mass or HMW-adiponectin, respectively.
Adiponectin, an adipokine with profound insulin-sensitizing effect, consists of heterogeneous species of multimers. These oligomeric complexes circulate as low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms and can exert differential biological effects. The aims of this study were to determine whether there is a change in circulating adiponectin multimers in the presence of gestational diabetes mellitus (GDM), overweight/obesity or with a treatment with sulfonylurea or insulin in patients with GDM.
This cross-sectional study included women with: 1) normal pregnancy (n=149); and 2) patients with GDM (n=72). Thirty three patients with GDM were managed with diet alone. Among the others 39 diabetic patients, 17 were treated with Glyburide and 22 with insulin. 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.
1) The median maternal serum of total, HMW, MMW and LMW were lower in patients with GDM than in those with normal pregnancies (p<0.001 for all comparisons); 2) patients with GDM had a lower HMW/Total adiponectin ratio and a higher MMW/Total and LMW/Total adiponectin ratio than those with a normal pregnancy (p<0.001 for all comparisons); and 3) among GDM patients, there were no differences in the concentrations and relative distribution of adiponectin multimers between those who were managed with diet, and those who were treated with pharmacological agents.
1) GDM is characterized by a distinctive pattern of concentrations and relative distribution of adiponectin multimers akin to Type-2 diabetes mellitus; 2) dysregulation of adiponectin multimeres can provide a mechanistic basis for the association between adiposity and GDM.
Adipokines; Pregnancy; High-molecular-weight (HMW) adiponectin; Medium-molecular-weight (MMW) adiponectin; Low-molecular-weight (LMW) adiponectin; BMI; Gestational Diabetes; Diabetes; Overweight; Obesity
The aim of this study was to determine whether retinol-binding protein 4 (RBP4), adiponectin and high molecular weight (HMW) adiponectin are associated with insulin resistance (IR) and metabolic parameters in non-diabetic hypertensive patients. Also, we sought to compare the predictive values of these adipocytokines for IR in non-diabetic hypertensive patients.
Materials and Methods
Analyses of RBP4, adiponectin, and HMW adiponectin were performed on 308 non-diabetic hypertensives (148 males, age 58 ± 10 years, 189 non-metabolic syndrome and 119 metabolic syndrome). The homeostasis model assessment (HOMA) index for IR, lipid profiles, and anthropometric measure-ments were assessed.
There was no significant difference in RBP4 levels according to the presence of metabolic syndrome, although adiponectin and HMW adiponectin were significantly lower in metabolic syndrome. Correlation analysis of log RBP4 with IR and metabolic indices revealed that there was no significant correlation of RBP4 with waist circumference (r = 0.056, p = 0.324), HDL cholesterol (r = 0.005, p = 0.934), ApoB/ApoAI ratio (r = 0.066, p = 0.270), and the HOMA index (r = 0.017, p = 0.756). However, adiponectin and HMW adiponectin showed significant correlations with the HOMA index (r = - 0.247, p < 0.001; r = - 0.296, p < 0.001) and metabolic parameters. With IR defined as HOMA index ≥ 2.5, HMW adiponectin did not demonstrate a superior predictive value for IR compared to adiponectin (AUC = 0.680 vs. 0.648, p = 0.083). The predictive value of RBP4 for IR was minimal (AUC = 0.534).
RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensives. HMW adiponectin didn't have a superior predictive value for IR compared to adiponectin. Therefore, we can suggest that RBP4 and HMW adiponectin don't have more additive information than adiponectin in non-diabetic hypertensives.
Retinol-binding proteins; adiponectin; hypertension; insulin resistance
Adiponectin is an anti-diabetic, anti-atherogenic, anti-inflammatory and angiogenic adipokine that circulates in oligomeric complexes including: low-molecular-weight (LMW) trimers, medium-molecular-weight (MMW) hexamers and high-molecular-weight (HMW) isoforms. The aim of this study was to determine whether there are changes in adiponectin multimers in pregnancy and as a function of maternal weight.
In this cross-sectional study, serum concentrations of total, HMW, MMW and LMW adiponectin were determined in women included in three groups: 1) normal pregnant women of normal body mass index (BMI) (n=466); 2) overweight/obese pregnant women (BMI ≥25; n=257); and 3) non-pregnant women of normal weight (n=40). Blood samples were collected once from each pregnant woman between 11 and 42 weeks of gestation. Serum adiponectin multimers concentrations were determined by ELISA. Non-parametric statistics were used for analysis.
1) The median HMW adiponectin concentration and the median HMW/Total adiponectin ratio were significantly higher and the median LMW adiponectin concentration was significantly lower in pregnant than in non-pregnant women; 2) among pregnant women, the median serum concentration of total, HMW and MMW adiponectin was significantly higher in normal weight women than in overweight/obese patients; 3) HMW adiponectin was the most prevalent multimer in maternal serum regardless of gestational age or BMI status; 4) there were no significant differences in the median concentration of total, MMW, LMW adiponectin, and their relative distribution with advancing gestation.
Human pregnancy is characterized by quantitative and qualitative changes in adiponectin multimers, especially of the most active isoform, HMW adiponectin.
Adiponectin; Adipokines; Pregnancy; High molecular weight (HMW) adiponectin; Medium molecular weigh (MMW) adiponectin; Low molecular weight (LMW) adiponectin; BMI
Adiponectin and resistin have been linked to inflammation, endothelial dysfunction, and/or insulin secretion or resistance. It remains to be elucidated which of these adipokines is associated primarily with biomarkers of all or only some of these categories i.e. biomarkers of inflammation, endothelial dysfunction, and/or insulin secretion or insulinemia.
Design and Methods
We studied 1065 healthy women, Nurses’ Health Study participants, who provided blood samples in 1989–1990. A cross-sectional analysis was conducted to assess the relationships between total and high molecular weight (HMW) adiponectin and resistin with inflammatory markers and biomarkers of endothelial dysfunction, insulin secretion and insulinemia.
Resistin was positively associated with the inflammatory markers sTNF-αRII and IL-6 but not with any biomarkers of endothelial function, glycemia, insulinemia or markers of insulin secretion after multivariate adjustment for age and BMI. In both crude and multivariate analyses, total adiponectin was inversely associated with insulin, proinsulin, C-peptide, HbA1c, sE-selectin, and CRP levels. HMW adiponectin was inversely associated with circulating insulin, proinsulin, C-peptide, HbA1c, sE-selectin and CRP concentrations, even after adjustment for age, BMI, lifestyle factors, exercise, the use of medications as well as the other biomarkers of interest. Total and HMW adiponectin demonstrated negative associations with sICAM-1 which became nonsignificant after adjustment for confounders, whereas positive associations between sVCAM-1 and total adiponectin became significant only after multivariate adjustment.
Total and HMW adiponectin are inversely associated with markers of insulin secretion/insulinemia, endothelial function, and inflammation. Resistin is positively associated only with markers of inflammation
Background. High adiponectin/leptin ratio may be protective from metabolic risks imparted by high triglyceride, low HDL, and insulin resistance. Methods. This cross-sectional study examines plasma adipokine levels in 428 adult men
who were subgrouped according to low (<6.5 μg/mL)and high (≥6.5 μg/mL)adiponectin levels or a low or high ratio of adiponectin/leptin. Results. Men with high adiponectin/leptin ratio had lower plasma triglyceride and higher HDL cholesterol than those with low ratio. Similarly, those with high adiponectin/leptin ratio had lower TG/HDL cholesterol ratio and HOMA2-IR than those with low ratio. In contrast, levels of adiponectin or the ratio of adiponectin/leptin did not associate with systolic blood pressure. But the ratio of adiponectin/leptin decreased progressively with the increase in the number of risk factors for metabolic syndrome. Conclusion. Adipokine levels may reflect adipose tissue triglyceride storage capacity and insulin sensitivity. Leptin is an index of fat mass, and adiponectin is a biomarker of triglyceride metabolism and insulin sensitivity. Men with high adiponectin/leptin ratios have better triglyceride profile and insulin sensitivity than men with a low ratio regardless of waist girth.
Higher levels of the adipocyte-specific hormone adiponectin have been linked to increased HDL and lower insulin resistance. This study was conducted to determine the influence of macronutrient intake on adiponectin levels. One hundred and sixty-four pre- and stage-1 hypertensive adults participated in OMNI-Heart, a cross-over feeding study originally testing the effects of macronutrients on blood pressure. Participants underwent three 6-week feeding periods: one rich in carbohydrates (CARB), one rich in monounsaturated fat (MUFA), and one rich in protein (PROT), while maintaining body weight. Their median plasma high molecular weight (HMW) and total adiponectin levels were 2.3 and 8.2 μg/ml, respectively, resulting in an average of 27% HMW adiponectin. Both HMW and total adiponectin levels decreased after baseline while the percent HMW adiponectin remained unchanged. Between diets, the MUFA diet maintained a higher level of both HMW and total adiponectin level than either the CARB (HMW: +6.8%, p=0.02; total: +4.5%, p=0.001) or PROT (HMW: +8.4%, p=0.003; total: +5.6%, p<0.001) diets. Changes in total adiponectin levels were positively correlated to changes in HDL cholesterol irrespective of diets (Spearman r = 0.22–0.40). No correlation was found between changes in lipids, blood pressure, or insulin resistance (HOMA-IR). Macronutrient intake has effects on HMW and total adiponectin levels independent of weight loss. A diet rich in monounsaturated fat was associated with higher levels of total and HMW adiponectin in comparison to a carbohydrate- or protein- rich diet. Effects seen in adiponectin paralleled those found with HDL cholesterol.
adiponectin; cholesterol; diet; obesity
High molecular weight (HMW) adiponectin levels are reduced in humans with type 2 diabetes and insulin resistance. Similar to humans with insulin resistance, managed bottlenose dolphins (Tursiops truncatus) diagnosed with hemochromatosis (iron overload) have higher levels of 2 h post-prandial plasma insulin than healthy controls. A parallel reaction monitoring assay for dolphin serum adiponectin was developed based on tryptic peptides identified by mass spectrometry. Using identified post-translational modifications, a differential measurement was constructed. Total and unmodified adiponectin levels were measured in sera from dolphins with (n = 4) and without (n = 5) iron overload. This measurement yielded total adiponectin levels as well as site specific percent unmodified adiponectin that may inversely correlate with HMW adiponectin. Differences in insulin levels between iron overload cases and controls were observed 2 h post-prandial, but not during the fasting state. Thus, post-prandial as well as fasting serum adiponectin levels were measured to determine whether adiponectin and insulin would follow similar patterns. There was no difference in total adiponectin or percent unmodified adiponectin from case or control fasting animals. There was no difference in post-prandial total adiponectin levels between case and control dolphins (mean ± SD) at 763 ± 298 and 727 ± 291 pmol/ml, respectively (p = 0.91); however, percent unmodified adiponectin was significantly higher in post-prandial cases compared to controls (30.0 ± 6.3 versus 17.0 ± 6.6%, respectively; p = 0.016). Interestingly, both total and percent unmodified adiponectin were correlated with glucagon levels in controls (r = 0.999, p < 0.001), but not in cases, which is possibly a reflection of insulin resistance. Although total adiponectin levels were not significantly different, the elevated percent unmodified adiponectin follows a trend similar to HMW adiponectin reported for humans with metabolic disorders.
parallel reaction monitoring; marine mammal; assay; hemochromatosis; liver; diabetes
Adiponectin is an adipocyte-secreted hormone with insulin-sensitizing and anti-inflammatory actions. The assembly of trimeric, hexameric, and higher molecular weight (HMW) species of adiponectin is a topic of significant interest because physiological actions of adiponectin are oligomer-specific. In addition, adiponectin assembly is an example of oxidative oligomerization of multi-subunit protein complexes in endoplasmic reticulum (ER).
We previously reported that trimers assemble into HMW adiponectin via intermediates stabilized by disulfide bonds, and complete oxidation of available cysteines locks adiponectin in hexameric conformation. In this study, we examined the effects of redox environment on the rate of oligomer formation and the distribution of oligomers. Reassembly of adiponectin under oxidizing conditions accelerated disulfide bonding but favored formation of hexamers over the HMW species. Increased ratios of HMW to hexameric adiponectin could be achieved rapidly under oxidizing conditions by promoting disulfide rearrangement.
Based upon these observations, we propose oxidative assembly of multi-subunit adiponectin complexes in a defined and stable redox environment is favored under oxidizing conditions coupled with high rates of disulfide rearrangement.
OBJECTIVE—The objectives of this study were to determine age- and sex-specific concentrations of adiponectin in Asian Indian teenagers and adults and to assess whether its blood levels correlated with insulin resistance and other cardiometabolic parameters.
RESEARCH DESIGN AND METHODS—We studied 196 teenagers (94 boys, 102 girls) 12–18 years of age, selected from a cohort of 2,640 individuals from a cross-sectional school-based survey in Chennai, India. For comparison, adiponectin and plasma insulin were measured in 84 healthy adults. Correlation of adiponectin with plasma levels of insulin, proinsulin, insulin resistance, anthropometry, and family history of diabetes were studied.
RESULTS—Adiponectin showed a sex dimorphism, with girls having higher values (in μg/ml) (10.3 ± 5.0) than boys (8.4 ± 3.5) (P < 0.0001), and it showed a positive correlation with HDL cholesterol in boys only and not with other lipid parameters, insulin resistance, proinsulin, anthropometry, and family history of diabetes. In the adults, adiponectin correlated with fasting glucose and inversely with triglycerides.
CONCLUSIONS—In Asian Indian adults and teenagers, adiponectin did not correlate directly with measures of insulin sensitivity, overweight, and other cardiometabolic variables. This was at variance with several reports in other populations showing an inverse association of adiponectin with insulin resistance, proinsulin, and BMI, suggesting ethnic differences in the relationship of adiponectin with insulin sensitivity. The role of adiponectin in relation to action of insulin needs more detailed studies in Asian Indians.
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.