Adiponectin isoforms (4. Pro)

db/db mice

db/db mice, despite similar total adiponectin levels, display decreased HMW/(HMW + LMW) values compared with wild type littermates, as do type ii diabetic patients compared with insulin-sensitive individuals. Furthermore HMW/(HMW + LMW) improves with peroxisome proliferator-activated receptor-gamma agonist treatment (thiazolidinedione; TZD) in mice and humans changes in HMW/(HMW + LMW) in a number of type 2 diabetic cohorts serve as a quantitative indicator of improvements in insulin sensitivity obtained during TZD treatment, whereas changes in total serum adiponectin levels do not correlate well at the individual level. Acute alterations in HMW/(HMW + LMW) are strongly correlated with improvements in hepatic insulin sensitivity and are less relevant as an indicator of improved muscle insulin sensitivity in response to TZD treatment, further underscoring the conclusions from previous clamp studies that suggested that the liver is the primary site of action for the full-length protein ^Ref . A subsequent analysis of a cohort of diabetic patiens demonstrated that total adiponectin (r = 0.625, p = 0.0001), fasting insulin (r = –0.354, p = 0.040) and age (r = 0.567, p = 0.0001) correlated with HMW/(HMW + LMW). HMW/(HMW + LMW) showed a tighter, inverse correlation with 2-h glucose levels (r = –0.58, p = 0.0003) than total adiponectin (r = –0.38, p = 0.0001. This study demonstrates the importance of the HMW/(HMW + LMW) index as a better determinant of glucose intolerance than measurements of total adiponectin. The authors suggest that HMW adiponectin is the active form of the protein ^Ref .

Metabolic syndrom

The relationships between circulating levels of total adiponectin, adiponectin multimers, and the relative distribution (i.e., ratio) of multimeric forms with key features of the metabolic syndrome was studied in a comprehensive study. Total adiponectin (r = 0.45), HMW (r = 0.47), LMW (r = 0.31), and HMW-to-total adiponectin ratio (r = 0.29) were significantly correlated with insulin-stimulated glucose disposal rate. Similarly, total (r = –0.30), HMW (r =  –0.38), and HMW-to-total adiponectin ratio (r =  –0.34) were correlated with central fat distribution but not with total fat mass or BMI. Regarding energy metabolism, although there were no effects on resting metabolic rate, total (r = 0.41) and HMW (r = 0.44) were associated with increasing rates of fat oxidation. HMW-to-total adiponectin ratio increased as a function of total adiponectin, and it was HMW quantity (not total or HMW-to-total adiponectin ratio or LMW) that was primarily responsible for all of these relationships. Impact on nuclear magnetic resonance lipoprotein subclasses was also assessed. HMW and total adiponectin were correlated with decreases in large VLDL (r = –0.44 and –0.41); decreases in small LDL (r = –0.41 and  –0.36) and increases in large LDL (r = 0.36 and 0.30) particle concentrations accompanied by increased LDL particle size (r = 0.47 and 0.39); and increases in large HDL (r = 0.45 and 0.37) and HDL particle size (r = 0.53 and 0.47). Most of these correlations persisted after adjustment for metabolic covariables. In conclusion, first, serum adiponectin is associated with increased insulin sensitivity, reduced abdominal fat, and high basal lipid oxidation; however, it is HMW quantity, not total or HMW-to-total adiponectin ratio, that is primarily responsible for these relationships. Second, reduced quantities of HMW independently recapitulate the lipoprotein subclass profile associated with insulin resistance after correcting for glucose disposal rate and BMI. Finally, HMW adiponectin is an important factor in explaining the metabolic syndrome ^Ref .

In a working community-based cross-sectional study of 637 male subjects aged 30 to 65 years, total and HMW adiponectin concentrations in serum were measured by enzyme-linked immunosorbent assay using commercially available kits. Serum HMW adiponectin level was inversely correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = –0.375, p < .0001) even after adjustment for age and body mass index (r‘ = –0.245, p < .0001). When we divided the study subjects into quartile groups with equal numbers of subjects, HOMA-IR in the 4 groups based on serum HMW adiponectin level was significantly different (p < .01). Metabolic syndrome score in the 4 groups based on serum HMW adiponectin level was also significantly different (p < .01). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.73) to evaluate the presence of insulin resistance (HOMA-IR >2.5) was larger than that of total adiponectin (0.68) or HMW-total ratio (0.70). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.70) to evaluate the presence of metabolic syndrome (body mass index-based modified criteria) was also larger than that of total adiponectin (0.65), but equal to that of HMW-total ratio (0.70). These results suggest that simply measuring HMW adiponectin may be as effective as HMW-total ratio to evaluate the presence of insulin resistance and metabolic syndrome, at least in nondiabetic subjects who are not receiving any medication ^Ref .

Diabetes

High-molecular weight (HMW) and low-molecular weight (LMW) fractions of adiponectin in 11 type 2 diabetic and 7 nondiabetic subjects matched for age, sex, and BMI during basal conditions and during a hyperglycemic (approximately 9.5 mmol/l) hyperinsulinemic (approximately 700 pmol/l) clamp were measured. Under hyperinsulinemic conditions, total adiponectin levels dropped, primarily due to a reduction of the HMW form, whereas LMW forms were not significantly affected. HMW adiponectin and the ratio of HMW to total adiponectin are lower in individuals with diabetes than in nondiabetic subjects. We conclude that HMW adiponectin is downregulated in hyperinsulinemia and type 2 diabetes ^Ref .

A total of 53 diabetic and 68 nondiabetic subjects attending outpatient clinics underwent cross-sectional metabolic characterization. Circulating levels of HMW, hexameric, and trimeric adiponectin were measured using a multi- meric adiponectin ELISA based upon selective protease-mediated digestion. Both total and HMW adiponectin levels were inversely associated with body mass index, fasting glucose, homeostasis model of assessment of insulin resistance, triglycerides, and alanine aminotransferase (ALT) (all |r| >or= 0.22; p < 0.05), with the HMW isoform also positively correlated with high-density lipoprotein cholesterol (r = 0.19; p = 0.036). In contrast, hexameric and trimeric adiponectin were significantly associated with only body mass index (r = –0.23; p = 0.0102) and mid-upper arm circumference (r = 0.21; p = 0.039), respectively. HMW adiponectin, but not hexameric or trimeric, tracks with the metabolic correlates of total adiponectin ^Ref .

Coronary heart disease

A total of 298 patients admitted for diabetes treatment or coronary angiography served as study subjects. Receiver operator characteristic (roc) curves for the HMW ratio (HMWR; ratio of plasma level of HMW adiponectin to that of total adiponectin) and plasma total adiponectin levels were plotted to predict the presence of insulin resistance and metabolic syndrome. The area under the ROC curve (AUC) of the HMWR values to predict the presence of insulin resistance was significantly larger than that of plasma total adiponectin level in total subjects (0.713 [95% ci 0.620–0.805] vs. 0.615 [0.522– 0.708], p = 0.0160). The AUC for the HMWR values to predict the presence of metabolic syndrome was significantly larger than that for plasma total adiponectin levels in men (0.806 [0.747–0.865] vs. 0.730 [0.660–0.800], p = 0.0025) and in women (0.743 [0.659–0.828] vs. 0.637 [0.532–0.742], p = 0.0458). Thus, the authors suggest that the HMWR value has better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level ^Ref .

Total adiponectin and HMW adiponectin was measured by enzyme-linked immunosorbent assay and serum levels were correlated with defined coronary scores and established cardiovascular risk factors. Significant inverse correlations between angiographic scores and HMW adiponectin [extent score (es): r=-0.39; Gensini score (GS): r=-0.35; and severity score (ss): r=-0.40, all p<0.001], and the HMW/total-adiponectin ratio (es: r=-0.49; Gs: r=-0.46; ss: r=-0.46; all p<0.001) were found. Multivariable regression analyses revealed that HMW adiponectin and the HMW/total-adiponectin ratio were significantly associated with the extent of CAD (both p<0.001). roc analyses demonstrated that the predictive value of HMW adiponectin and the HMW/total-adiponectin ratio for the extent of coronary atherosclerosis significantly exceeded that of total adiponectin (p<0.001, p=0.010, respectively). The authors conclude that HMW adiponectin and the HMW/ total-adiponectin ratio inversely correlate with the extent of CAD. HMW adiponectin in particular seems to be a better marker for CAD extent than total adiponectin ^Ref .

Endothelial function

One hundred apparently healthy young men without overt cardiovascular disease (mean age 30 years) were recruited in this cross-sectional study based on voluntary enrollment. Endothelial function estimated by flow-mediated dilatation (FMD) of the brachial artery during reactive hyperaemia was determined, and total and HMW adiponectin levels were measured. Both HMW and non-HMW adiponectin levels showed a significant, inverse correlation with body mass index (BMI). FMD was significantly correlated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), malondialdehyde-modified low density lipoprotein (MDA-LDL), LDL particle size, and HMW adiponectin (r = 0.320, p = 0.001), but not non-HMW adiponectin (r = 0.125, p = 0.22). In multivariate analysis, HMW adiponectin and MDA-LDL were selected as independent factors capable of influencing FMD. these results suggest that even in young men, plasma adiponectin levels can predict endothelial dysfunction before any overt vascular disease has occurred. HMW adiponectin may be more useful as a marker of endothelial dysfunction than total adiponectin ^Ref .

Obesity

In a study involving Japanese obese children, after adjustment for age and sex, both total and HMW adiponectin were inversely correlated with insulin and homeostasis model of assessment-insulin resistance, whereas HMW adiponectin (but not total adiponectin) inversely correlated with visceral fat area, as determined by computed tomography ^Ref .

HMW and total adiponectin concentrations were measured in samples from 108 individuals and from 20 morbidly obese patients before and at 1, 3, 6, and 12 months after gastric-bypass surgery. Body mass index (BMI)- and sex-related changes were more pronounced for HMW adiponectin and percentage of HMW adiponectin than for total adiponectin. HMW and total adiponectin increased after bypass surgery, but changes in HMW adiponectin were more pronounced and preceded changes in total adiponectin ^Ref .
In addition to weight loss, bariatric surgery for severe obesity dramatically alleviates insulin resistance. 19 women who were undergoing roux-en-Y gastric bypass surgery were studied prior to, and 1 and 12 months after surgery. One month after surgery, total plasma adiponectin concentrations were unchanged. Nevertheless, increases in both HMW (by 40+/-15%, p=0.006) and the proportion of adiponectin in the HMW form (from 40+/-2 to 50+/- 2%, p<0.0001) were observed. At 12 months, total and HMW adiponectin concentrations were increased by 58+/-8% and 118+/-21%, respectively (both p<0.001). The majority (80%) of the increase of total adiponectin was due to an increase of the HMW form. After adjustment for covariates, increases of HMW and total adiponectin at 12 months were correlated with the decrease of fat mass (HMW, p=0.0076; total, p=0.0302). in subjects with improved insulin sensitivity at 12 months after surgery (n=18), the increase of HMW, but not that of total adiponectin, predicted the relative decrease of insulin resistance (HMW: p=0.0044; total: p=0.0775, after adjustment for covariates). These data suggest that the reduction of fat mass following gastric bypass surgery is an important determinant of the increase of HMW adiponectin concentrations, which in turn is associated with and may contribute to the resulting improvement of insulin sensitivity ^Ref .

A moderate weight loss after biliopancreatic diversion (BPD) increases total and HMW adiponectin oligomers. the significant correlation between BMI and HMW (percentage) adiponectin oligomers but not between BMI and total adiponectin might indicate a role of body fat mass in regulation of adiponectin multimerization. These data suggest that HMW oligomers represent a very sensitive parameter to short-term BMI changes after BPD ^Ref .

Prader-Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. 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 ^Ref .

Anorexia nervosa

Anorectic (AN )women and adolescents showed, at admission, leptin levels that were significantly lower, whereas insulin sensitivity (assessed by homeostasis model assessment-insulin resistance), adiponectin levels, and the ratio of high molecular weight (HMW) adiponectin to total adiponectin were significantly higher compared with controls. during weight recovery, leptin levels and homeostasis model assessment-insulin resistance increased significantly, whereas adiponectin and HMW adiponectin/total adiponectin ratio decreased significantly, to levels similar to controls. An initial increase in adiponectin levels was observed after 1 month of refeeding. There was no correlation between adiponectin and either T(4) or cortisol levels. This study demonstrates hyperadiponec­tinemia, increased adiponectin HMW isoform, and increased insulin sensitivity in adolescent An female patients and reversal of these findings with weight rehabilitation. it is hypothesized that increased adiponectin levels may have a protective role in maintaining energy homeostasis during extreme malnourishment ^Ref .

Chronique kidney disease

Despite the favourable effects of adiponectin on the vasculature and insulin resistance (ir), levels are increased in patients with end-stage kidney disease (ESKD), in whom both ir and atherosclerosis are prevalent. The proportion of the high molecular weight (HMW) isoform of adiponectin was increased in the dialysis group (p = 0.001), even though these patients were significantly insulin resistant compared with controls (p = 0.006). Adipor1 and Adipor2 on PBMC were also increased in patients with ESKD (p < 0.05 and p = 0.007, respectively). it was concluded that this receptor-ligand axis is up-regulated and may be a beneficial response to the inflammatory milieu of ESKD ^Ref .
In chronique kidney disease (CKD) patiens, a significantly lower event-free survival rate in the lower adiponectin group (<4.39 microg/ml in men, <6.84 microg/ml in women, chi-square 4.88, p <0.03). The risk factor-adjusted cox regression showed that an increase in adiponectin per 1 microg/ml was associated with a decrease in the risk of CVD to 0.86 (95% confidence interval 0.75 to 0.96, p = 0.004). in the subgroup with previous ischemic heart disease (IHD; n = 65), a significantly lower event-free survival rate of IHD was also observed in the lower adiponectin group (<4.45 microg/ml inmen, <4.49 microg/ml in women, chi-square 3.96, p <0.05). the relative distribution of adiponectin isoforms was examined in patients with severe CKD, and the percentage of the high-molecular-weight form in patients with IHD during follow-up (n = 3) was significantly smaller than that in those without IHD (n = 4, p <0.02). In conclusion, renal function is a significant regulator of adiponectin when categorized by CKD stage, whereas hypoadiponectinemia is a predictor of CVD, including recurrent IHD ^Ref .

Pregnancy

HMW and total adiponectin were measured in 121 women at the time of oral glucose tolerance testing (OGTT) in late pregnancy, following an abnormal glucose challenge test. Based on the OGTT, there were 41 women with and 80 without GDM. Median HMW adiponectin concentration was lower in women with GDM (3.5 microg/ml) than in those without GDM (5.5 microg/ml) (p < 0.0001). After full adjustment for covariates, mean HMW adiponectin remained significantly lower in women with GDM compared with their peers (3.6 vs. 5.3 microg/ml, p = 0.0035). HMW adiponectin was positively associated with insulin sensitivity (IS(OGTT)) (r = 0.38, p < 0.0001) and pancreatic B- cell function [insulin secretion-sensitivity index (issi)] (r = 0.33, p = 0.0002) and inversely related to blood glucose levels, including area-under-the-glucose-curve during the OGTT (AUC(glucose)) (r =  –0.31, p = 0.0007). on separate multiple linear regression analyses, HMW adiponectin emerged as an independent determinant of AUC(glucose), IS(OGTT) and ISSI, respectively, mirroring the relationships of total adiponectin. The authors conclude that HMW adiponectin is significantly decreased in women with GDM. Deficiency of HMW adiponectin may be an early event in the natural history of T2DM ^Ref .

Preeclampsia

High molecular weight (HMW) adiponectin concentrations were significantly higher in women with preeclampsia (n=14; median, 11.2 microg/ml; interquartile range, 9.2–15.8) compared to normal pregnant women (n=14; 6.8 microg/ml, 5.4–10.7; p=0.04). in contrast, medium molecular weight and low molecular weight adiponectin concentrations were substantially equal between the groups. The ratio of HMW adiponectin to total adiponectin was also markedly higher in preeclamptic women (52.3%, 49.5–58.7) than control women (43.0%; 39.8–48.0; p=0.004). Taken together with other reports our findings imply a physiological feedback response to minimize endothelial damage in preeclamptic women ^Ref .

TNF-alpha neutralization

tumor necrosis factor (TNF)-alpha neutralization improves inflammatory markers and total adiponectin in patients with the metabolic syndrome, without improving insulin sensitivity. 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). This might explain the lack of effect on insulin sensitivity ^Ref .

the proportion of maternal serum adiponectin in HMW form (S(A)) is independently and inversely associated with infant birthweight. Thus, adiponectin isoform distribution, rather than total adiponectin concentration, may be a correlate of foetal size ^Ref .

Moderate alcohol consumption tended to increase HMW adiponectin by 57% (p = 0.07) and medium molecular weight adiponectin by 12.5% (p = 0.07), but not low molecular weight (LMW) adiponectin. Concentrations of HMW adiponectin in particular were positively associated with skeletal muscle oxidative capacity ^Ref .

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