Adiponectin isoforms (5. Contra)

Diabetes

in a recent study, 60 men and women with normal glucose tolerance (n = 20), impaired glucose tolerance (IGT) (n = 20), or type 2 diabetes (n = 20) at baseline and after 4 weeks of training were enrolled to measure metabo- lic variables. HMW adiponectin and total adiponectin had similar ability to predict the presence of insulin resistance. Total adiponectin, as measured by radioimmunoassay and enzyme-linked immunosorbent assay (ELISA), correlated most strongly with measures of insulin sensitivity (p < 0.01) and lipid profile (p < 0.01) at baseline, showed greater improvements of adiponectin levels (p < 0.001), was more closely associated with improvements of lipid measures with exercise training (p < 0.01), and more accurately predicted insulin resistance and IGT in comparison with total adiponectin or HMW. these results do not support the superiority of HMW over total adiponectin (measured using currently available assays) in assessing metabolic variables at baseline or in response to physical training. Moreover, there are significant differences in the ability of commercially available assays for total adiponectin to predict metabolic variables ^Ref .

Coronary artery disease

A total of 186 consecutive male coronary Artury disease (CAD) patients participated in a study and were categorized into quartiles based on their total adiponectin level. The interquartile cut-off points were 4.0, 5.5 and 7.0 microg/ml. The HMW adiponectin levels were significantly lower in the quartile of lower total adiponectin levels both in non-diabetic and diabetic patients. in contrast, low molecular weight adiponectin levels (which were calculated as the total – HMW) were constant. In univariate analysis, total adiponectin correlated negatively with body mass index and hemoglobin (Hb) A1c, and HMW adiponectin correlated negatively with HbA1c in non-diabetic patients. on the other hand, total and HMW adiponectin correlated positively with high-density lipoprotein-cholesterol (HDL-C) in diabetic patients. multiple regression analysis revealed that HMW adiponectin correlated negatively with HbA1c in non-diabetic patients, and total and HMW adiponectin correlated positively with HDL-C in diabetic patients. The authors conclude that the change in the HMW isoform reflects a change in total adiponectin level. measurement of total and HMW adiponectin were equally useful in assessing metabolic risk in CAD patients ^Ref

Chronique heart failure

the plasma levels of total and HMW adiponectin, atrial natriuretic peptide, brain natriuretic peptide (BNP), and N-terminal-proBNP (NT-proBNP), and haemodynamic parameters were measured in 449 consecutive chronique heart failure (CHF) patients. Based on body mass index (BMI), patients were classified into three groups: low (<21 kg/m(2), n = 133), normal (21–25 kg/ m(2), n = 205), and high (>25 kg/m(2), n = 111). After adjustment for clinical variables associated with CHF including haemodynamics, plasma total adiponectin level was an independent prognostic predictor but HMW adiponectin was not in the overall patient group. On subgroup analyses, in patients with abnormal BMI, plasma total adiponectin level was not an independent prognostic predictor, but in patients with normal BMI, plasma levels of log NT-proBNP (p = 0.017) and log total adiponectin (p = 0.003) were independent prognostic predictors. These findings indicate that total adiponectin is more useful for assessing mortality risk than HMW adiponectin and a high plasma total adiponectin is an independent prognostic predictor especially in CHF patients with normal BMI ^Ref .

Insulin-resistance

following ingestion of two high carbohydrate mixed meals, net muscle glycogen synthesis was reduced by approximately 60% in young, lean, insulin- resistant subjects compared with a similar cohort of age-weight-body mass index-activity-matched, insulin-sensitive, control subjects. In contrast, hepatic de novo lipogenesis and hepatic triglyceride synthesis were both increased by >2-fold in the insulin-resistant subjects. These changes were associated with a 60% increase in plasma triglyceride concentrations and an approximately 20% reduction in plasma high-density lipoprotein concentrations but no differences in plasma concentrations of TNF-alpha, IL-6, adiponectin, resistin, retinol binding protein-4, or intraabdominal fat volume. These data demonstrate that insulin resistance in skeletal muscle, due to decreased muscle glycogen synthesis, can promote atherogenic dyslipidemia by changing the pattern of ingested carbohydrate away from skeletal muscle glycogen synthesis into hepatic de novo lipogenesis, resulting in an increase in plasma triglyceride concentrations and a reduction in plasma high-density lipoprotein concentrations. Furthermore, insulin resistance in these subjects was independent of changes in the plasma concentrations of TNF-alpha, IL-6, high-molecular-weight adiponectin, resistin, retinol binding protein-4, or intra-abdominal obesity, suggesting that these factors do not play a primary role in causing insulin resistance in the early stages of the metabolic syndrome ^Ref .

662 Japanese male high school students aged 16 to 17 years and 282 healthy Japanese male adults aged 30 to 61 years who received annual health checkups were studied. High-molecular weight (HMW) adiponectin levels were significantly lower in adolescents (4.18 +/- 2.24 mug/mL) than in adults (4.84 +/- 3.20 mug/mL), despite body mass index (BMI) being significantly lower in adolescents. The HMW adiponectin levels correlated negatively with BMI and the homeostasis model assessment of insulin resistance index (HOMA-IR) in adults. In adolescents, HMW adiponectin correlated negatively with BMI and waist circumference, but not with HOMA-IR or other metabolic parameters except high-density lipoprotein cholesterol. Leptin levels correlated positively with HOMA-IR, triglycerides, tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 and negatively with high-density lipoprotein cholesterol even after adjustment for BMI. These findings suggest that serum leptin is a more useful biomarker of fat accumulation-related insulin resistance, inflammation, and metabolic abnormalities than HMW adiponectin in the general population of male adolescents. The inverse correlation between adiponectin and insulin resistance may manifest in the later phase of obesity development ^Ref .

Polycystic ovary syndrom

thirty PCOS patients randomized to pioglitazone, 30 mg/day, or placebo for 16 weeks and 14 weight-matched healthy females were studied. Total and HMW adiponectin levels were measured, and euglycaemic hyperinsulinaemic clamps and indirect calorimetry were performed. Delta-values denoted changes during pioglitazone treatment (16 weeks–basal). Pretreatment adiponectin levels were decreased in PCOS patients vs. Controls (p < 0.05), whereas no significant differences were found in HMW adiponectin levels. Following pioglitazone treatment, total and HMW adiponectin increased (all p < 0.05), whereas no significant changes were observed with placebo. Delta-total adiponectin levels correlated positively with the rate of delta-insulin-stimulated glucose disposal (R(d)) (r = 0.89) and delta-oxidative glucose metabolism (r = 0.71) and inversely with delta-fasting free fatty acid (FFA) levels (r = –0.69) and delta-lipid oxidation (r = 0.73) during insulin stimulation (all p < 0.01). Weaker correlations were found between delta-HMW adiponectin levels and delta-measures of glucose and lipid metabolism during insulin stimulation than with delta-total adiponectin. A close correlation between increased total adiponectin levels and increased insulin-stimulated glucose metabolism during pioglitzone treatment supports the hypothesis that the insulin-sensitizing effect of pioglitazone in PCOS is, at least in part, mediated by adiponectin. Measures of changes in HMW adiponectin did not add further information to this relationship ^Ref .

Fenofibrate

Fenofibrate treatment did not increase insulin sensitivity indices (G/I ratio and HOMA-IR) between before and after treatment. The treatment did not alter the levels of serum total adiponectin, while serum HMW adiponectin increased significantly. this study demonstrates that fenofibrate increases serum HMW adiponectin levels without improving insulin sensitivity ^Ref .

Niacin

20 men with the metabolic syndrome received 1500mg niacin for 6 weeks. Low- and medium-molecular weight adiponectin increased by 35% and 33%, respectively, but HMW adiponectin by 88% (all p<0.05). The increase in HMW adiponectin was almost two times as large in patients with lower BMI and better insulin sensitivity. However, treatment with niacin induced a deterioration of insulin sensitivity, as assessed by the HOMA-IR, independently of the increase in HMW adiponectin. HMW adiponectin is the fraction most affected by treatment with niacin. The niacin-associated deterioration of insulin sensitivity, however, occurs even in subgroups with the greatest increase of HMW adiponectin ^Ref .

Monocytes were isolated from normal weight and overweight controls and patients with type 2 diabetes mellitus (T2D) and monocytic release of IL-6 positively correlated with the body mass index (BMI). HMW-adiponectin further enhanced and LMW-adiponectin reduced IL-6 release in monocytes. systemic total adiponectin, and the HMW isoform were not different in these groups but MMW-adiponectin was lower in T2D, and LMW-adiponectin was reduced in the obese and T2D. Circulating LMW-adiponectin negatively correlated to monocytic IL-6 release. Systemic IL-6 was higher in the obese control group and T2D, respectively, but did not correlate with monocytic IL-6 secretion. Therefore, the current study indicates that HMW-adiponectin exerts pro- and LMW-adiponectin antiinflammatory effects and reduced LMW-adiponectin in obesity may partly contribute to elevated monocytic IL-6 release ^Ref .

Preeclampsia newborns showed a significantly lower gestational age (GA), total adiponectin and HMW adiponectin levels than the controls. No differences in adiponectin levels were found between case and control groups when correcting for gestational age (GA). Adiponectin in cord blood from PE pregnancies may not be a tentative risk marker for metabolic syndrome- linked diseases. HMW adiponectin is the dominant form of adiponectin in cord blood. its role during pregnancy and postnatal life should be further explored ^Ref .

Other situations

In chronique hepatitis B (CHB) patiens , serum adiponectin was detected at levels ranging over fourfold magnitude with advancing fibrosis stage and correlated positively with fibrosis stage [r=0.45, p<0.001]. CHB patients with stage 0–1 fibrosis had higher composition of high molecular weight (HMW) form of adiponectin when compared with CHB patients with liver cirrhosis [mean+/-SEM 51.2+/-2.1% vs. 40.9+/-1.7%, respectively, p=0.001]. After antiviral therapy, patients with fibrosis reduction had marked decline in serum adiponectin level and increase in HMW form of adiponectin [mean+/- SEM 43.5+/-1.2% vs. 37.0+/-3.0%, respectively, p=0.04]. Thus, serum adiponectin may have a role in fibrosis progression in CHB infection. A marked decline in serum adiponectin after antiviral therapy is associated with fibrosis reduction ^Ref .

T-cadherin was identified as a receptor for the hexameric and high-molecular-weight species of adiponectin but not for the trimeric or globular species. only eukaryotically expressed adiponectin bound to T-cadherin, implying that posttranslational modifications of adiponectin are critical for binding. An adiponectin mutant lacking a conserved N-terminal cysteine residue required for formation of hexamer and high-molecular-weight species did not bind T-cadherin in coimmunopreci­pitation studies. Although lacking known cellular functions, T-cadherin is expressed in endothelial and smooth muscle cells, where it is positioned to interact with adiponectin. Because T-cadherin is a glycosylphospha­tidylinositol-anchored extracellular protein, it may act as a coreceptor for an as-yet-unidentified signaling receptor through which adiponectin transmits metabolic signals ^Ref .

In a recent study, the alteration of each isoform of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) during the choline-deficient L-amino acid-defined (CDAA) diet-induced rat liver fibrosis development. The methylation status of all receptors was also elucidated. The serum level of total adiponectin significantly increased during the liver fibrosis development. Among the three isoforms, only HMW adiponectin was significantly up-regulated whereas MMW and LMW were not. The expression of T-cadherin, which exclusively binds with HMW adiponectin, was significantly augmented as well. the AdipoR2 expression was markedly decreased and showed no marked difference from that of AdipoR1. No obvious methylation change was observed in all three receptors, suggesting that another mechanism is involved in the alteration of receptor gene expression. Collectively, since the specific ligand and receptor were augmented together, crosstalk between HMW adiponectin and T-cadherin may play an important role during liver fibrosis development in rats ^Ref .

Immortalized human stellate cells (HSC) line htert and primary rat HSCs were stimulated with platelet-derived growth factor (PDGF) with or without pretreatment with AMPK activator 5-aminoimidazole-4-carboxamide-1–4– ribofuranoside (AICAIR), metformin, or high molecular weight (HMW) adiponectin. HMW adiponectin dose-dependently suppressed PDGF-induced HSC proliferation. Adenoviral transduction with dominant-negative AMPK (DN-AMPK) abolished the suppressive effect of adiponectin in HSCs. AICAR, metformin, or transduction of constitutively active AMPK attenuated PDGF- induced [(3)H]thymidine incorporation, which was abolished by either a chemical AMPK inhibitor or transduction of DN-AMPK, consistent with an antiproliferative effect of AMPK. The suppressive effect of AMPK on HSC proliferation is mediated through multiple mechanisms, including (1) an inhibition of the AKT pathway, (2) inhibition of nAdpH oxidase-dependent reactive oxygen species (ros) production via induction of antioxidant enzymes, and (3) an increase in the expression of the cyclin-dependent kinase inhibitors p27(kip1) and p21(cip1). Adiponectin inhibits HSC proliferation via activation of AMPK. AMPK activation by AICAR or metformin inhibits HSC proliferation via suppression of ROS production and subsequent inhibition of AKT pathway. thus, adiponectin and AMPK inhibit HSC proliferation and hepatic fibrosis via multiple molecular mechanisms ^Ref .