Circulating ZAG Levels Research Articles

Association between circulating zinc-α2-glycoprotein levels and the different phenotypes of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) diagnosis combines various clinical phenotypes. The definition of PCOS is still controversial because insulin resistance (IR) and dysmetabolism do not constitute PCOS diagnostic criteria. We analyzed whether a circulating biomarker zinc-α2-glycoprotein (ZAG) related to IR and metabolic dysfunction can predict PCOS phenotypes. We then recruited 100 PCOS patients and 99 healthy women as the control group to assess the relationship between ZAG and metabolic characteristics. The euglycemic-hyperinsulinemic clamp helped assess insulin sensitivity, and the enzyme immunometric assay was deployed for ZAG levels. Our PCOS cohort presented sixty-nine patients with hyperandrogenism, eighty-six patients with chronic oligoanovulation, and eighty-one patients with polycystic ovaries by ultrasonographic evaluation. Additionally, the circulating ZAG levels were considerably reduced in all PCOS patients compared with healthy women (p < 0.05 or p < 0.01). Additionally, sixty-nine PCOS patients had IR, and circulating ZAG levels were also different among the phenotypes. Furthermore, the normoandrogenic type specifically exhibited the highest circulating ZAG levels among all PCOS phenotypes (p < 0.05 or p < 0.01). Additionally, normoandrogenic phenotype patients had reduced HOMA-IR scores and greater M-values than those in the classic phenotypes (p < 0.05). The circulating ZAG levels, however, were not associated with oligoanovulation but were correlated with hyperandrogenism and PCO morphology. In summary, circulating ZAG levels serve as suitable PCOS phenotype biomarkers, aiding physicians to identify women who merit screening.

Circulating zinc-α2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment.

The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.

Circulating zinc-\u03b12-glycoprotein levels are low in newly diagnosed patients with metabolic syndrome and correlate with adiponectin

BackgroundZinc-α2-glycoprotein (ZAG) is a novel adipokine that reduces insulin resistance, protecting against type 2 diabetes. However, past studies have been contradictory. This cross-sectional study aims to investigate the association of circulating ZAG with metabolic syndrome (MetS) in middle-aged and older Chinese adults.MethodsFour hundred eighty nine individuals (234 healthy controls and 255 MetS patients) were examined. All individuals were screened for MetS according to the diagnostic guidelines of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Circulating ZAG and ADI levels were measured by ELISA. Blood fat, glucose and insulin were measured with a commercial kit. Circulating ZAG levels were compared with various parameters in study subjects.ResultsPlasma ZAG levels were lower in MetS patients compared to those of the healthy controls (35.0 ± 11.7 vs. 46.1 ± 18.6 mg/L, P < 0.01). ZAG showed a positive correlation with age, HDL-C, HOMA-β and ADI, but a negative correlation with Fat%, BMI, WHR, blood pressure, triglycerides, FFA, FBG, 2 h–BG, fasting insulin, 2 h–Ins, HbA1c and HOMA-IR (P < 0.01). When the population was divided according to tertiles of ADI, subjects in the highest tertile had the highest ZAG levels. The analysis of ROC curves revealed that the best cutoff value for plasma ZAG to predict MetS was 45.2 mg/L (sensitivity 92%, specificity 59%, and AUC 0.80).ConclusionsWe found that circulating ZAG levels were decreased in patients with MetS. In fact, circulating ZAG decreased progressively with an increasing number of MetS components and associated with ADI levels, suggesting that ZAG is related to IR and MetS and may be a sensitizer.Trial RegistrationChiCTR-OCC-11001422. Registered 23 June 2011.

Circulating Zinc-α2-glycoprotein levels and Insulin Resistance in Polycystic Ovary Syndrome.

The aim of study was to assess the relationship between zinc-α2-glycoprotein (ZAG) and androgen excess with insulin resistance in polycystic ovary syndrome (PCOS) women. 99 PCOS women and 100 healthy controls were recruited. Euglycemic-hyperinsulinemic clamp (EHC) was preformed to assess their insulin sensitivity. Circulating ZAG was determined with an ELISA kit. In healthy subjects, circulating ZAG levels exhibited a characteristic diurnal rhythm in humans, with a major nocturnal rise occurring between midnight and early morning. Circulating ZAG and M-value were much lower in PCOS women than in the controls. In all population, overweight/obese subjects had significantly lower circulating ZAG levels than lean individuals. Multiple linear regression analysis revealed that only M-value and the area under the curve for glucose were independently related factors to circulating ZAG in PCOS women. Multivariate logistic regression analysis showed that circulating ZAG was significantly associated with PCOS even after controlling for anthropometric variables, blood pressure, lipid profile and hormone levels. The PCOS women with high ZAG had fewer MetS, IGT and polycystic ovaries as compared with the low ZAG PCOS women. Taken together, circulating ZAG levels are reduced in women with PCOS and ZAG may be a cytokine associated with insulin resistance in PCOS women.

Effects of sitagliptin on circulating zinc-α2-glycoprotein levels in newly diagnosed type 2 diabetes patients: a randomized trial.

Zinc-α2-glycoprotein (ZAG) has recently been characterized as a potent metabolic regulator. However, the effects of anti-diabetic agents on circulating ZAG levels in humans remain largely unknown. To explore the possible mechanisms by which the dipeptidyl peptidase-IV (DPP-IV) inhibitor improves insulin resistance, we investigated the effect of sitagliptin, a DPP-IV inhibitor, on circulating cytokine levels in newly diagnosed type 2 diabetes (nT2DM) patients. A subset of 141 subjects with nT2DM were assigned to receive placebo (n=47) or sitagliptin (n=94) for 3 months. Before and after treatment, subjects received a 75 g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp (EHC), and measurement of ZAG and adiponectin (ADI) concentrations. Circulating ZAG levels were lower in nT2DM than in control individuals (P<0.01). After 3 months of sitagliptin treatment, HbA1c, fasting plasma glucose, postprandial glucose, 2-h insulin after glucose overload, triglycerides, and homeostasis model assessment of insulin resistance (HOMA-IR) were decreased significantly compared with pre-treatment (P<0.05 or P<0.01), whereas the glucose infusion rate during the stable period of the clamp (M values) during EHC were significantly increased (P<0.01). In addition, circulating ZAG and ADI concentrations were significantly increased along with improved glucose metabolism and insulin sensitivity compared with pre-treatment (both P<0.01) and the change of ZAG (ΔZAG) was positively associated with ΔADI, ΔHOMA-IR, ΔBMI, Δfasting insulin and negatively associated with Δ tumor necrosis factor-α (TNF-α). Furthermore, sitagliptin treatment resulted in significantly lowered plasma TNF-α level (P<0.05). A low level of circulating ZAG is associated with insulin resistance and sitagliptin treatment significantly increases circulating ZAG levels. These observations have implications in relation to the mode of action of the DPP-IV inhibitor as an insulin sensitizing agent.

The correlation between zinc-α2-glycoprotein and adiponectin in population with different glucose tolerance

Objective To investigate the relationship of circulating zinc-α2-glycoprotein (ZAG) as well as adiponectin with adiposity and insulin resistance in humans.Methods Serum ZAG and adiponectin levels were determined by ELISA in 285 subjects with normal glucose tolerance (NGT),impaired glucose tolerance (IGT),and newly diagnosed cases with type 2 diabetes mellitus(T2DM).The relationships between circulating ZAG and insulin resistance or metabolic parameters were also explored.Results Circulating ZAG and adiponectin levels were all lower in T2 DM and IGT subjects than those in control subjects [ZAG:(37.14 ± 13.25 and 48.84 ± 18.74 vs 59.36 ± 16.20) mg/L,P＜0.05 or P＜0.01 ; adiponectin:(27.79 ± 11.23 and 33.00 ± 9.42 vs 41.81 ± 13.68) μg/L,P＜0.01].Circulating ZAG was correlated positively with high density lipoprotein-cholesterol and adiponectin (all P＜0.01),and inversely with body mass index,waist-hip ratio,FAT％,diastolic blood pressure,triglyceride,fasting blood glucose,fasting insulin,HbA1C,and homeostasis model assessment for insulin resistance(HOMA-IR,P＜0.05 or P＜0.01).By multivariate analysis,ZAG levels were independently associated with body mass index,HOMA-IR,diastolic blood pressure,and adiponectin (P＜0.05 or P＜0.01).Conclusions ZAG levels,associated with fat,insulin sensitivity,and adiponectin expression,are likely to play an important role in insulin resistance and energy homeostasis in humans. Key words: Zinc-α2-glycoprotein; Adiponectin; Insulin resistance; Diabetes mellitus, type 2

Zinc-α2-Glycoprotein Is Associated With Insulin Resistance in Humans and Is Regulated by Hyperglycemia, Hyperinsulinemia, or Liraglutide Administration

OBJECTIVEZinc-α2-glycoprotein (ZAG) has been proposed to play a role in the pathogenesis of insulin resistance. Previous studies in humans and in rodents have produced conflicting results regarding the link between ZAG and insulin resistance. The objective of this study was to examine the relationships between ZAG and insulin resistance in cross-sectional and interventional studies.RESEARCH DESIGN AND METHODSSerum ZAG (determined with ELISA) was compared with various parameters related to insulin resistance in subjects with normal glucose tolerance, impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM), and in women with or without polycystic ovary syndrome (PCOS). Euglycemic-hyperinsulinemic clamps were performed in healthy and PCOS women. Real-time RT-PCR and Western blotting were used to assess mRNA and protein expression of ZAG. The effect of a glucagon-like peptide-1 agonist on ZAG was studied in a 12-week liraglutide treatment trial.RESULTSCirculating ZAG was lower in patients with IGT and newly diagnosed T2DM than in controls. Circulating ZAG correlated positively with HDL cholesterol and adiponectin, and correlated inversely with BMI, waist-to-hip ratio, body fat percentage, triglycerides, fasting blood glucose, fasting insulin, HbA1c, and homeostasis model assessment of insulin resistance (HOMA-IR). On multivariate analysis, ZAG was independently associated with BMI, HOMA-IR, and adiponectin. ZAG mRNA and protein were decreased in adipose tissue of T2DM patients. Moreover, circulating ZAG levels were lower in women with PCOS than in women with high insulin sensitivity. Liraglutide treatment for 12 weeks significantly increased circulating ZAG levels.CONCLUSIONSWe conclude that ZAG may be an adipokine associated with insulin resistance.

Serum levels of the adipokine zinc- α2-glycoprotein are increased in chronic hemodialysis

Zinc- α2-glycoprotein (ZAG) has recently been proposed as a new adipokine involved in body weight control. In the current study, we investigated renal elimination of this adipokine by comparing circulating ZAG levels in patients on chronic hemodialysis (CD) with controls. Sixty CD patients and 60 controls with a glomerular filtration rate greater than 50 mL/min were included. Serum concentrations of ZAG were determined by enzyme-linked immunosorbent assay; and its relationship with renal function, glucose and lipid metabolism, as well as inflammation was studied in both groups. Median ZAG serum levels were almost 2-fold higher in CD patients (94.4 ± 29.4 mg/L) as compared with controls (48.3 ± 23.5 mg/L) ( P < .001). Furthermore, circulating ZAG was negatively correlated with fasting insulin, homeostasis model assessment of insulin resistance, and leptin in controls in univariate analysis. Moreover, CD independently predicted ZAG concentrations in multiple regression analysis. Renal filtration appears to be an important route of ZAG elimination, and markers of renal function should be included in studies on ZAG physiology.