Correlation analysis of IGF-1, ZAG, nesfatin-1, HbA1c levels, and type 2 diabetes mellitus complicated with hypothyroidism.

ABSTRACT: To analyze the correlation between IGF-1, ZAG, nesfatin-1, HbA1c levels, and type 2 diabetes mellitus (T2DM) complicated with hypothyroidism.Fifty-five patients with type-2 diabetes who were admitted to our hospital from August 2018 to February 2020 were selected as the control group, and 55 patients with type 2 diabetes combined with hypothyroidism who were admitted to the hospital at the same period were selected as the combined group, and 56 patients who came to our hospital for physical examination at the same period were selected as the healthy group. The general clinical data and relevant laboratory indexes of all patients in the three groups were collected and statistically analyzed. Besides, the correlation between IGF-1, ZAG, nesfatin-1, HbA1c levels, and T2DM complicated with hypothyroidism was analyzed.Levels of FPG, FINS, TC, TG, LDL, 2hPBG, TPOAb, TgAb, and HOMA-IR in the diabetes group and combined group were all significantly higher than those in the healthy group, while HDL and T4 levels in the diabetes group and combined group were lower than those in the healthy group (P < .05). The levels of FPG, FINS, TC, TG, LDL, 2hPBG, TPOAb, and TgAb in the combined group were significantly higher than those in the diabetes group (P < .05), and the levels of HDL and T4 were lower than those in the diabetes group. In addition, the IGF-1 level was positively correlated with ZAG, nesfatin-1, and HbA1c levels in the combined group (P < .05), and IGF-1 (OR: 0.964, 95% CI: 0.943-0.983, P = .001), ZAG (OR: 1.298, 95% CI: 1.121-1.401, P = .005), nesfatin-1 (OR: 0.876, 95% CI: 0.751-0.901, P = .002), and HbA1c (OR: 1.321, 95% CI: 1.121-1.401, P = .012) were independent risk factors for T2DM complicated with hypothyroidism.Regular detection of IGF-1, ZAG, nesfatin-1, and HbA1c levels are of great value for the diagnosis and treatment of patients with T2DM complicated with hypothyroidism.

Elevated serum levels of S100A1 and zinc α2-glycoprotein in patients with heart failure.

BACKGROUND AND AIMS: Heart failure (HF) is a growing concern worldwide. S100A1 and zinc α2-glycoprotein (ZAG) play an important role in heart function. We examined serum levels of S100A1 and ZAG in HF patients and their association with anthropometric indices and body composition. METHODS AND RESULTS: Sixty-four patients with HF, mean age 56.2, 48 male and 16 females, with ejection fraction <30-35%, were recruited from Shahid Madani Heart Hospital in Tabriz, Iran, from April to October 2019. Two groups, cachexia (n = 32) and non-cachexia (n = 32), which were divided based on weight loss of at least 7.5% in the last six months, were compared with the control group (n = 26). S100A1 and ZAG serum levels were determined by ELISA. Serum median (min-max) levels of S100A1 and ZAG were significantly greater in HF patients [326 (184.8-635.2) and 150.4 (61.5-520.7)] than healthy controls [265.4 (43.6-658.8) and 119.8 (16.7-533)], both p = 0.001. S100A1 Serum levels in cachexia group was significantly higher than non-cachexia group [331 (245.6-469.6) vs. 318 (184.8-635.2), p = 0.03]. A strong positive association was observed between S100A1 and ZAG serum levels in patients (r = 0.70, p < 0.0001). Serum levels of these two proteins negatively and significantly associated with BMI (r = -0.25, p = 0.044 and r = -0.28, p = 0.024, respectively) and arm circumference (r = -0.26, p = 0.037 and r = -0.25, p = 0.047, respectively). CONCLUSION: The results indicate that S100A1 and ZAG are likely to contribute to the pathogenesis of HF disease and weight loss, as well as the strong association between S100A1 and ZAG possibly indicating a similar mechanism of action for these two proteins.

Zinc-α2-glycoprotein is associated with non-albuminuric chronic kidney disease progression in type 2 diabetes: a retrospective study with 4-year follow-up.

AIM: To investigate the association between baseline plasma zinc-α2-glycoprotein and non-albuminuric chronic kidney disease progression in type 2 diabetes. METHODS: Adults with normoalbuminuria at entry (n=341; age 57±10 years, 52% men) were analysed. Chronic kidney disease progression was defined as a decrease in chronic kidney disease stage and a decline of ≥25% in estimated GFR from baseline. Baseline plasma zinc-α2-glycoprotein levels were quantified by immunoassay, and analysed either as a continuous variable or by tertiles in Cox proportional hazards models. Model discrimination was assessed using Harrell's C-index. A sensitivity analysis was performed on a subset of individuals who maintained normoalbuminuria during follow-up. RESULTS: Chronic kidney disease progression occurred in 54 participants (16%). Zinc-α2-glycoprotein levels were elevated in chronic kidney disease progressors (P = 0.011), and more progressors were assigned to the higher zinc-α2-glycoprotein tertile than non-progressors. In the unadjusted Cox model, zinc-α2-glycoprotein, both as a continuous variable (hazard ratio 1.72, 95% CI 1.08-2.75) and tertile 3 (vs tertile 1; hazard ratio 2.14, 95% CI 1.10-4.17), predicted chronic kidney disease progression. The association persisted after multivariable adjustment. The C-index of the Cox model increased significantly after incorporation of zinc-α2-glycoprotein into a base model comprising renin-angiotensin system antagonist usage. Sensitivity analysis showed that zinc-α2-glycoprotein independently predicted chronic kidney disease progression among individuals who maintained normoalbuminuria during follow-up. CONCLUSIONS: Plasma zinc-α2-glycoprotein is associated with chronic kidney disease progression, and may serve as a useful early biomarker for predicting non-albuminuric chronic kidney disease progression in type 2 diabetes.

Zinc-α2-Glycoprotein (ZAG): A New Deficiency in Vitiligo Patients.

Zinc-α2-glycoprotein (ZAG), a recently identified adipokine, is a multidisciplinary protein, which is secreted in various body fluids. The ZAG plays roles in lipolysis, regulation of metabolism, cell proliferation and differentiation, regulation of melanin synthesis, cell adhesion, and immunoregulation. The aim of this study is to estimate serum and tissue levels of ZAG in patients with vitiligo. The study included 30 vitiligo patients and 30 healthy controls. Lesional skin biopsy was performed, and blood sample was retrieved to determine the level of ZAG in blood using ELISA kit. In this study, the mean level of ZAG was found to be significantly lower in the vitiligo patients' tissue in comparison with the healthy control subjects' tissue ( p=0.001); the level of ZAG was also lower in vitiligo patients' serum in comparison with the healthy control subjects' serum ( p=0.001). A highly significant correlation was observed between the duration of the disease and the level of ZAG in the tissue of patients (r =0.9; p=0.001). Also a highly significant positive correlation was observed between the age of patients and the level of ZAG in the tissue (r =0.5; p=0.006). Diminishing of ZAG in serum and tissue of vitiligo patients is another important player sharing in the complex pathogenesis of vitiligo.

Serum zinc-α2-glycoprotein levels are elevated and correlated with thyroid hormone in newly diagnosed hyperthyroidism.

BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a recently novel lipolytic adipokine implicated in regulation of glucose and lipid metabolism in many metabolic disorders. In vitro and animal studies suggest that thyroid hormones (TH) up-regulates ZAG production in hepatocytes. However, there is no data evaluating the possible relationship between ZAG and TH in a human model of hyperthyroidism. The objective of the present study is to assess the association of serum ZAG levels with TH and lipid profile in patients with hyperthyroidism before and after methimazole treatment. METHODS: A total of 120 newly diagnosed overt hyperthyroidism and 122 healthy control subjects were recruited. Of them, 39 hyperthyroidism patients were assigned to receive methimazole treatment as follow-up study for 2 months. RESULTS: The clinical consequence showed that serum ZAG levels were elevated in patients with hyperthyroidism (P < 0.01). Adjust for age, gender and BMI, serum ZAG levels were positively related with serum free T3 (FT3), free T4 (FT4) levels and negatively correlated with serum total cholesterol (TC), low density lipoprotein cholesterol (LDLC) levels in hyperthyroidism subjects (all P < 0.01). After methimazole treatment, serum ZAG levels were decreased and the decline was associated with decreased FT3, FT4 and increased TC levels (all P < 0.001). CONCLUSION: We conclude that ZAG may be involved in the pathogenesis of lipid metabolism disorder in patients with hyperthyroidism. TRIAL REGISTRATION: ChiCTR-ROC-17012943 . Registered 11 October 2017, retrospectively registered.

Increased serum levels of S100A1, ZAG, and adiponectin in cachectic patients with COPD.

BACKGROUND: COPD is a common irreversible obstructive airway disease. S100A1, ZAG, and adiponectin are important regulators of energy metabolism and body weight. Therefore, the aim of this study was to assess resting metabolic rate (RMR) and its association with serum levels of S100A1, ZAG, and adiponectin in cachectic and noncachectic COPD patients. PATIENTS AND METHODS: Ninety men with COPD, aged 40-70 years, were enrolled in the study. Patients were divided into the following two groups based on the unintentional weight loss of .7.5% in previous 6 months: noncachectic (n=45) and cachectic (n=45). The groups were matched based on age and body mass index (BMI). RMR was measured by indirect calorimetry method. Anthropometric indices and body composition were also measured. Serum levels of S100A1, ZAG, and adiponectin were measured by ELISA. RESULTS: Cachectic patients had significantly higher RMR than controls (P<0.001). Serum levels of ZAG, S100A1, and adiponectin were significantly higher in the cachexia group (P<0.0001). RMR was not significantly associated with S100A1, ZAG, and adiponectin levels. However, weight loss of patients was significantly associated with serum levels of ZAG and adiponectin (both, ß=0.22, P=0.03). Strong and positive association were found between the serum levels of S100A1 and ZAG (ß=0.88, P<0.0001), S100A1 and adiponectin (ß=0.86, P<0.0001), and also ZAG and adiponectin (ß=0.83, P<0.0001). CONCLUSION: The potential role of these factors in the wasting process is considerable. Also, the association between serum levels of S100A1, ZAG, and adiponectin represents that these three proteins are probably related to specific functions.

Serum levels of the adipokine zinc-alpha2-glycoprotein (ZAG) predict mortality in hemodialysis patients.

Wasting has been associated with increased cardiovascular and all-cause mortality in chronic kidney disease (CKD). We investigated whether serum zinc-alpha2-glycoprotein (ZAG), a potent cachectic and lipid-mobilizing factor that is increased in patients with CKD, predicts clinical outcomes in patients on chronic hemodialysis. We quantified serum ZAG at baseline in a prospective cohort of 252 patients undergoing maintenance hemodialysis. Serum ZAG concentrations were inversely associated with serum albumin, creatinine, and triglycerides and, conversely, positively associated with age. Although ZAG is strongly linked to protein energy wasting (PEW) in patients with cancer, higher ZAG concentrations were not associated with PEW in our cohort. During a mean study follow-up of 954 days, 49 patients died and 62 patients experienced a cardiovascular event. Kaplan-Meier analysis revealed a significant correlation between serum ZAG concentrations and all-cause mortality and cardiovascular events. In separate multivariable Cox regression models, serum ZAG concentrations remained significantly associated with all-cause mortality and cardiovascular events after adjustment for demographic factors (age, sex, and dialysis vintage), metabolic parameters (serum albumin, prealbumin, triglycerides, cholesterol, normalized protein catabolic rate, and body mass index), and cardiovascular risk factors (diabetes, dyslipidemia, history of cardiovascular disease, smoking, and diuretic use as a proxy of residual renal function). Thus, serum ZAG appears to be a strong and independent predictor of mortality and cardiovascular events in patients with end-stage renal disease. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms.

Cord blood concentrations of leptin, zinc-α2-glycoprotein, and adiponectin, and adiposity gain during the first 3 mo of life.

OBJECTIVES: Adipose tissue development starts in intrauterine life and cytokines are involved in this process. Therefore, understanding the role of cytokines in the fat mass gain of infants is crucial to prevent obesity later in life. Furthermore, recent evidence indicates a sex-specific link between cytokines and adipose tissue development. The objective of this study was to assess sex-specific relationships of cord blood concentrations of the cytokines leptin, zinc-α2-glycoprotein (ZAG), and adiponectin with infant adiposity during the first 3 mo of life. METHODS: This was a prospective cohort study of 104 mother-infant pairs that were selected from a maternity hospital in Sao Paulo, Brazil. Cord blood leptin, ZAG, and adiponectin were determined by enzyme-linked immunosorbent assays. The body composition of the infants was assessed monthly by air displacement plethysmography. A multiple linear regression analysis was conducted with the average fat mass gain from birth to the third month of life as the outcome and cord blood leptin, ZAG, and adiponectin as the variables of interest. RESULTS: Leptin was inversely associated with fat mass gain in the first 3 mo of life (P = 0.003; adjusted R2 = 0.09). There were inverse associations of leptin (P = 0.021), ZAG (P = 0.042), and maternal body mass index (P = 0.04) with fat mass gain in girls (adjusted R2 = 0.29) but fat mass gain in boys was positively associated with gestational age (P = 0.01; adjusted R2 = 0.15). CONCLUSIONS: The results of this study suggest that adiposity programming is sex-specific, which highlights the need to investigate the different metabolic mechanisms that are involved in adipogenesis.

Comparative Assessment of Serum Adipokines Zinc-α2-glycoprotein and Adipose Triglyceride Lipase, and Cardiovascular Risk Factors Between Normal Weight and Obese Patients with Hemodialysis.

BACKGROUND: Little is known about the potential relationship of obesity, adipose tissue and novel adipokines with cardiometabolic risk factors in end-stage renal disease. Zinc-α2-glycoprotein (ZAG) and adipose triglyceride lipase (ATGL) are novel adipokines with proposed desirable effects on inflammation, and lipid and glucose metabolism. The aim of this study was to investigate serum concentrations of ZAG and ATGL, and the relationship of these adipokines with cardiovascular risk factors in normal weight (NW) and obese (OB) patients undergoing hemodialysis. METHODS: Patients with regular hemodialysis including 44 normal weight (18.5

Effects of Zinc Alpha2 Glycoprotein on Lipid Metabolism of Liver in High-Fat Diet-Induced Obese Mice.

Zinc alpha2 glycoprotein (ZAG) is a new type of adipokine involved in adipose tissue mobilization, however, little is known about its lipid metabolism effect in liver. Therefore, we investigated the effects of ZAG in the regulation of hepatic lipid accumulation. Mice were randomly divided into two groups; one was fed a normal diet and another was fed a high-fat diet for eight weeks to establish obesity model. After that, the normal diet group was divided into ND (injection of pcDNA3.1) and NDZ (injection of ZAG recombinant plasmid) and the high-fat diet group was divided into HF (injection of pcDNA3.1) and HFZ (injection of ZAG recombinant plasmid). The mice were weighed once per week and injected with plasmid once every three days for eight times. The results showed that body weight and hepatic TG content were decreased dramatically in HFZ group compared with HF group. The stearoyl-CoAdesaturase1 (SCD1) and Acyl-CoA Synthetase-1 (ACSS1) protein levels in HFZ group were significantly decreased. Furthermore, phosphorylated hormone sensitive lipase (P-HSL) was significantly higher in HFZ group. In HFZ group, hepatic fatty acid translocase (CD36) and fatty acids binding protein-1 (FABP1) protein levels were reduced. In addition, the expression of phosphorylated protein kinase A (PPKA) in HFZ group was higher than the HF group. Meanwhile, NDZ group showed significantly decreased body weight and increased P-HSL level though the hepatic TG content showed no significantly changes compared with the ND group. Therefore, we conclude that ZAG may be beneficial for preventing high-fat-diet-induced hepatic lipid metabolic disorders.

Down-regulation of S100A1 protein in patients with metabolic syndrome and its association with zinc-α2-glycoprotein.

Objectives It has been proposed that zinc-α2-glycoprotein and S100A1 are possibly linked to the development of lipogenesis and obesity. We aimed to measure serum levels of S100A1 and zinc-α2-glycoprotein in patients with metabolic syndrome and investigate any associations of these two novel peptides with each other or components of metabolic syndrome. Methods Forty-four patients with metabolic syndrome and the equivalent number of healthy controls participated in this study. The participants' body mass index, waist circumference, systolic and diastolic blood pressure were measured. Serum levels of low- and high-density lipoprotein cholesterol, total cholesterol, triglyceride, fasting blood sugar, insulin, zinc-α2-glycoprotein and S100A1 protein were determined. Results Higher levels of anthropometric and lipid indices, metabolic factors and also SBP and DBP were observed in the metabolic syndrome group. Serum S100A1 levels were significantly lower in the metabolic syndrome group than the control group ( P = 0.008). There was a strong positive correlation between serum zinc-α2-glycoprotein and S100A1 levels ( r = 0.80, P < 0.0001). Serum levels of both S100A1 ( P = 0.03) and zinc-α2-glycoprotein ( P = 0.02) were potentially higher in subjects with hypertension than those with normal blood pressure, though these were found as part of multiple testing. Conclusion The results indicate that changes in the circulating level of S100A1 protein occur in metabolic syndrome patients. The strong correlation between serum zinc-α2-glycoprotein and S100A1 might suggest that production or release of these two proteins could be related mechanistically.

[Correlation of serum zinc alpha 2 glycoprotein with blood lipid and reproductive hormone levels in men].

OBJECTIVE: To study the changes of the serum zinc alpha 2 glycoprotein (ZAG) level in men and its relationship with blood lipid male reproductive hormones. METHODS: We enrolled 297 men aged 25－ 65 years in this study, 152 with hyperlipemia (HL) and the other 145 with normal blood lipid (normal control). We divided them into four age groups (25－35 yr, 36－45 yr, 46－55 yr, and 56－65 yr) and three tertile groups (Q1, Q2, and Q3) according to the tertiles of the serum ZAG level, and examined their blood lipid, blood glucose, serum ZAG, and reproductive hormones. RESULTS: The serum ZAG level was decreased gradually with the increase of age in both the HL patients and normal controls, significantly in the 36－45 and 56－65 yr age groups (P <0.05), and markedly lower in the HL than in the control men in the 25－35 and 36－45 yr groups (P <0.05). The levels of follicle-stimulating hormone (FSH) and total testosterone (TT) changed significantly with the ZAG level. The level of serum ZAG was correlated negatively with age (r = －0.58, P<0.05), waist circumference (r = －0.21, P <0.05), body mass index (BMI) (r = －0.22, P <0.05), fasting blood glucose (r = －0.16, P <0.05) , and triglyceride (TG) (r = －0.27, P <0.05) but positively with TT (r = 0.36, P <0.05). Age, BMI and TG were independent factors influencing the serum ZAG level. CONCLUSIONS: The serum ZAG level is decreased with the increase of age and associated with lipid metabolism, abdominal obesity, and reproductive hormone levels in males.

Combined serum and EPS-urine proteomic analysis using iTRAQ technology for discovery of potential prostate cancer biomarkers.

Prostate cancer (PCa) is one of the most common malignant tumors and a major cause of cancer-related death for men worldwide. The aim of our study was to identify potential non-invasive serum and expressed prostatic secretion (EPS)-urine biomarkers for accurate diagnosis of PCa. Here, we performed a combined isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis to compare protein profiles using pooled serum and EPS-urine samples from 4 groups of patients: benign prostate hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), localized PCa and metastatic PCa. The differentially expressed proteins were rigorously selected and further validated in a large and independent cohort using classical ELISA and Western blot assays. Finally, we established a multiplex biomarker panel consisting of 3 proteins (serum PF4V1, PSA, and urinary CRISP3) with an excellent diagnostic capacity to differentiate PCa from BPH [area under the receiver operating characteristic curve (AUC) of 0.941], which showed an evidently greater discriminatory ability than PSA alone (AUC, 0.757) (P<0.001). Importantly, even when PSA level was in the gray zone (4-10 ng/mL), a combination of PF4V1 and CRISP3 could achieve a relatively high diagnostic efficacy (AUC, 0.895). Furthermore, their combination also had the potential to distinguish PCa from HGPIN (AUC, 0.934). Our results demonstrated that the combined application of serum and EPS-urine biomarkers can improve the diagnosis of PCa and provide a new prospect for non-invasive PCa detection.

Plasma zinc alpha2-glycoprotein levels correlate positively with frailty severity in female elders.

Frailty is a geriatric syndrome associated with adiposity. Zinc alpha2-glycoprotein (ZAG), a novel adipokine, is a modulator of body fat mass and positively correlates with age. This observational study aims to investigate the relationship between plasma ZAG levels and frailty in the elderly.We enrolled 189 elder participants from a hospital-based comprehensive geriatric assessment program in Taiwan from January 2007 to June 2008. The demographic data, body weight, body mass index, appendicular skeletal muscle mass index (ASMI), body fat mass percentage, metabolic and inflammatory parameters including plasma tumor-necrosis factor alpha, C-reactive protein and ZAG levels, were assessed. The frailty score was assessed by Fried Frailty Index.The mean age of all participants (91 [48.1%] men and 98 [51.9%] women) was 77.19 ±â€Š6.12 years. Judged by the FFI score, 46 (24.34%) elders were robust, 106 (56.08%) were pre-frail, and 37 (19.58%) were frail. Older men showed greater ASMI and lower fat mass percentage in comparison to older women (P < 0.0001). The log-transformed mean plasma ZAG (µg/mL) level of overall was 1.82 ±â€Š0.11, and it was higher in men than in women (1.85 ±â€Š0.12 vs 1.79 ±â€Š0.1, P = 0.0006). Plasma ZAG levels were different among the robust, pre-frail and frail subgroups (1.78 ±â€Š0.09, 1.83 ±â€Š0.12, 1.83 ±â€Š1.10, respectively, P = 0.028), and the differences were more significant in woman elders (P = 0.005). Further multiple linear regression analysis showed plasma ZAG levels positively correlated with frailty severity in women (P for trend = 0.0435).Plasma ZAG levels positively correlated with frailty severity in woman elders. The difference between sexes suggests certain sex-specific mechanisms may exist to affect the association between plasma ZAG levels and frailty.

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.

The natural logarithm of zinc-α2-glycoprotein/HOMA-IR is a better predictor of insulin sensitivity than the product of triglycerides and glucose and the other lipid ratios.

AIM: The euglycemic-hyperinsulinemic clamp (EHC) is not available in most clinical settings and is costly, time consuming and invasive, and requires trained staff. Therefore, an accessible and inexpensive test to identify insulin resistance (IR) is needed. The aim of this study is to assess whether zinc-α2-glycoprotein (ZAG) index [Ln ZAG/homeostasis model assessment of IR (HOMA-IR)] is a better surrogate index for estimating IR or metabolic syndrome (MetS) compared with other surrogate indices. METHODS: We performed a population-based cross-sectional study. Two hundred healthy subjects, 102 polycystic ovary syndrome (PCOS) patients, 97 newly diagnosed type 2 diabetes mellitus (nT2DM) and 84 impaired glucose tolerance (IGT) subjects were enrolled. The EHC was performed to identify IR. Circulating ZAG and adiponectin levels were determined by ELISA. RESULTS: The ZAG index was significantly lower in participants with IR including IGT, nT2DM and PCOS than in those without IR. In addition, subjects with MetS had lower ZAG indices and higher the product of fasting triglycerides and glucose (TyG) indices than those without MetS. The ZAG index showed a significantly stronger association with M values than the other surrogate indices, whereas the TyG index showed a stronger association with MetS. The optimal cutoff value of the ZAG index for detection of IR was 2.97 with a sensitivity of 88% and a specificity of 91%, whereas the optimal cutoff value of TyG index for detection of MetS was 4.90 with a sensitivity of 82% and a specificity of 86%. CONCLUSION: The ZAG index is a better marker than the other surrogate indices for identifying IR, whereas the TyG index has high sensitivity and specificity for identifying MetS.

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

OBJECTIVE: 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. DESIGN AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Zinc-α2-Glycoprotein Modulates AKT-Dependent Insulin Signaling in Human Adipocytes by Activation of the PP2A Phosphatase.

OBJECTIVE: Evidence from mouse models suggests that zinc-α2-glycoprotein (ZAG) is a novel anti-obesity adipokine. In humans, however, data are controversial and its physiological role in adipose tissue (AT) remains unknown. Here we explored the molecular mechanisms by which ZAG regulates carbohydrate metabolism in human adipocytes. METHODS: ZAG action on glucose uptake and insulin action was analyzed. ß1 and ß2-adrenoreceptor (AR) antagonists and siRNA targeting PP2A phosphatase were used to examine the mechanisms by which ZAG modulates insulin sensitivity. Plasma levels of ZAG were measured in a lean patient cohort stratified for HOMA-IR. RESULTS: ZAG treatment increased basal glucose uptake, correlating with an increase in GLUT expression, but induced insulin resistance in adipocytes. Pretreatment of adipocytes with propranolol and a specific ß1-AR antagonist demonstrated that ZAG effects on basal glucose uptake and GLUT4 expression are mediated via ß1-AR, whereas inhibition of insulin action is dependent on ß2-AR activation. ZAG treatment correlated with an increase in PP2A activity. Silencing of the PP2A catalytic subunit abrogated the negative effect of ZAG on insulin-stimulated AKT phosphorylation and glucose uptake but not on GLUT4 expression and basal glucose uptake. ZAG circulating levels were unchanged in a lean patient cohort stratified for HOMA-IR. Neither glucose nor insulin was associated with plasma ZAG. CONCLUSIONS: ZAG inhibits insulin-induced glucose uptake in human adipocytes by impairing insulin signaling at the level of AKT in a ß2-AR- and PP2A-dependent manner.

Expression and clinicopathological significance of FSIP1 in breast cancer.

AIM: To investigate the clinicopathological significance of the expression of fibrous sheath interacting protein 1 (FSIP1) in breast cancer, serum samples, and wound fluid from patients with breast cancer. METHODS: Wound fluid and serum samples from female patients with primary breast cancer, recurrent and metastatic breast cancer, and benign tumors were analyzed for FSIP1 expression using ELISA. 286 paraffin-embedded surgical specimens from breast cancer patients with at least 5 years of follow-up were included for FSIP1 expression assay using immunohistochemistry. RESULTS: Expression of FSIP1 protein was significantly higher in breast cancer tissues compared to tumor-adjacent tissues (p = 0.001). Strong correlation was observed between FSIP1 expression and human epidermal growth factor receptor 2 (Her-2) or Ki67 expression in breast cancer (p = 0.027 and 0.002, respectively). Similarly, serum level of FSIP1 was higher in patients with recurrent and metastatic breast cancer compared to that of primary breast cancer (7, 713 ± 3, 065 vs. 4, 713 ± 3, 065 pg/ml, p = 0.003). Finally, patients with high FSIP1 expression showed a worse post-operative disease-specific survival (p = 0.024). CONCLUSION: FSIP1 may play an important role in the tumorigenesis and invasion of breast cancer and is a potential biomarker for breast cancer diagnosis or prognosis.