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

Abstract

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.

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

“…Therefore, we speculated that sitagliptin can increase the release of adipocytokines related to increase insulin sensitivity, indirectly confirming that DPP-IV inhibitor improves insulin resistance. Furthermore, these results are also similar to our previous report that liraglutide, a glucagon-like peptide 1 (GLP 1) analogue, treatment for 16 weeks in nT2DM patients leads to a significant increase in circulating ZAG levels (10). Therefore, it might be speculated that increased ZAG levels can be due to a prolonged activation of the GLP-1 receptor or due to inhibition of DPP-IV and thereby higher availability of endogenous GLP-1.…”

“…Very recently, we have demonstrated that circulating ZAG levels are lower in the patients with impaired glucose tolerance (IGT) and patients with newly diagnosed type 2 diabetes mellitus (nT2DM) than in control subjects. Circulating ZAG levels are also positively correlated with ADI, but inversely with BMI, waist-to-hip ratio (WHR), TG, fasting plasma glucose (FPG), fasting insulin (FIns), HbA1c, and homeostasis model assessment of insulin resistance (HOMA-IR) (10). Since the biological actions of ZAG have not been fully understood, it is important to characterize the effect of anti-diabetic treatment, especially new anti-diabetic agents, on the plasma levels of ZAG in nT2DM patients.…”

“…In our previous study, we demonstrated that circulating ZAG was lower in patients with IGT and nT2DM, and it correlated positively with ADI, and correlated inversely with BMI, WHR, FAT (%), and HOMA-IR. Therefore, we consider ZAG may be an adipokine associated with insulin sensitivity (10).…”

“…The limit of detection was 21 pg/ml, and intra-and inter-assay coefficient of variations (CV) were !10 and !15%, respectively. Circulating ADI level was also measured by ELISA (Cusabio Co., Wuhan Hubei, China) as previously described (10). Detection range was 1.562-100 ng/ml, and intra-and inter-assay variations were !8 and 10%, respectively.…”

The detection and measurement of interleukin-6 in venous and capillary blood samples, and in sweat collected at rest and during exercise

“…However, in agreement with Raiszadeh et al, the present data do not support the notion that IL-6 is present in sweat in detectable levels and we suggest that measurement of IL-6 in sweat is not a valid or reliable measurement of systemic IL-6. Moreover, of 180 proteins identified in sweat, only albumin, zinc α2 glycoprotein, gelsolin, apolipoprotein D and clusterin 1 were present in both sweat and plasma (Raiszadeh et al 2012), indicating that future work aimed at using sweat as a potential vehicle for biomarkers or disease should focus on these proteins, as they have already been linked to a number of diseases and pathological conditions (Ceperuelo-Mallafré et al 2009;Dubois et al 2010;Hassan et al 2008;Mracek et al 2011;Rydén et al 2012;Yang et al 2013). …”