Abstract
ZAG has recently been characterized as a potent metabolic regulator, but the effect of anti-diabetic agents on ZAG in humans remains unknown. Our aim was to study the effects of SGLT2 inhibitor on circulating ZAG and ADI in nT2DM. 162 subjects with nT2DM were treated by a placebo or DAPA. After 3-months of DAPA therapy, HbA1c, FBG, 2h-PBG, FFA, TG, blood pressure, BMI, WHR, body weight, FAT%, FINS, and HOMA-IR in T2DM patients decreased significantly, whereas HDL-C was significantly increased. Importantly, circulating ZAG and ADI levels in these patients were also significantly increased after DAPA therapy. Basal ZAG levels were associated with changes in BMI, FAT%, TC, HbA1c, HDL-C and ADI at post-treatment, whereas basal ADI levels were associated with changes in FAT%, TC, HbA1c, FFA and HDL-c. In vitro, DAPA treatment showed increased ZAG expression and secretion in HepG2 cells. When combined with a PPAR-γinhibitor GW9662, the effect of DAPA on ZAG was abrogated. These findings suggest that circulating ZAG can be regulated by DAPA, and DAPA promotes the expression and secretion of ZAG in the liver via the activation of PPAR-γ. The changes in ZAG induced by DAPA may play a physiologic role in enhancing insulin sensitivity.
Highlights
Zinc-alpha-2-glycoprotein (ZAG) is a 41-kDa glycoprotein assigned to the Major Histocompatibility complex (MHC) class I family of proteins[1] and is a soluble protein first identified in human blood which represents 0.2% of total serum protein[2]
After three months of treatment with DAPA, HbA1c, fasting blood glucose (FBG), 2hPBG, free fatty acid (FFA), TG, blood pressure, body mass index (BMI), waist-to-hip ratio (WHR), body weight, FAT%, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-insulin resistance (IR)) significantly declined in T2DM patients (P < 0.05 or P < 0.01), whereas high-density lipoprotein cholesterol (HDL-C) significantly increased (P < 0.05)
DAPA treatment led to a significant decrease in circulating tumor necrosis factor-α(TNF-α) levels when compared with pretreatment (9.15 ± 0.33 vs. 13.5 ± 0.55 μg/L, P < 0.01, Fig. 1C), whereas TNF-αlevels were unchanged by placebo treatment (11.7 ± 0.32 vs. 12.0 ± 0.63 μg/L, Fig. 1C)
Summary
Zinc-alpha-2-glycoprotein (ZAG) is a 41-kDa glycoprotein assigned to the Major Histocompatibility complex (MHC) class I family of proteins[1] and is a soluble protein first identified in human blood which represents 0.2% of total serum protein[2]. The biological functions of ZAG are not completely known, but it has been shown that ZAG is a novel adipokine and that its expression is down-regulated in the adipose tissue of obese subjects[3]. Balaz et al reported that silencing ZAG resulted in reduced adiponectin (ADI), insulin receptor substrate-1(IRS-1) and glucosetransporters-4 (GLUT4) gene expression in primary human adipocytes indicating that ZAG plays an important role in modulating whole-body and adipose tissue insulin sensitivity[5]. Works from our group have shown that circulating ZAG levels are lower in patients with nT2DM and correlated positively with ADI and inversely with body mass index (BMI), waist-to-hip ratio (WHR), and homeostasis model assessment of insulin resistance (HOMA-IR), further suggesting that ZAG may be an adipokine associated with insulin resistance (IR)[6]. The aim of this study is to evaluate the effects of Dapaglifozin (DAPA), a SGLT2 inhibitor, on ZAG in vivo and vitro
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