Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Increases Circulating Zinc-Α2-Glycoprotein Levels in Patients with Type 2 Diabetes

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.

Tofogliflozin decreases body fat mass and improves peripheral insulin resistance

“…Both basic and clinical studies have shown that insulin resistance is improved by the direct hypoglycaemic effect of SGLT2 inhibitors, as well as by alleviation of glucotoxicity and weight loss (reduction of BW and body fat) 1,[8][9][10][11] ; thus, it is clinically important to evaluate insulin resistance during SGLT2 inhibitor treatment.…”

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

“…37 It has also been found that inhibitors of sodium-glucose cotransporter 2 in both humans and rodents enhance ZAG expression that might contribute to the positive cardiac and vascular effects of the sodium-glucose cotransporter 2 inhibitor. 38,39 The functional effect of elevated serum ZAG levels in humans, and particularly in those with renal disease, remains unclear and controversial. Because we thought that ZAG could play a role in metabolism complications and CV events, we measured the serum concentrations of ZAG in a large cohort of patients on HD, sought its functional correlates, and tested its predictive power for all-cause mortality and CV events.…”

Lansoprazole enhances the antidiabetic effect of dapagliflozin in fortified diet‐fed streptozotocin‐treated diabetic rats

“…This result is in consistent with that reported in a previous study that showed that the decreased activation of PPAR-γ occurred in insulin-resistance T2D patients that could be counteracted by DAPA. [88] Yet, the current study is the first to address new machineries that may underline the insulin-sensitizing effect of LPZ by increasing the ADP/LEP ratio combined with PPAR-γ activation.…”