Insulin Sensitivity with Dapagliflozin: Impact of ZAG

Dapagliflozin may increase insulin sensitivity by increasing blood levels of zinc-Α2-glycoprotein (ZAG), according to a study published online in Scientific Reports.¹

ZAG is an adipokine that may play an important role in metabolic regulation. Although ZAG’s biological actions have yet to be fully described, ZAG is thought to be involved in promoting lipolysis, as well as modulating insulin sensitivity. Originally thought to be expressed only from tumors, recent research suggests that ZAG may also be produced in white and brown adipose tissue, as well as in the liver, heart, and lungs, according to background information in the article.

“These data suggest that some aspect of dapagliflozin positively regulates ZAG and adiponectin expression and their release into the circulation. These results further support that whole-body insulin sensitivity is increased after SGLT2 inhibitor treatment and the increase in ZAG and adiponectin may contribute to insulin sensitization,” wrote lead author Gangyi Yang, PhD, of Zunyi Medical University (Guizhou, China), and colleagues.

Recent work by this group has found lower ZAG levels in individuals with T2DM. In these individuals, increasing ZAG levels were linked to increased levels of adiponectin (ADI), which is known to increase insulin sensitivity. In addition, increasing ZAG levels were linked to decreased BMI, waist to hip ratio, and homeostasis model assessment of insulin resistance (HOMA-IR), suggesting a role for ZAG in insulin sensitivity.²

The double blind, randomized placebo controlled study took place in two Chinese medical centers between February 2012 and December 2013. It included 162 participants aged 40 to 75 with newly diagnosed T2DM, who were randomized to placebo (n=45) or dapagliflozin 10 mg daily (n=117) for three months.

Key Results:

• Compared to baseline, three months of dapagliflozin treatment was associated with:

♦ Significant increases in ZAG (P<0.01) and ADI (P<0.01), which was unchanged with placebo

♦ Significant decreases in HbA1c (P<0.01), fasting blood glucose (P<0.01), two-hour post-prandial blood glucose (P<0.01), free fatty acids (P<0.01), triglycerides (P<0.01), blood pressure (P<0.01), BMI (P<0.05), waist to hip ratio (P<0.05), body weight (P<0.05), percent fat (P<0.05), fasting insulin (P<0.01), and HOMA-IR (P<0.01)

♦ Significant decrease in TNF-α (P<0.01), which was unchanged with placebo

In vitro studies showed increased ZAG expression and secretion in human liver cells treated with dapaglifozin. These experiments also showed significantly increased mRNA and protein expression of peroxisome proliferator-activated receptor-γ (PPARγ) (P<0.01), thought to be involved in regulating ZAG synthesis.

Adding a PPARγ inhibitor negated the effect of dapagliflozin, suggesting that ZAG may increase hepatic expression of ZAG by activating PPARγ, according to the authors.

Further in vitro studies showed that dapagliflozin was associated with decreased lipid droplet accumulation and total triglyceride content in human liver cells, which may suggest a role for dapagliflozin in inhibiting hepatic lipogenesis and promoting lipolysis.

The authors also highlighted the decrease in TNFα levels after treatment with dapagliflozin, which may point to a role for the drug in improving low-grade inflammation and insulin sensitivity in T2DM.

“These results support the notion that SGLT2 inhibitor treatment can improve insulin resistance through weight loss or other conceivable mechanisms, such as increasing insulin sensitizer levels and/or decreasing inflammatory cytokine levels,” they concluded “…The dapagliflozin-mediated increase in circulating ZAG could be caused by the increase in ZAG expression and secretion in insulin target tissues, whereas PPAR-γ may be a key regulator of the effect of dapagliflozin on ZAG.”

Take-home Points

• ZAG is an adipokine thought to be involved in promoting lipolysis, as well as modulating insulin sensitivity.

• Results from a Chinese study suggest that three months of dapagliflozin treatment may increase insulin sensitivity by increasing blood levels of ZAG.

• ZAG was also linked to significant decrease in TNF-α.

• In vitro studies in human liver cells treated with dapagliflozin showed increased ZAG expression and secretion, and this effect was negated by adding a PPARγ inhibitor; dapagliflozin was also associated with decreased lipid droplet accumulation and total triglyceride content in human liver cells.

• SGLT2 inhibitors may improve insulin resistance through weight loss, increasing levels of insulin sensitizers like ZAG, or decreasing inflammatory cytokines.

References:

1. Liao X, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitor increases circulating zinc-A2-glycoprotein levels in patients with type 2 diabetes. Sci Rep. 2016 Sep 9;6:32887

2. Yang M, et al. Zinc-α2-glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes. Diabetes Care. 2013 May; 36(5):1074-1082.