Estradiol Prevents High Glucose-Induced β-cell Apoptosis by Decreased BTG2 Expression

Abstract

Hyperglycemia stimulates several pathways to induce pancreatic β-cell apoptosis. In our previous study by mRNA analysis, we demonstrated that B-cell translocation gene 2 (BTG2) expression was up-regulated in INS-1 cells cultured under high glucose conditions, but this effect was reversed by estrogen. In the present study, we demonstrated that BTG2 mRNA and protein expressions in both INS-1 cells and mouse pancreatic islets increased under high glucose conditions compared to those cultured under basal glucose conditions, while in the presence of estrogen, the BTG2 mRNA and protein expressions decreased. SiRNA-BTG2 significantly reduced cell apoptosis, cleaved-caspase 3, and Bax, compared to the siRNA-control in INS-1 cultured under high glucose conditions. We further demonstrated that BTG2 promoter activity was activated under high glucose conditions whereas estrogen significantly reduced it. The effects of estrogen on BTG2 expression were inhibited by estrogen receptor inhibitors. Also, under high glucose conditions, p53 and Bax mRNA and protein expressions increased, but they decreased in the presence of estrogen. Again, the effect of estrogen on p53 and Bax expression was inhibited by estrogen receptor inhibitors. Taken together, this study demonstrates that estrogen reduces pancreatic β-cell apoptosis under high glucose conditions via suppression of BTG2, p53, and Bax expressions.

G protein-coupled estrogen receptor activation by Bisphenol-A disrupts protection from apoptosis conferred by estrogen receptors ERα and ERβ in pancreatic beta cells

“…It has been shown that E2 protects beta cells from several pro-apoptotic stimuli, such oxidative stress (le May et al, 2006), proinflammatory cytokines (Contreras et al, 2002) and high glucose (Kooptiwut et al, 2018). These studies suggest that ERα is crucial for pancreatic islet survival.…”

Cross-sectional and prospective relationships of endogenous progestogens and estrogens with glucose metabolism in men and women: a KORA F4/FF4 Study

“… 35 E2 can prevent acute oxidative injury in β-cells in a hyperglycemic state by suppressing the β-cell translocation gene 2 (BTG 2 )-p53-Bax pathway. 36 ERα localization in pancreatic β cells shows that E2 can confer protective effects against oxidative stress directly on β cells 37 and additionally in hepatocytes 38 to prevent insulin-deficient diabetes. A meta-analysis showed women undergoing HRT had alterations in metabolic syndrome components, 39 thereby supporting that perturbations in sex hormone levels can impair glucose homeostasis.…”

Plasma exosome-derived B-cell translation gene 1: a predictive marker for the prognosis in patients with non-small cell lung cancer

“…BTG-1 is a member of the BTG/Tob antiproliferation gene family 27 , 28 and has been shown to block the rate of cell proliferation 29 , 30 by modulating the cell cycle distribution. For example, when cells are in the G 0 /G 1 phase, BTG-1 expression is high, which can promote neovascularization and cell differentiation 31 . The occurrence and development of tumors are related to unrestricted cell proliferation and reduced apoptosis rates 32 .…”