Abstract
Aims: To explore the molecular mechanism by which 17β-estradiol (estrogen 2, E2) regulates glucose transporter 2 (GLUT2) and insulin secretion in islet β cells through G protein-coupled estrogen receptor (GPER) via Akt/mTOR pathway.Methods: SPF-grade SD male rats were used to establish an in vivo type 2 diabetes model treated with E2. Rat insulinoma cells (INS-1) were cultured in normal or high glucose media with or without E2. Immunofluorescence double staining was used to detect GPER, GLUT2, insulin, and glucagon immunolocalization in rat islet tissues. Western blot was used to detect GPER, Akt, mTOR, and GLUT2 protein immunocontent. Real-time PCR detected Slc2a2 and glucose kinase (GK) content, and ELISA was used to detect insulin levels. Glucose uptake, GK activity and pyruvate dehydrogenase (PDH) activity were analyzed with glucose detection, GK activity and PDH activity assay kit.Results: Immunofluorescence double staining confocal indicated that E2 treatment up-regulated expression levels of GPER, GLUT2, and insulin, while down-regulated glucagon. Western blot results revealed E2 increased GPER, Akt/mTOR pathway, and GLUT2 protein immunocontent. Real-time PCR showed E2 elevated Slc2a2, GK content. Moreover, E2 improved insulin secretion, glucose uptake, GK activity, and PDH activity.Conclusion: Our findings indicated that exogenous E2 up-regulated GPER via the Akt/mTOR pathway to increase GLUT2 protein content and insulin secretion in islet β cells.
Highlights
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease with high morbidity and mortality that are of increasing concern [1]
Our results showed that the immunolocalization levels of G-coupled estrogen receptor (GPER) and glucose transporter 2 (GLUT2) in rat islet tissues were significantly more decreased in the TM group than those of the NC group
Our research showed that Slc2a2, glucose kinase (GK) content and GLUT2 protein in the TM group was down-regulated, indicating that GLUT2 glucose transport and metabolic functions were damaged in T2DM rats, which is demonstrated in the supplemental results
Summary
Type 2 diabetes mellitus (T2DM) is a chronic progressive disease with high morbidity and mortality that are of increasing concern [1]. The prevalence of T2DM significantly increases in postmenopausal women [2], which indicates that the prevalence may be related to a decrease of estrogen. Extensive attention has been given to one estrogen membrane receptor called G-coupled estrogen receptor (GPER). The recent research shows that E2 preserves functional β-cell mass and affects insulin secretion in islet β cells via GPER [6, 7]. There are studies which demonstrated E2 and GPER agonist improves insulin secretion on human and mice islets via GPER [8]. No studies have confirmed whether E2 makes an action in promoting insulin secretion through glucose transporter 2 (GLUT2)
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