The glucocorticoid receptor (GR) is known as a receptor of steroids - potent anti-inflammatory ligands that are commonly used for the medication of allergy or asthma in children and adults. However, chronic use of steroids is associated with a significant risk of developing visceral adiposity and insulin resistance, a medical condition that is known as the Cushing syndrome. We hypothesized that excessive GR activation is deleterious to beta-cells such that genetic GR depletion would preserve beta-cell mass and function in response to metabolic stress. To address this hypothesis, we generated beta-cell specific GR knockout (KO) mice, using an inducible Pdx1-CreERT2-loxP system. We then fed beta-cell GR-KO and WT littermates both regular chow and high-fat diet for up to 30 weeks, followed by determination of beta-cell mass and function. We found that GR-deficient mice, as opposed to WT littermates, developed high blood glucose levels and glucose intolerance. This effect was not secondary to alterations in weight gain or insulin sensitivity. Instead, we detected a significant reduction in glucose-stimulated insulin secretion, correlating with abnormal glucose metabolism in GR-KO mice. We reproduced these findings in both male and female GR-KO mice. Anti-insulin immunohistochemistry revealed that GR-KO mice had significantly reduced beta-cell mass, and decreased beta-cell replication, as visualized by in vivo BrdU-labeling assay. GR deficiency appears to impair the ability of beta-cells to compensate for fat-elicited obesity and insulin resistance, resulting in prediabetes in GR-KO mice. These results unveiled an unexpected role of the glucocorticoid-GR signaling in safeguarding beta-cell mass and function in response to metabolic stress.
J. Yamauchi: None. S. Lee: None. H. Dong: None.