Introduction and Objective: Gestational β-cell compensation is an adaptive mechanism by which maternal islets increase insulin secretion to overcome pregnancy-induced insulin resistance. Defective β-cell compensation leads to gestational diabetes mellitus (GDM). We characterized the role of glucocorticoid receptor (GR) in gestational β-cell compensation. Methods: We generated β-cell GR-knockout (βGR-KO) mice, followed by determining the abilities of βGR-KO versus WT islets to compensate for maternal insulin resistance during pregnancy. Results: Virgin female βGR-KO mice maintained normoglycemia, but pregnant βGR-KO mice developed GDM, as evidenced by impaired glucose tolerance and reduced glucose-stimulated insulin secretion. These effects were attributable to significant reduction of β-cell mass and insulin content in maternal islets of βGR-KO versus WT dams at gestational day 15.5. βGR-KO dams had decreased β-cell versus α-cell ratios along with skewed α-cell dispersal in the center of islets, indicative of a distortion of maternal islet architecture in βGR-KO dams. Mechanistically, GR acts as a trans-repressor in regulating β-cell compensation for pregnancy. βGR-KO led to marked upregulation of key genes in β-cell dysfunction and oxidative stress including ALDOB and ATF3, correlating with the development of GDM in βGR-KO dams. GR protein was upregulated in primary human islets in response to prolactin, indicating that β-cell GR activity is subject to gestational hormone regulation. Plasma glucocorticoid levels surged in late pregnancy, correlating with the physiological induction of gestational β-cell compensation. Conclusion: Glucocorticoid activation of GR signaling is pivotal for maternal islets to undergo β-cell compensation for pregnancy in protecting against GDM. Disclosure H. Yeh: None. T. Usman: None. H. Dong: None. Funding UPMC Children‘s Hospital Foundation Cochrane-Weber Grant (CHP0016945)
Yeh et al. (Sun,) studied this question.