199-OR: Beta-Cell IRS1 Deficiency Predisposes Female Mice to Developing Gestational Diabetes

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without previously diagnosed diabetes. To understand the mechanism of GDM, we characterized the role of IRS1 in β-cell compensation for pregnancy. We generated β-cell conditional IRS1-knockout (βIRS1-KO) mice. While virgin βIRS1-KO mice maintained normal metabolism, pregnant βIRS1-KO mice developed GDM, culminating in the onset of fasting hyperglycemia and glucose intolerance at gestational day 15.5. These effects were attributable to the reduction of glucose-stimulated insulin secretion in pregnant βIRS1-KO mice. Anti-insulin immunohistochemistry revealed that pregnant βIRS1-KO vs. WT mice had significantly diminished islet size and reduced β-cell mass. Anti-Ki67 immunostaining showed that βIRS1-KO vs. WT mice had minimal β-cell replication during pregnancy. Islet RNA transcriptome analysis demonstrated that IRS1-deficient islets were associated with a significant downregulation of GATA4 and its targets Reg1 and Reg3a, key factors critical for β-cell replication. In pregnant WT mice, β-cell IRS1 along with GATA4, Reg1 and Reg3a was upregulated in islets, coinciding with the physiological induction of β-cell mass expansion during pregnancy. These effects were totally abolished in IRS1-deficient islets, correlating with impaired β-cell compensation in pregnant βIRS1-KO mice. Mechanistically, IRS1 underwent prolactin-stimulated phosphorylation at Tyr632. This effect correlated with the induction of GATA4, Reg1 and Reg3a expression in islets of pregnant WT mice. We recapitulated these findings in INS1 cells in response to prolactin. Our studies uncovered a new IRS1-GATA4-Reg1/Reg3a signaling cascade in integrating gestational hormones to β-cell compensation, an adaptive mechanism that acts to overcome maternal insulin resistance and protect against GDM. Disclosure X. Wang: None. T. Usman: None. G. Chhetri: None. W. Zheng: None. H. Yeh: None. M.F. White: Board Member; Housey Pharmaceutical Research Laboratories. H. Dong: None.