Beta-Cell IRS1 in Pregnancy and Gestational Diabetes - Abstract: Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosed diabetes. GDM is one of the most common obstetrical complications, imposing a long-lasting adverse impact on the health of both mothers and infants. In the US, about 1 of 10 pregnant women develop GDM. The prevalence of GDM is markedly higher among women with maternal obesity or advanced age at the time of gestation. The underlying etiology of GDM remains elusive. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain, especially in the 3rd trimester of pregnancy. To overcome insulin resistance, maternal islets are conditioned to release more insulin into the blood. Such an adaptive mechanism, termed “b-cell compensation”, is essential for maintaining normoglycemia during pregnancy. In at-risk pregnant women, b-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. How b-cells compensate for maternal insulin resistance in normal pregnancy and what causes b-cell dysfunction in GDM are poorly understood. Our objective is to understand the mechanism of b-cell compensation for pregnancy and gain mechanistic insights into the etiology of GDM. b-cells express IRS1 and IRS2, two major insulin receptor substrates that mediate insulin action on b- cell growth and differentiation. Genetic variants of IRS1, but not IRS2, are associated with a higher risk of GDM in pregnant women. To understand the mechanism of GDM associated with IRS1 deficiency, we generated b- cell-specific IRS1 knockout (bIRS1-KO) mice. We found that virgin bIRS1-KO mice maintained normoglycemia, but pregnant bIRS1-KO mice developed GDM, as reflected by impaired glucose tolerance and reduced glucose- stimulated insulin secretion at gestational day 15.5, the time that is equivalent to the 3rd trimester in humans. These data underscore the importance of IRS1 in governing b-cell adaptation to pregnancy, spurring the hypothesis that IRS1 is pivotal in mounting b-cell compensation for maternal insulin resistance. b-cell IRS1 deficiency would impair b-cell compensation for maternal insulin resistance, resulting in GDM. To address this hypothesis, we will characterize the role of IRS1 in regulating b-cell mass and function in female mice in virgin vs. pregnant states. We will determine the mechanism by which IRS1 integrates gestational hormonal signaling to adaptative changes in b-cell mass and function during pregnancy. We will decipher the mechanism by which b-cell IRS1 deficiency impedes maternal b-cell compensation, contributing to GDM. We will determine the impact of bIRS1-KO on pregnancy outcomes and risk of postpartum diabetes in mother mice. Moreover, we will determine the clinical significance of IRS1 in maternal b-cell compensation in primary human islets. Accomplishing this project will deepen our understanding of the mechanism underlying maternal b-cell compensation for pregnancy, providing new mechanistic insights into the etiology of GDM.
