Abstract
Gestational diabetes mellitus (GDM) is characterized by glucose intolerance in pregnant women without a previous diagnosis of diabetes. While the etiology of GDM remains elusive, the close association of GDM with increased maternal adiposity and advanced gestational age implicates insulin resistance as a culpable factor for the pathogenesis of GDM. Pregnancy is accompanied by the physiological induction of insulin resistance in the mother secondary to maternal weight gain. This effect serves to spare blood glucose for the fetus. To overcome insulin resistance, maternal β-cells are conditioned to release more insulin into the blood. Such an adaptive response, termed β-cell compensation, is essential for maintaining normal maternal metabolism. β-cell compensation culminates in the expansion of β-cell mass and augmentation of β-cell function, accounting for increased insulin synthesis and secretion. As a result, a vast majority of mothers are protected from developing GDM during pregnancy. In at-risk pregnant women, β-cells fail to compensate for maternal insulin resistance, contributing to insulin insufficiency and GDM. However, gestational β-cell compensation ensues in early pregnancy, prior to the establishment of insulin resistance in late pregnancy. How β-cells compensate for pregnancy and what causes β-cell failure in GDM are subjects of investigation. In this mini-review, we will provide clinical and preclinical evidence that β-cell compensation is pivotal for overriding maternal insulin resistance to protect against GDM. We will highlight key molecules whose functions are critical for integrating gestational hormones to β-cell compensation for pregnancy. We will provide mechanistic insights into β-cell decompensation in the etiology of GDM.