Insulin Resistance and SIK1 Hyperactivation: Implications for Vascular Remodeling in Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) is a multifactorial condition, with nearly half of cases remaining unexplained, and maternal insulin resistance is identified as a significant contributor. This study examined the role of SIK1 in RPL patients associated with insulin resistance using villi samples, in vitro trophoblast models, and an insulin resistant mouse model. Our results revealed that a marked increase in miscarriage risk was observed in women with higher value of homeostatic model assessment for insulin resistance (>2.41). SIK1 expression was elevated in the villous tissues of RPL patients with insulin resistance, as well as insulin-treated trophoblast models. Overexpression of SIK1 impaired trophoblast migration and invasion by downregulating MMP2 and MMP9, and disrupted decidual natural killer cell-mediated vascular remodeling. Co-cultured decidual natural killer cells exhibited altered cytokine expression, leading to endothelial dysfunction. In vivo, insulin resistant mice showed elevated placental SIK1 expression, reduced pregnancy success, and defective spiral artery remodeling. These findings suggest that SIK1 activation driven by insulin resistance impairs trophoblast and decidual natural killer cell functions, thereby contributing to recurrent pregnancy loss.