The dynamic interplay between insulin resistance and autophagy: Exploring the coordinated regulation of multiple...

This narrative review summarizes recent advances in understanding the interrelationship among insulin resistance (IR), autophagy, and miscarriage. As a critical regulator of metabolic homeostasis, IR not only contributes to the development of various metabolic disorders but is also associated with an increased risk of miscarriage. IR elevates miscarriage risk through multiple mechanisms, including altering the intrauterine environment, modulating androgen levels, impairing mitochondrial function, enhancing oxidative stress, and activating inflammatory pathways via increased reactive oxygen species (ROS). Triggered by stressors like oxidative stress, autophagy regulates placental development and function through its effects on trophoblasts, macrophages, and decidualization, consequently, dysregulated autophagy can contribute to miscarriage. Furthermore, IR inhibits autophagic activity via activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway (through the PI3K-AKT axis), which suppresses ULK1. Chronic IR leads to oxidative stress (increased ROS) and mitochondrial dysfunction, which in turn promotes autophagy by inhibiting mTORC1 through the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. Moderate autophagy improves insulin sensitivity by removing damaged mitochondria and alleviating endoplasmic reticulum stress. However, excessive autophagy, such as in pancreatic β-cells, can degrade insulin granules and reduce insulin secretion, thereby exacerbating IR. This review explores the interactions among IR, autophagy and miscarriage, aiming to provide new insights for the prevention and treatment of miscarriage.