Autophagic Flux in Gestational Diabetes Mellitus

Autophagy is a process essential for energy and cellular homeostasis through protein catabolism. Autophagic degradation activity is a dynamic process and best described by the term “autophagic flux”. Defects in autophagy lead to the etiology of many diseases, including gestational diabetes mellitus (GDM), cancer, neurodegeneration and stress-related disorders [1] [2] [3]. In the last decade, autophagy has attracted increasing attention as a target for the development of novel therapeutics particularly in the field of metabolic diseases. The most potent nongenetic inducers of autophagy are caloric restriction and therapeutic fasting, which are often associated with improvement in mood, cognition, as well as metabolic state[1] [2] [3]. GDM is a growing health issue associated with significant maternal and fetal morbidity and mortality[4]. While autophagy is pivotal in pancreatic beta cell dysfunction and insulin resistance in type 2 diabetes mellitus[5], its role in GDM is largely unknown. Here, we used maternal peripheral blood mononuclear cells (PBMCs)[6]and placental tissue to determine the autophagic flux in GDM pregnancies (GDM, n=3; control, n=5). In placentas of GDM patients, our pilot data revealed increased protein levels of p62 and decreased levels of LC3B lipidation, two hallmarks in autophagy signaling. Likewise, we found increased protein levels of p62 in maternal PBMCs. A cohort of maternal PBMCs was treated with chloroquine (CQ). CQ raises the lysosomal pH, which inhibits the fusion between autophagosomes and lysosomes, thus blocking a late step of autophagy¹. While CQ caused a strong increase of LC3B lipidation in controls, there was no change in GDM patients. Taken together, these results provide first evidence of strongly impaired autophagic flux through hyperglycaemia during pregnancy and suggest a novel target for GDM prevention.

Publication History

Article published online:
26 November 2021

• References

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