NEK7-mediated activation of NLRP1 and NLRP3 inflammasomes in the progression of Gestational Diabetes Mellitus

Abstract

Gestational Diabetes Mellitus (GDM) is characterized by impaired glucose metabolism and insulin resistance affecting up to 14.7 % of pregnancies. GDM is associated with adverse perinatal outcomes and long-term health risks for the offspring, including obesity and type 2 diabetes (T2DM). Maternal inflammation plays a key role in driving these complications, aggravating metabolic disturbances, and contributing to adverse developmental programming. In recent years, inflammasomes have emerged as the key regulators of inflammation. This study hypothesizes that NEK7 activates the inflammasomes in GDM pathogenesis. PCR analysis revealed that NEK7 expression, along with NLRP1 and NLRP3, was significantly overexpressed in pregnant women with GDM (n = 20) when compared to healthy pregnant women (n = 20). Further, a positive correlation was observed between NEK7 and the expression of NLRP1 and NLRP3, suggesting a potential mechanistic link in the regulation of inflammation in GDM. Additionally, the expression levels of NLRP1 and NLRP3 were found to strongly correlate with BMI, fasting glucose, postprandial glucose, HOMA-IR, and HbA1c levels in GDM patients. Furthermore, inflammatory cytokines, including IL-1β, IL-18, IL-6, and TNF-α, were significantly upregulated in GDM patients and positively correlated with the expression, suggesting the regulation of inflammation through inflammasomes. To validate the hypothesis, BeWo cells were cultured in a hyperglycemic environment. The results demonstrated that NEK7, along with inflammasomes and inflammatory cytokines, were significantly overexpressed in BeWo cells exposed to high glucose. Collectively, this study suggests that NEK7 upregulation may trigger inflammasome activation, contributing to the pathogenesis of GDM. These findings highlight the need for further research to develop the therapeutic approaches that target NEK7 to mitigate inflammation in GDM.

Keywords: GDM; Inflammation; NEK7; NLRP1; NLRP3; Pro-inflammatory cytokines.