Gestational Diabetes Mellitus and Maternal Immune Dysregulation: What We Know So Far

Abstract

Gestational diabetes mellitus (GDM) is an obstetric complication that affects approximately 5-10% of all pregnancies worldwide. GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy, and is characterized by exaggerated insulin resistance, a condition which is already pronounced in healthy pregnancies. Maternal hyperglycaemia ensues, instigating a 'glucose stress' response and concurrent systemic inflammation. Previous findings have proposed that both placental and visceral adipose tissue play a part in instigating and mediating this low-grade inflammatory response which involves altered infiltration, differentiation and activation of maternal innate and adaptive immune cells. The resulting maternal immune dysregulation is responsible for exacerbation of the condition and a further reduction in maternal insulin sensitivity. GDM pathology results in maternal and foetal adverse outcomes such as increased susceptibility to diabetes mellitus development and foetal neurological conditions. A clearer understanding of how these pathways originate and evolve will improve therapeutic targeting. In this review, we will explore the existing findings describing maternal immunological adaption in GDM in an attempt to highlight our current understanding of GDM-mediated immune dysregulation and identify areas where further research is required.

Keywords: gestational diabetes mellitus; immunology; inflammation; insulin resistance; mitochondrial dysfunction; pharmacology; therapeutics.

Figure 1

An overview characterising immune cell phenotypes in maternal circulation, adipose tissue and placental tissue in healthy uncomplicated pregnancy compared to pregnancy complicated by GDM. Created with Biorender.com. ↑, increased; ↓, decreased; GDM, gestational diabetes mellitus; NK, natural killer; Th2, T-helper 2 cell; Th1, T-helper 1 cell; Th17, T-helper 17 cell; Treg, regulatory T cell; dNK, decidual NK cell.

Figure 2

Immune-mediated effects of both clinically approved and potential therapeutic options for GDM. Created with Biorender.com. ↑, increased; ↓, decreased; TLR, Toll-like receptor; CRP, c-reactive protein; IL, interleukin; TNF, tumour necrosis factor; ROS, reactive oxygen species; DC, dendritic cell; Th1, T-helper 1 cell; Th2, T-helper 2 cell; Treg, regulatory T cell; NET, neutrophil extracellular trap; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3.