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.

Monocytes and macrophages in pregnancy: The good, the bad, and the ugly*

“…190,191 It has been suggested that upregulation of circulating cytokines and altered frequencies of circulating immune cells may contribute to the development of GDM. 192 When compared to a healthy pregnancy, GDM was associated with an increased frequency of circulating CD14 + cells, yet a lower frequency of CD14 + CD16 + cells and monocytes and expression of TLR4, 193,194 a potential compensatory mechanism to limiting inflammation. 21 Additionally, increased levels of circulating soluble CD14 + have been reported with GDM.…”

“…21 Additionally, increased levels of circulating soluble CD14 + have been reported with GDM. 193,194 It has been proposed…”

“…When compared to a healthy pregnancy, GDM was associated with an increased frequency of circulating CD14 + cells, yet a lower frequency of CD14 + CD16 + cells and monocytes and expression of TLR4, 193,194 a potential compensatory mechanism to limiting inflammation 21 . Additionally, increased levels of circulating soluble CD14 + have been reported with GDM 193,194 . It has been proposed that the increase in circulating monocytes is a result of higher levels of monocyte chemoattractant protein‐1 (MCP‐1) 195 .…”

Flavonoids on diabetic nephropathy: advances and therapeutic opportunities

“…Diabetes mellitus is a group of metabolic diseases characterized by hyperglycaemia that is divided into type I and type II. Recent studies have shown that long-term high glucose levels cause chronic damage to and dysfunction of several tissues, in particular the eyes, kidneys, heart, blood vessels, and nerves [ 7 , 8 ]. Diabetic nephropathy (DN) is the most common complication of diabetes and affects at least 30% of diabetic patients, representing great burden on public health [ 9 ].…”

The birth of cardiac disease: Mechanisms linking gestational diabetes mellitus and early onset of cardiovascular disease in offspring

“…Free mtDNA can trigger various inflammatory and apoptotic pathways once in the cytosol (Bronner & O'Riordan, 2016). Aberrant maternal immune cell adaption is related to GDM low-grade inflammation and poor fetal health outcomes (Kivelä et al, 2021;C. J. McElwain et al, 2021).…”