Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, with a steadily increasing prevalence, in parallel to the global rise in type 2 diabetes mellitus (T2DM) and obesity. Approximately 15% of pregnancies worldwide are complicated by GDM [1].

Pregnancy undergoes various anatomical, biochemical, physiological, and hormonal changes to meet the increased metabolic demands for fetal development. During early gestation, insulin sensitivity increases in order to control glucose metabolism and promote the uptake of glucose into adipose stores in preparation for the energy demands of mid- and late pregnancy. In adapting to ensure an adequate supply of carbohydrates (CHO) for the fetus and consequently maintaining the necessary glucose levels to meet its energy demands, a state of peripheral insulin resistance (IR) is gradually established [2]. As a result, blood glucose is slightly elevated across the placenta to fuel the growth of the fetus [3]. Thus, as the pregnancy progresses, a surge of hormones, including estrogen, progesterone, leptin, cortisol, placental lactogen, and placental growth hormones together promote a state of IR [3]. As part of the normal response, maternal tissues such as muscle and fat become relatively insulin-resistant. These maternal tissues increase the use of other fuel sources, such as fatty acids and ketone bodies [4]. Increased estrogen, progesterone, and insulin favor lipid deposition and the accumulation of maternal fat stores in early and mid-pregnancy and enhance fat mobilization in late pregnancy [5]. Protein catabolism is decreased as fat stores are used to provide energy for metabolism [6,7,8]. Hyperinsulinemia ensues as a compensatory response to the increased insulin production by β-cells as a means of compensating for the IR [1]. In addition to the hormonal imbalance, gestational IR is further exacerbated by genetic and epigenetic variables [9], increased visceral fat, altered gut microbiota [10], and obesity (Figure 1).

Also, a number of signaling pathways may play a role in the pathophysiology of GDM; NF-κB contributes to the development of GDM by promoting adipocyte inflammation and impairing insulin-related functions, such as glucose uptake, peroxisome proliferator-activated receptors (PPARs), sirtuins (SIRTs), 5′ AMP-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK3), PI3K/mTOR, inflammasomes, and the endoplasmic reticulum (ER) [11]. These key pathways often interact with and alongside each other, as T2DM studies have shown. Unfortunately, there is no clear evidence to indicate that these pathways act and contribute to GDM development [12].

A growing body of research highlights that hyperglycemia during pregnancy influences epigenetic processes, inducing changes through histone modification, DNA methylation, and the disrupted function of non-coding ribonucleic acid (ncRNA), including microRNAs (miRNAs) [15,16]. Mainly epigenetic changes lead to the dysregulation of gene transcription, modifying the phenotype of the developing child [17,18]. Short-term effects on offspring include respiratory distress syndrome, hypoglycemia, hyperbilirubinemia, hypocalcemia, hypomagnesemia, polycythemia, and adverse fetal programming, contributing to long-term risks including childhood obesity, T2DM, hypertension, and CVD in adolescence and adulthood [19,20,21]. Children of mothers with GDM or pregnant women with preexisting diabetes of any type (T1DM, T2DM, MODY, LADA, etc.) have an eight-times-higher risk of developing prediabetes or diabetes, compared to children of non-diabetic mothers [20].