Molecular Modelling of Islet β-Cell Adaptation to Inflammation in Pregnancy and Gestational Diabetes Mellitus

Abstract

Gestational diabetes mellitus (GDM), a metabolic disease that develops with the increase in insulin resistance during late pregnancy, is currently one of the most common complications affecting pregnancy. The polygenic nature of GDM, together with the interplay between different genetic variants with nutritional and environmental factors has hindered the full understanding of the etiology of this disease. However, an important genetic overlap has been found with type 2 diabetes mellitus (T2DM) and, as in the case of T2DM, most of the identified loci are associated with β-cell function. Early detection of GDM and adequate interventions to control the maternal glycemia are necessary to avoid the adverse outcomes for both the mother and the offspring. The in utero exposure to the diabetic milieu predispose these children for future diseases, among them T2DM, originating a vicious circle implicated in the increased prevalence of both GDM and T2DM. The involvement of inflammatory processes in the development of GDM highlights the importance of pancreatic β-cell factors able to favor the adaptation processes required during gestation, concomitantly with the protection of the islets from an inflammatory milieu. In this regard, two members of the Pax family of transcription factors, PAX4 and PAX8, together with the chromatin remodeler factor HMG20A, have gained great relevance due to their involvement in β-cell mass adaptation together with their anti-inflammatory properties. Mutations in these factors have been associated with GDM, highlighting these as novel candidates for genetic screening analysis in the identification of women at risk of developing GDM.

Thyroid hormones in diabetes, cancer, and aging

“…Genetic studies have revealed susceptibility genes for this syndrome, which include the human leukocyte antigen, cytotoxic T-lymphocyte-associated antigen 4, protein tyrosine phosphatase non-receptor type 22, forkhead box P3, and the interleukin-2 receptor alpha/CD25 gene region(Dittmar & Kahaly, 2010). These genes are involved in immunological synapse and T-cell activation, suggesting that similar pathogenic processes occur in T1DM and thyroid diseases of autoimmune origin(Dittmar & Kahaly, 2010).Gestational DM is a common complication that affects ~10% of all pregnancies associated with adverse pregnancy outcomes, such as preeclampsia, macrosomia, and caesarean delivery (International Association of Diabetes, 2010;Petra et al, 2019). Upon delivery,…”

Intermittent Fasting, Dietary Modifications, and Exercise for the Control of Gestational Diabetes and Maternal Mood Dysregulation: A Review and a Case Report

“…These process subsequently are associated with modulation of signal transduction conducive to oxidative damage, increased stress of the ER, and stimulation of mitochondria-related cell death signaling cascades [ 47 , 66 ]. In this respect, cumulative evidence shows that an inflammatory milieu during pregnancy endangers pancreatic islets through the promotion of mutations in pancreatic β-cell factors, paired domain homeobox ( Pax ) family of transcription factors ( PAX4 and PAX8 ), and the chromatin remodeler factor high mobility group protein 20A ( HMG20A ) [ 1 ]. Indeed, experimental evidence confirms the contribution of obesity to autophagic failure and heightened apoptosis in pancreatic islets [ 67 ].…”

“…Gestational diabetes mellitus (GDM) is an abnormal metabolic condition characterized by hyperglycemia during pregnancy [ 1 , 2 ]. GDM impacts around 5% of pregnant women in the United States [ 3 ], and reports from other countries indicate that it may affect more than 36% of pregnant women [ 4 , 5 ].…”

“…Maternal insulin resistance and increased body mass index (BMI) during pregnancy are associated with changes in placental levels of multiple major metabolites such as lipids, carbohydrates, acylcarnitines, branched-chain amino acids, folate, and choline which correlate, in part, to fetal size [ 20 , 21 ]. GDM, along with its related obesity, contributes to placental DNA methylation, which can negatively affect the developing fetus [ 1 , 2 , 20 ]. GDM increases the rates of miscarriage, dystocia, cesarean section, neonatal death, premature birth, congenital anomalies, macrosomia, respiratory distress, neonatal jaundice, hypoglycemia, hypocalcemia, and polycythemia [ 18 , 22 , 23 ].…”

“…GDM increases the rates of miscarriage, dystocia, cesarean section, neonatal death, premature birth, congenital anomalies, macrosomia, respiratory distress, neonatal jaundice, hypoglycemia, hypocalcemia, and polycythemia [ 18 , 22 , 23 ]. GDM-related fetal hyperglycemia and hyperinsulinemia are associated with aberrant DNA methylation at the insulin-like growth factor (IGF) 2 and neighboring H19DMRs , which increase the risk of developing childhood obesity, neoplasms, and diabetes, in addition to metabolic and cardiovascular diseases during adulthood in children of GDM mothers [ 1 , 5 , 23 , 24 ]. More GDM complications occur in women with high pre-pregnancy BMI, currently overweight/obese, and over the age of 35 years [ 19 , 22 ].…”