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.

Keywords: HMG20A; PAX4; PAX8; fetal growth alteration; gestational diabetes; gestational hypertension; inflammation; pregnancy.

Figure 1

Gestational diabetes mellitus (GDM) derived effects in offspring as precursors of increased type 2 diabetes mellitus (T2DM) and GDM prevalence. The older age of pregnancy and the increase in maternal BMI are important risk factors for GDM development, which results in increased incidence of diseases for the mother later on in life, as well as for the offspring, who are primed for obesity and T2DM, that in turn will increase next-generation prevalence of GDM and thus T2DM. (The figure was generated using Servier Medical Art templates: Available online: http://www.servier.com).

Figure 2

PAX4, HMG20Aand PAX8 regulated pathways that may be implicated in the protection against GDM. A transient increase in PAX4 expression during pregnancy, correlating with the increase in β-cell proliferation, confers higher protection to β-cells against ER stress and inflammation, ensuring the maintenance of an adequate functional β-cell mass able to counteract the increase in insulin resistance that takes place during pregnancy. HMG20A, one of the regulators of PAX4 in islets is also modulated during pregnancy, correlating with functional maturation of β-cells. Interestingly, HMG20A has important roles in the Central Nervous system (CNS), likely regulating the interaction between astrocytes and neurons during central regulation of glucose homeostasis. During pregnancy PAX8 expression in islets increases their protection from cytokines and is likely involved in the modulation of the inflammatory response. Additionally, PAX8 is a key factor for thyroid gland maintenance and secretion of thyroid hormones (THs), which increase β-cell proliferation and enhance insulin secretion. The important role of these three factors PAX4, HMG20A and PAX8 during pregnancy is supported by the association of SNPs/mutations in these factors with the development of GDM.

Figure 3

Proposed molecular model for the interaction between PAX4, HMG20A and PAX8 in pancreatic β-cells during islet adaptation in response to pregnancy and inflammation. The initial increase in PAX4 during pregnancy that allows the expansion of the β-cell mass is followed by a subsequent increase in the expression of the chromatin remodeler factor HMG20A, which downregulates Pax4 expression. The decrease in PAX4 levels is necessary for the acquisition of a fully mature phenotype of these newly formed β-cells, which can then boost insulin expression/secretion to compensate for the increase in insulin demand that takes place during pregnancy. Additionally, PAX8, which is only expressed in islet during gestation, can blunt PAX4 activity through protein-protein interactions, further enhancing the inhibitory action of HMG20A on PAX4, allowing a faster maturation of the young β-cells. The combined anti-inflammatory actions of PAX4 and PAX8 will ensure a local permissive environment for the maintenance of a functional β-cell mass.