Maternal β-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes

Abstract

Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic β-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired β-cell adaptation. Understanding these pathways, as well as mechanisms of β-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM.

Keywords: gestational diabetes mellitus; insulin; placenta; pregnancy; β-cell.

Figure 1

Adaptations in peripheral tissue in late gestation occur to spare glucose for fetal growth; if insulin resistance is too severe (such as in pregnancies complicated by pre-existing obesity), gestational diabetes can occur.

Figure 2

Signalling by pregnancy hormones prolactin (PrL) and placental lactogen (PL) through the prolactin receptor (PrlR) through the Jak/Stat pathway improves glucose stimulated insulin secretion (GSIS), prevents apoptosis and promotes proliferation and expansion. Hepatocyte growth factor (HGF) signals through AKT and mTOR via cMet to improve β-cell adaptations. Epidermal growth factor (EGF) through epidermal growth factor receptor (EGF-R) and ras/extracellular signal-related kinases (ERK) signalling can mediate proliferation and expansion; the ras/ERK pathway can also be mediated lactogens. Transcription factors (such as Hnf4a, FoxD3, FoxM1) can modulate expression of genes that mediate these adaptations.

Figure 3

Peripheral insulin resistance and resulting hyperlipidemia and hyperglycemia can overwhelm the capacity of the β-cell, leading to lipotoxicity and glucotoxicity. Lipotoxicity and glucotoxicity can trigger oxidative stress, generation of reactive oxygen species (ROS) and lead to endoplasmic reticulum (ER) stress and apoptosis; these detrimental pathways impair β-cell adaptation in pregnancy and can lead to gestational diabetes mellitus (GDM).