The role of oestrogens in the adaptation of islets to insulin resistance

Abstract

Pregnancy is characterized by peripheral insulin resistance, which is developed in parallel with a plasma increase of maternal hormones; these include prolactin, placental lactogens, progesterone and oestradiol among others. Maternal insulin resistance is counteracted by the adaptation of the islets of Langerhans to the higher insulin demand. If this adjustment is not produced, gestational diabetes may be developed. The adaptation process of islets is characterized by an increase of insulin biosynthesis, an enhanced glucose-stimulated insulin secretion (GSIS) and an increase of beta-cell mass. It is not completely understood why, in some individuals, beta-cell mass and function fail to adapt to the metabolic demands of pregnancy, yet a disruption of the beta-cell response to maternal hormones may play a key part. The role of the maternal hormone 17beta-oestradiol (E2) in this adaptation process has been largely unknown. However, in recent years, it has been demonstrated that E2 acts directly on beta-cells to increase insulin biosynthesis and to enhance GSIS through different molecular mechanisms. E2 does not increase beta-cell proliferation but it is involved in beta-cell survival. Classical oestrogen receptors ERalpha and ERbeta, as well as the G protein-coupled oestrogen receptor (GPER) seem to be involved in these adaptation changes. In addition, as the main production of E2 in post-menopausal women comes from the adipose tissue, E2 may act as a messenger between adipocytes and islets in obesity.

Figure 1. Scheme of the changes in hormone levels during pregnancy in humans and rodents

A, in humans, there is an increase in serum placental lactogen (hPL), prolactin (PRL), progesterone (P) and 17β-oestradiol (E2) during pregnancy. Data are from Guyton & Hall (2001) and Freemark (2001). B, in rodents, during early pregnancy there is an increase in E2 and P levels as well as two early surges of PRL (not represented); PLs begin to increase at about day 10. During late pregnancy there is a strong increase in E2, as well as in PRL and PLs; however, P decreases. This scheme is based on data from Parsons et al. (1992); Cesen-Cummings et al. (2000); and Soares (2004).

Figure 2. End-points regulated by prolactin receptor (PRLr), progesterone receptor (PR) and oestrogen receptors (ERs) in rodent islets of Langerhans

PRLr is involved in the increment of β–cell mass, insulin biosynthesis, glucose-stimulated insulin secretion (GSIS) and decrease of apoptosis. PR has been demonstrated to participate in reducing β–cell mass. ERs are involved in incrementing insulin biosynthesis and GSIS, and decreasing apoptosis.