Adaptation of Islets of Langerhans to Pregnancy: β-Cell Growth, Enhanced Insulin Secretion and the Role of Lactogenic Hormones

Abstract

Pregnancy is a unique event in the life span of islet beta-cells. Under the influence of pregnancy islet beta-cells undergo major long term up-regulatory structural and functional changes in response to the increased demand for insulin. Adaptive changes that occur in islets during normal pregnancy include: 1) increased glucose-stimulated insulin secretion with a lowered threshold for glucose-stimulated insulin secretion, 2) increased insulin synthesis, 3) increased beta-cell proliferation and islet volume, 4) increased gap-junctional coupling among beta-cells, 5) increased glucose metabolism, and 6) increased c-AMP metabolism. Of the islet changes that occur during pregnancy the increase in beta-cell division and enhanced glucose sensitivity of insulin secretion are most notable. The increase in beta-cell division leads to an increase in islet mass that contributes to the ability of islets to respond to the increased need for insulin. However, the increased glucose sensitivity of beta-cells is likely to be more important. The lowering of the threshold for glucose stimulated insulin secretion is the primary mechanism by which beta-cells can release significantly more insulin under normal blood glucose concentrations. Although the hormonal changes which occur during pregnancy are complex, it appears that lactogenic influences (either placental lactogen and/or prolactin) are sufficient to induce all of the up-regulatory changes that occur in islets during pregnancy. We have demonstrated that rat placental lactogens I and II are the hormones responsible for up-regulating islets during rodent pregnancy. Although most studies have been done using rodent islets, available evidence strongly suggests that human placental lactogen and/or human prolactin are the responsible lactogens for up-regulating islets during human pregnancy. A model for how lactogens up-regulate islets during pregnancy is proposed.

A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus

“…A recent report demonstrated that TCF7L2 is expressed in pancreatic beta cells [13]. Thus, by affecting the WNT signalling, the variant could influence the beta cell proliferation (and hence insulin secretion) that normally takes place during pregnancy [33,35]. The effect size for gestational diabetes mellitus conferred by this variant is similar to that reported in patients with type 2 diabetes [12].…”

“…During pregnancy beta cells undergo structural and functional changes in response to the increased insulin requirements. These changes include, among others, enhanced glucose-stimulated insulin secretion, increased insulin synthesis and increased beta cell proliferation and islet volume [33]. Genetic factors might therefore predispose to abnormal glucose tolerance during pregnancy by influencing one or more of these physiological processes.…”

Adenoviral overexpression of interleukin-1 receptor antagonist protein increases β-cell replication in rat pancreatic islets

“…1 b-Cell mass depends on the changes in b-cell formation, b-cell volume and b-cell death. The specific contribution of replication to b-cell mass adaptation has been shown in different physiological and experimental conditions, among them normal lifespan, 2 pregnancy, 3 glucose infusion, 4 partial pancreatectomy 5,6 and islet transplantation. 7 Type I diabetes is an autoimmune disease characterized by the destruction of b-cells, and it is believed that proinflammatory cytokines released by activated T cells and macrophages infiltrating the pancreas are important mediators of b-cell damage.…”

Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate

“…Among these, PDX-1 plays a critical role in the development of the pancreas, since mutations in this gene result in pancreatic agenesis in both mice and humans [4,5]. Moreover, studies on the dynamics of the adult pancreas have shown that adult beta cells adjust their mass to distinct metabolic states that occur during the life span, such as pregnancy [6] or obesity [7,8]. The mechanisms involved in this dynamic state shape a delicate balance Diabetes is a major public health problem.…”