Beta cell adaptation in pregnancy: a major difference between humans and rodents?

Abstract

Increasing evidence demonstrates that the insulin-producing beta cells can dynamically adapt their size, number and function in response to a variety of experimental and pathological conditions. Whether this dynamic adaptation also takes place under physiological conditions is less clear, with the notable exception of pregnancy [1, 2]. Under this condition, it has long been known that rodents undergo a rapid and substantial expansion of beta cell mass [3–5] due to increased beta cell size (hypertrophy) and replication (hyperplasia) [4], without detectable evidence of islet neogenesis [5]. These changes are induced by prolactin, placental lactogen and growth hormone, whose receptors are upregulated in beta cells after two-thirds of the gestational duration [1, 6]. They are also rapidly reversed at about the time of delivery, due to progesterone-controlled activation of beta cell apoptosis [7]. Recent studies have implicated selected genes controlling beta cell replication, survival and apoptosis in these changes [8–10]. In rodents, the changes in beta cell mass (about threeto fivefold) cannot alone account for those in insulin output (about eightfold), implicating a further functional improvement [1]. Thus, serum insulin increases by ∼75% due to increased glucose-stimulated insulin secretion, and this happens despite a 25% reduction in plasma glucose [5, 11, 12]. The increase in glucose-stimulated insulin secretion is mostly due to a significant decrease in the threshold for glucose stimulation [1, 12, 13], possibly as a result of higher levels of GLUT2, glucokinase and beta cell to beta cell coupling [13, 14]. It has also long been known that the progressive development of insulin resistance during human pregnancy increases the metabolic demand on beta cells, as evidenced by increased insulin secretion [11]. Due to the difficulty of obtaining pancreas from pregnant women, the adaptive mechanism underlying this change remains poorly investigated. However, islet enlargement, attributed to increased beta cell proliferation and decreased beta cell apoptosis, has been reported in a limited number of human samples [15], suggesting that similar mechanisms are responsible for beta cell adaptation in rodent and human pregnancy. This tentative conclusion needs to be critically revisited in view of recent data. First, the profile of genes that control beta cell proliferation differs in rodents and humans [2, 16]. Second, several studies have now documented that, in contrast with rodents, human beta cells do not proliferate under most conditions, probably due to an age-dependent epigenetic regulation of specific genes [17]. Moreover, a new pathology study has now raised the possibility that the adaptation of human beta cells to pregnancy may be significantly less extensive than in rodents and also due to a quite different mechanism [18]. Thus, in this issue of Diabetologia, Butler et al. [18] document that the volume density of beta cells was increased by only ∼1.4-fold in human pregnancy due to increased numbers of small islets, and not to beta cell size. These changes were associated with increased numbers of scattered and duct-associated beta cells, in the absence of detectable changes in beta cell replication and apoptosis. Thus, two studies of human samples [15, 18] concur in showing that beta cells increase as a function of the increasing gestational demand, but they M. Genevay Division of Pathology, Geneva University Hospital, Geneva, Switzerland