Contribution of a Non-β-Cell Source to β-Cell Mass during Pregnancy

Abstract

β-cell mass in the pancreas increases significantly during pregnancy as an adaptation to maternal insulin resistance. Lineage tracing studies in rodents have presented conflicting evidence on the role of cell duplication in the formation of new β-cells during gestation, while recent human data suggest that new islets are a major contributor to increased β-cell mass in pregnancy. Here, we aim to: 1) determine whether a non-β-cell source contributes to the appearance of new β-cells during pregnancy and 2) investigate whether recapitulation of the embryonic developmental pathway involving high expression of neurogenin 3 (Ngn3) plays a role in the up-regulation of β-cell mass during pregnancy. Using a mouse β-cell lineage-tracing model, which labels insulin-producing β-cells with red fluorescent protein (RFP), we found that the percentage of labeled β-cells dropped from 97% prior to pregnancy to 87% at mid-pregnancy. This suggests contribution of a non-β-cell source to the increase in total β-cell numbers during pregnancy. In addition, we observed a population of hormone-negative, Ngn3-positive cells in islets of both non-pregnant and pregnant mice, and this population dropped from 12% of all islets cells in the non-pregnant mice to 5% by day 8 of pregnancy. Concomitantly, a decrease in expression of Ngn3 and changes in its upstream regulatory network (Sox9 and Hes-1) as well as downstream targets (NeuroD, Nkx2.2, Rfx6 and IA1) were also observed during pregnancy. Our results show that duplication of pre-existing β-cells is not the sole source of new β-cells during pregnancy and that Ngn3 may be involved in this process.

Impaired proliferation of pancreatic beta cells, by reduced placental growth factor in pre‐eclampsia, as a cause for gestational diabetes mellitus

“…Although most previous studies have demonstrated that beta cell replication is the predominant mechanism for post-natal beta cell expansion (28)(29)(30)(31)(32), specially during pregnancy (32,(34)(35)(36)(37)(38)(39)(40), involvement of beta cell neogenesis has also been reported (41,42). Thus, we (a) Beta cell mass quantification at G17 showed significant reduction in beta cell mass in L-NAME-treated pregnant mice.…”

“…Although most previous studies have demonstrated that beta cell replication is the predominant mechanism for post‐natal beta cell growth during pregnancy , there have also been reports suggesting occurrence of beta cell neogenesis . Thus, we examined possible changes in beta cell proliferation and beta cell neogenesis in the l‐ NAME‐treated mice.…”

“…Adequate functional beta cell mass is critical for maintaining appropriate glucose-stimulated insulin release in response to metabolic need, and changes in metabolic need require adaption of beta cell mass, for example, during pregnancy (27). Although most previous studies have demonstrated that beta cell replication is the predominant mechanism for post-natal beta cell population expansion (28)(29)(30)(31)(32)(33), specially during pregnancy (32,(34)(35)(36)(37)(38)(39)(40), there have also been reports suggesting occurrence of beta cell neogenesis by other means (41,42). As evaluation of beta cell mass in PE/ GDM patients is hard to be performed, corresponding studies on experimental animals are very informative, have been largely lacking.…”

Adaptive β-Cell Neogenesis in the Adult Mouse in Response to Glucocorticoid-Induced Insulin Resistance

“…In other situations of increased b-cell mass, including high-fat diet (17), drug-induced insulin resistance (18), or the physiological insulin resistance of pregnancy (19), b-cell proliferation, and not neogenesis, has been proposed as the main adaptive mechanism in rodents. However, recent studies have suggested that b-cell neogenesis also may contribute to the b-cell mass increase observed during pregnancy in mice (20) and humans (21).…”

The Elusive Pancreatic Stem Cell

“…One example is pancreas growth during pregnancy in mice, where islet mass is increased and is a process recently shown to be dependent on serotonin levels [66]. To date, the source of these new beta cells during pregnancy is unclear [67]. However, the Kaestner group showed that islet expansion and beta cell hypertrophy occurred during pregnancy, and these processes induce both proliferative and survival pathways in response to increased metabolic demands [68].…”