Non-β-cell progenitors of β-cells in pregnant mice

Abouna, Sylvie; Old, Robert; Pelengaris, Stella; Epstein, D. B. A.; Ifandi, Vasiliki; Sweeney, Ian; Khan, Michael

doi:10.4161/org.6.2.10374

Cited by 39 publications

(45 citation statements)

References 43 publications

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“…Similar to our findings, Abouna et al used a tamoxifen-dependent Cre/loxP-based system that marked β-cells with human placental alkaline phosphatase (HPAP) and found that 44% of β-cells are HPAP-positive before pregnancy which dropped to 33% during pregnancy, suggesting a non-β-cell source of β-cells in pregnancy [14]. Both of these systems, however, do not allow us to identify the origin of this non-β-cell source(s).…”

Section: Discussionsupporting

confidence: 90%

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

et al. 2014

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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.

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Section: Discussionsupporting

confidence: 90%

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

et al. 2014

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“…Whether β-cell neogenesis from non-β-cell progenitors is one of the processes involved in the maternal β-cell expansion during pregnancy has not yet been determined. A recent study showed that following a labeling pulse before pregnancy, there is a decrease in the labeling index of β-cells during gestation, suggesting that conversion of non-β-cell progenitors into β-cells might also contribute to maternal β-cell expansion in pregnancy 116,117 .…”

Section: β-Cell Mass In Response To Pregnancymentioning

confidence: 99%

Natural history of β-cell adaptation and failure in type 2 diabetes

Alejandro

Gregg

Blandino-Rosano

et al. 2015

Molecular Aspects of Medicine

197

121

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Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

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“…β-cell proliferation is maximally increased at gestational days 13–15 (two- to five-fold), declining thereafter to reach control levels at day 18–19 [5,26,28–31,42]. Whether β-cell neogenesis from non-β-cell progenitors is one of the processes involved in the maternal β-cell expansion during pregnancy has not yet been deciphered, but a recent study by Abouna et al using lineage tracing analysis in pregnant mice marks the first step in this direction [43]. This study shows that following a labeling pulse before pregnancy, there is a decrease in the labeling index of β-cells during gestation, suggesting that conversion of non-β-cell progenitors into β-cells might also contribute to maternal β-cell expansion in pregnancy [43].…”

Section: β-Cell Mass Expansion During Pregnancy: Rodent Modelsmentioning

confidence: 99%

Mechanisms in the adaptation of maternal β-cells during pregnancy

Ernst¹,

Demirci²,

Valle³

et al. 2011

Diabetes Management

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SUMMARY Pancreatic β-cell mass adapts to changing insulin demands in the body. One of the most amazing reversible β-cell adaptations occurs during pregnancy and postpartum conditions. During pregnancy, the increase in maternal insulin resistance is compensated by maternal β-cell hyperplasia and hyperfunctionality to maintain normal blood glucose. Although the cellular mechanisms involved in maternal β-cell expansion have been studied in detail in rodents, human studies are very sparse. A summary of these studies in rodents and humans is described below. Since β-cell mass expands during pregnancy, unraveling the endocrine/paracrine/autocrine molecular mechanisms responsible for these effects can be of great importance for predicting and treating gestational diabetes and for finding new cues that induce β-cell regeneration in diabetes. In addition to the well known implication of lactogens during maternal β-cell expansion, additional participants are being discovered such as serotonin and HGF. Transcription factors, such as hepatocyte nuclear factor-4α and the forkhead box protein-M1, and cell cycle regulators, such as menin, p27 and p18, are important intracellular signals responsible for these effects. In this article, we summarize and discuss novel studies uncovering molecular mechanisms involved in the maternal β-cell adaptive expansion during pregnancy.

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Non-β-cell progenitors of β-cells in pregnant mice

Cited by 39 publications

References 43 publications

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

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

Natural history of β-cell adaptation and failure in type 2 diabetes

Mechanisms in the adaptation of maternal β-cells during pregnancy

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