The Transcriptional Response of the Islet to Pregnancy in Mice

Abstract

The inability of the ss-cell to meet the demand for insulin brought about by insulin resistance leads to type 2 diabetes. In adults, ss-cell replication is one of the mechanisms thought to cause the expansion of ss-cell mass. Efforts to treat diabetes require knowledge of the pathways that drive facultative ss-cell proliferation in vivo. A robust physiological stimulus of ss-cell expansion is pregnancy and identifying the mechanisms underlying this stimulus may provide therapeutic leads for the treatment of type 2 diabetes. The peak in ss-cell proliferation during pregnancy occurs on d 14.5 of gestation in mice. Using advanced genomic approaches, we globally characterize the gene expression signature of pancreatic islets on d 14.5 of gestation during pregnancy. We identify a total of 1907 genes as differentially expressed in the islet during pregnancy. The islet's ability to compensate for relative insulin deficiency during metabolic stress is associated with the induction of both proliferative and survival pathways. A comparison of the genes induced in three different models of islet expansion suggests that diverse mechanisms can be recruited to expand islet mass. The identification of many novel genes involved in islet expansion during pregnancy provides an important resource for diabetes researchers to further investigate how these factors contribute to the maintenance of not only islet mass, but ultimately ss-cell mass.

Serotonin competence of mouse beta cells during pregnancy

“…A first interesting regulated gene cluster concentrates on the direct biological effects of the PRLR itself. Confirming earlier reports, it was found that the mRNA signal encoding PRLR is significantly upregulated during pregnancy [16], indicating the presence of a positive feedback loop by which initial stimulation of PRLR by PL leads to reinforcement of the signalling axis. On the other hand, the feed-forward signal is counterbalanced by upregulation of two transcripts encoding suppressors of cytokine signalling, CISH [20] and SOCS2 [21].…”

“…In the liver of male mice, however, expression of the short PRLR isoform was detected [14,15]. Moreover, in pancreatic islets of pregnant mice, Prlr expression was upregulated but no change occurred in Ghr expression [16,17]. We will further comment on the differences between human and mouse islets in a separate section.…”

“…2a) and Tph2 [16,18,19,24]. These isoforms catalyse the same chemical reaction: the NADPH-dependent hydroxylation of carbon 5 of tryptophan to form 5-hydroxytryptophan, which is the substrate of the second step of serotonin biosynthesis mediated by the enzyme aromatic amino acid decarboxylase (also known as DOPA decarboxylase or DDC) [25].…”

“…To better understand the molecular basis of PL on pancreatic beta cells, several research groups have analysed mRNA in murine islets of Langerhans during pregnancy [16][17][18][19] and differentially expressed genes have been classified into various clusters. A first interesting regulated gene cluster concentrates on the direct biological effects of the PRLR itself.…”

Elevation of transcription factor Islet-1 levels in vivo increases β-cell function but not β-cell mass

“…2G and H; and data not shown). Real-time PCR analysis of isolated islets for Ki67 and Birc5 expression, markers for proliferating cells, 17 further confirmed that there were no significant changes in proliferation in the islets of Pdx1 PB -Isl-1-Myc mice (Fig. 2I).…”