Regulation of pancreatic islet gene expression in mouse islets by pregnancy

Abstract

Pancreatic b cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in b cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased b cell proliferation (E13 . 5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine-induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using realtime reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13 . 5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy.

Serotonin competence of mouse beta cells during pregnancy

“…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].…”

“…Previous literature mentions the tissue-specific use of the two paralogous genes: Tph1 in enterochromaffin cells, mammary and pineal glands [26,27] and Tph2 in the raphe nuclei of the brain [28]. A new tissue pattern was found in islets where both Tph1 and Tph2 are induced during pregnancy [16,18,19,24], fitting the idea that endocrine beta cells share many characteristics with neuronal cells [29]. Moreover, in one study [24] it was verified that the spectacular increase in Tph expression occurred specifically in pancreatic islets and not in other tissues.…”

“…However, the findings of Kim et al [18] were not confirmed by other groups. For instance, Layden et al [19] screened for Gpcr mRNA signals in pancreatic islets, detected mRNA expression of 343 different GPCRs in mouse islets and found 216 GPCRs above the detection limit in islets from pregnant mice. However, these authors did not find pregnancy-related changes in Htr2b mRNA in islets and reported the Htr1d signal to be undetectable [19].…”

“…For instance, Layden et al [19] screened for Gpcr mRNA signals in pancreatic islets, detected mRNA expression of 343 different GPCRs in mouse islets and found 216 GPCRs above the detection limit in islets from pregnant mice. However, these authors did not find pregnancy-related changes in Htr2b mRNA in islets and reported the Htr1d signal to be undetectable [19]. In our laboratory, we performed quantitative RT-PCR analysis on mRNA of islets from pregnant and nonpregnant mice: signals for both Htr1d and Htr2b mRNA were below the detection limit [24].…”

“…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.…”