The role of Raf-1 kinase inhibitor protein in the regulation of pancreatic beta cell proliferation in mice

Abstract

Aims/hypothesis Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. Methods Rkip1 (also known as Pebp1) knockout (Rkip1 −/− ) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 −/− mice after streptozotocin treatment. Results Rkip1 −/− mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 −/− mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice.Electronic supplementary material The online version of this article (doi:10.1007/s00125-012-2696-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration.

Striking Similarity in the Gene Expression Levels of Individual Myc Module Members among ESCs, EpiSCs, and Partial iPSCs

“…GSE30056 associated with Hayashi et al [29] for EpiSCs and EpiLCs; GSE14012 associated with Sridharan et al [31] for MEFs, iPSCs, and piPSCs; GSE34799 associated with Rugg-Gunn et al [32] for ESCs and EpiSCs; GSE21222 associated with Hanna et al [33] for human iPSCs in naïve and primed states; GSE11274 associated with Ko et al [34] for germline stem cells (GSCs), germline-derived pluripotent stem cells (gPSCs), and neural stem cell (NSC)s; GSE31028 associated with Lien et al [35] for quiescent and activated hair follicular stem cell (HFSC)s; GSE6506 associated with Chambers et al [36] for long-term hematopoietic stem cell (LT-HSC)s, granulocytes, and B cells; GSE9954 associated with Thorrez et al [37] for ovary, testis, bone marrow, placenta, adipose tissue, kidney, liver, pancreas, lung, brain, and heart; GSE19233 associated with Walker et al [38] for bone marrow mesenchymal stem cell (MSC)s; GSE31150 associated with Pardo et al [39] for pancreas. Microarray expression data were background subtracted and normalized by the robust multi-array analysis method [40] using R-package 2.8.1 with Bioconductor 2.6 [41].…”

Generation of a Conditional Allele of the Transcription Factor Atonal Homolog 8 (Atoh8)

“…Islets were isolated using collagenase digestion and Histopaque gradient (Sigma-Aldrich) purification as described elsewhere [ 16 ]. Separate batches of 8 freshly isolated islets were used to determine insulin secretion in static incubation assays as previously described [ 16 ]. Insulin was measured using a mouse insulin ELISA kit (Mercodia).…”

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“…Next, we wanted to identify disease associated transcriptional patterns by comparing mRNA profiles obtained from normal murine pancreas [19] with those from pancreatic and pituitary tumors of LSL-MYCN;hGFAP-Cre mice. Using principle component analyses, we were able to separate expression patterns of pancreatic tumors from pituitary tumors and from normal pancreatic control tissue ( Figure 4A).…”