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

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 KB (NF-KB) 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. 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. Pancreatic gene expression of Rkip-1 (Raf kinase inhibitor 1) knockout (KO) and wild type (WT) mice, including three biological replicates in each group.研究目的与假说：旨在增加β细胞质量的干预策略已被提出作为糖尿病治疗的再生医学策略。Raf-1激酶抑制蛋白1（Raf-1 kinase inhibitor protein 1，RKIP1）是丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）与核因子κB（nuclear factor KB，NF-κB）通路的共同调控节点，因此可能参与β细胞稳态的调控。本研究旨在探讨RKIP1在β细胞质量与功能调控中的作用。 研究方法：本研究对Rkip1（亦称为Pebp1）基因敲除（knockout，KO）小鼠（Rkip1-/-）的胰腺与葡萄糖稳态进行了表征，涵盖形态学与功能学分析。检测了小鼠的葡萄糖耐量与胰岛素敏感性，随后对分离胰岛进行葡萄糖诱导的胰岛素分泌评估，并通过形态计量法定量β细胞质量。进一步的表征分析包括内分泌与外分泌细胞增殖、细胞凋亡、MAPK活化检测，以及全基因组基因表达分析。此外，在链脲佐菌素处理后的成年Rkip1-/-小鼠中评估了其逆转糖尿病表型的能力。 研究结果：Rkip1-/-小鼠的胰腺体积呈中度增大，β细胞质量与胰腺胰岛素含量均升高，这与全身葡萄糖耐量的整体改善相关。该表型在出生后早期即已形成，其机制涉及细胞增殖增强，而细胞死亡未出现显著改变。值得注意的是，与对照组小鼠相比，成年Rkip1-/-小鼠可快速逆转链脲佐菌素诱导的糖尿病。 结论与阐释：本研究数据表明，RKIP1参与胰腺生长与β细胞扩增的调控，从而揭示RKIP1可作为促进β细胞再生的潜在药理学靶点。本数据集包含Rkip-1（Raf激酶抑制蛋白1）基因敲除与野生型（wild type，WT）小鼠的胰腺基因表达数据，每组均包含3个生物学重复样本。