Laboratory of Diabetes and Obesity, IDIBAPS, Centre Esther Koplowitz, Rosselló 153, Barcelona, Spain.
Diabetologia. 2012 Dec;55(12):3331-40. doi: 10.1007/s00125-012-2696-9. Epub 2012 Aug 29.
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.
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.
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.
目的/假设：旨在增加β细胞数量的操作已被提议作为糖尿病治疗的再生医学策略。Raf-1 激酶抑制剂蛋白 1（RKIP1）是丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）途径的常见调节节点，因此可能参与β细胞稳态的调节。本研究旨在研究 RKIP1 在控制β细胞质量和功能中的作用。
研究人员对 Rkip1（也称为 Pebp1）敲除（Rkip1（-/-））小鼠进行了胰腺和葡萄糖稳态方面的特征描述，包括形态学和功能分析。检测了葡萄糖耐量和胰岛素敏感性，然后评估了分离胰岛中的葡萄糖诱导的胰岛素分泌和通过形态计量学定量β细胞质量。进一步的特征描述包括测定内分泌和外分泌细胞增殖、细胞凋亡、MAPK 激活和全基因组基因表达测定。通过链脲佐菌素治疗评估成年 Rkip1（-/-）小鼠逆转糖尿病表型的能力。
Rkip1（-/-）小鼠表现出胰腺略大、β细胞数量增加和胰腺胰岛素含量增加，这与整体改善全身葡萄糖耐量相关。这种表型在出生后的早期阶段就已经建立，涉及细胞增殖增强，而细胞死亡没有明显变化。重要的是，与对照小鼠相比，成年 Rkip1（-/-）小鼠在接受链脲佐菌素治疗后迅速逆转了糖尿病。
结论/解释：这些数据表明 RKIP1 参与调节胰腺生长和β细胞扩张，从而揭示 RKIP1 作为促进β细胞再生的潜在药物靶点。
